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Insulin administration results in vasodilation, decreased mean arterial blood pressure (MAP) and increased conductances (flow/MAP) in various vascular beds. beta-adrenergic blockers antagonize this response, but the mechanism of the interplay between insulin-induced vasodilation and beta-adrenergic antagonism is unknown. In this study, we evaluated the effects of beta-blockade using the selective beta(2) antagonist ICI 118551 or the general beta-antagonist propranolol on insulin-induced cardiac and regional flow responses in normal rats. Insulin-induced responses were also examined following adrenalectomy. Rats were anaesthetized and the femoral vein and artery were cannulated for infusions, sampling or monitoring of MAP and heart rate (HR). The iliac, renal, and superior mesentery arteries were equipped with pulsed-Doppler flow probes. Blood samples were collected at selected intervals. Insulin decreased blood glucose, MAP and increased conductances. Pretreatment with propranolol not only antagonized the insulin-induced decrease in MAP and increased conductance but insulin also then increased MAP and decreased conductances. ICI 11851, like propranolol, antagonized the insulin-induced decrease in MAP and increased iliac and renal artery conductances. Adrenalectomy did not alter the maximum insulin-induced effects on MAP and conductances but prevented the rebound recovery phase. beta-blockade following adrenalectomy had the same effects as beta-blockade alone on the insulin-induced responses. We conclude that the insulin-induced decrease in MAP and the increased flow in the selective vascular beds are modulated by a sympathetic beta(2)-receptor-mediated pathway and this response is not due primarily to the release of adrenal catecholamine.

Restenotic neointimal lesions, a major limitation to coronary angioplasty, develop in response to diverse signals and depend on three properties of activated arterial smooth muscle cells (SMCs): proliferation, migration, and abnormal production of extracellular matrix. Most of the pharmacologic approaches targeting specific pathogenic factors facilitating development of restenosis have failed in clinical trials. Our results indicate that the polysulfonated naphthylurea suramin, a "non-specific drug" that interferes with multiple cellular proteins, inhibits neointimal formation in rabbit iliac arteries after balloon-catheter injury administered throughout the critical period of several weeks after the procedure. In vitro studies aimed at dissecting the mechanism(s) underlying the suramin-dependent effect demonstrated that, in addition to an inhibitory effect on SMC proliferation, suramin inhibited fibronectin and elastin deposition and the migration of SMCs through elastin membranes and into scratch gaps of monolayer cultures. We also demonstrated that suramin causes cell-surface accumulation of the elastin binding protein, a receptor that not only anchors SMCs to the extracellular matrix, but also inhibits SMC response to interleukin-1beta (IL-1beta). We conclude that suramin acts as a multitarget inhibitor of SMC activation and has a therapeutic potential as an agent that may attenuate arterial restenosis after angioplasty.

J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist.

The effect of daily spontaneous running (DSR) on endothelial function was examined in spontaneously hypertensive rats (SHR). Following 8-11 weeks of DSR (n=15) or sedentary control (SED, n=15), rats were instrumented with arterial and venous catheters and mesenteric and iliac Doppler ultrasonic flow probes. Hemodynamic responses to vasodilator-mediated substances were determined under two experimental conditions; 1) bolus injection of indomethacin (10 mg/kg) and 4 bolus doses of acetylcholine (0.5-2.0 microg/kg); 2) bolus injection of N(omega)-nitro-L-arginine (5 mg/kg) and 4 bolus doses of nitroglycerin (3-12 microg/kg). Hindlimb vascular conductance decreased more in response to indomethacin in DSR vs. SED rats (-18.3+/-2.8% vs. -10.4+/-2.5%). However, the mesenteric or hindlimb vascular conductance responses to N(omega)-nitro-L-arginine were not different between DSR and SED rats. DSR also enhanced mesenteric and hindlimb vascular conductance responses to acetylcholine. Results suggest that DSR enhances acetylcholine-induced vasodilation in SHR.

Three series of cycloalkanecarboxylic esters derived from the naturally occurring clavine alkaloids lysergol, dihydrolysergol-I, and elymoclavine were synthesized to study their interaction with 5-HT2A receptors and alpha1-adrenoceptors in rat tail artery and aorta, respectively. Especially cycloalkanecarboxylic esters derived from lysergol showed complex behavior as partial agonists and antagonists of the contractile effect of 5-HT. Within this group, partial 5-HT2A receptor agonist activity was most potent for cyclopropanecarboxylic ester 6a (pKP = 7.67, alpha = 0.21) and decreased as the volume requirement of the alicyclic ring increased. This tendency was echoed in experiments where the compounds were used as antagonists of the contractile effect of 5-HT. From the structure-activity study, the N-1-isopropyl homologue of 6a, compound 6b, emerged as the ligand with the highest affinity for rat 5-HT2A receptors (pA2 = 8.74). For cycloalkanecarboxylic esters derived from dihydrolysergol-I and elymoclavine, no clear structure-affinity relationship could be deduced, although those compounds that had smaller cycloalkyl rings in the acyl portion and an isopropyl substituent at N-1 showed the highest 5-HT2A receptor affinity. On the other hand, cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine displayed low or marginal affinity at alpha1-adrenoceptors. A further aim of the study was to examine to what extent the complete removal of the acyl portion of the esters would affect 5-HT2A receptor affinity. The parent alcohols of the three series of N-1-isopropyl homologues, 1-isopropyllysergol (1b), 1-isopropyldihydrolysergol-I (2b), and 1-isopropylelymoclavine (3b), displayed higher affinity for 5-HT2A receptors (pA2 = 9.15, 8.50, 9.14) than the corresponding esters. Compounds 1b-3b had no contractile effects by themselves and displayed low affinity at guinea-pig 5-HT1B receptors and rat alpha1-adrenoceptors. The high affinity for rat 5-HT2A receptors was retained when clavines even more simple in structure than 1b-3b, compounds 4b and 5b, were examined as 5-HT2A receptor antagonists. The nanomolar antagonist activity of simple clavines (1b-5b) in the rat suggests that the indolo[4,3-fg]quinoline system of the ergolines is the molecular fragment that is responsible for 5-HT2A receptor affinity, and not the substituent at position C-8.

In support of an in vivo investigation in swine of the influence of changes in fluid dynamic wall shear on arterial macromolecular permeability, a procedure has been developed to alter the flows in the porcine posterior arterial vasculature by opening and closing a reversible arteriovenous shunt placed on one of the femoral arteries. Laparoscopic techniques were used to place appropriately modified Transonic Systems ultrasonic flow probes on both external and circumflex iliac arteries, and on the terminal aorta. Flow measurements were made prior to shunt placement, and with the shunt open and closed, to measure the influence of altered external iliac artery flow on the distribution to the infrarenal abdominal vessels. Similar experiments were carried out to relate the flow rates in the external iliac arteries to those in the femoral arteries, which are more accessible. Based on the relationships among the measured flow rates, rules have been developed to estimate the major infrarenal flows in the pig, at baseline and with the shunt opened and closed, from only the flow rates measured at the two femoral arteries.

Local haemodynamic factors in large arteries are associated with the pathophysiology of cardiovascular diseases such as atherosclerosis and strokes. In search of these factors and their correlation with atheroma formation, quantitative haemodynamic data in realistic arterial geometry become crucial. At present no in vivo non-invasive technique is available that can provide accurate measurement of three-dimensional blood velocities and shear stresses in curved and branching sites of vessels where atherosclerotic plaques are found frequently. This paper presents a computer modelling technique which combines state-of-the-art computational fluid dynamics (CFD) with new noninvasive magnetic resonance imaging techniques to provide the complete haemodynamic data in 'real' arterial geometries. Using magnetic resonance angiographic and velocity images acquired from the aortic bifurcation of a healthy human subject, CFD simulations have been carried out and the predicted flow patterns demonstrate the non-planar-type flow characteristics found in experimental studies.

The three-dimensional flow through a rigid model of the human abdominal aorta complete with iliac and renal arteries was predicted numerically using the steady-state Navier Stokes equations for an incompressible. Newtonian fluid. The model adapted for our purposes was determined from data obtained from cine-CT images taken of a glass chamber that was constructed based on anatomical averages. The iliac arteries had a bifurcation angle of approximately 35 and a branch-to-trunk area ratio of 1.27. whereas the renal arteries had left and right branch angles of 40 and an area ratio of 0.73. The numerical tool FLOW3D (AEA Industrial Technology, Oxfordshire, UK) utilized body-fitted coordinates and a finite volume discretization procedure. Purely axial velocity profiles were introduced at the entrance of the model for a range of cardiac outputs. The four-branch numerical model developed for this investigation produced flow and shear conditions comparable to those found in other reported works. The total wall shear stress distribution in the iliac and renal arteries followed standard trends. with maximum shear stresses occurring in the apex region and lower shear stresses occurring along the lateral walls. Shear stresses and flow rate ratios in the downstream arteries were more effected by inlet Re than the upstream arteries. These results will be used to compare further simulations which take into effect the rotational component of flow which is present in the aortic arch.

To evaluate the influence of the sodium/proton exchanger (Na+,H+ exchanger) on the constriction of rat resistance vessels and on the iliac artery, the isometric vasoconstrictions of renal resistance vessels and strips from iliac artery derived from Wistar-Kyoto rats were measured using a vessel myograph. The Na+,H+ exchanger was activated by intracellular acidification using propionic acid. Cytosolic pH (pHi) and cytosolic free sodium concentration ([Na+]i) in vascular smooth muscle cells were measured using the fluorescent dye technique. The activation of the Na+,H+ exchanger increased the [Na+]i by 12.4 +/- 1.3 mmol/L (n = 8). The activation of the Na+,H+ exchanger caused a contractile response of the renal resistance vessels (increase of tension, 1.5 +/- 0.1 x 10(-3) N; n = 13) and of the rat iliac artery (increase of tension, 7.5 +/- 0.8 x 10(-3) N; n = 5). The contractile response after activation of the Na+,H+ exchanger was significantly inhibited in the absence of external sodium or in the presence of amiloride, confirming the involvement of the Na+,H+ exchanger. The contractile response after activation of the Na+,H+ exchanger was significantly reduced in the absence of external calcium, after inhibition of calcium channels by nifedipine, and in the presence of an intracellular calcium antagonist 8-(diethylamino-)-octyl-3,4,5-trimethoxybenzoate (TMB-8), indicating that the activation of the Na+,H+ exchanger consecutively caused transplasma membrane calcium influx. On the other hand, the inhibition of the Na+,Ca2+ exchanger by NiCl2 significantly increased the vasoconstriction of renal resistance vessels after activation of the Na+,H+ exchanger. The activation of the Na+,H+ exchanger produces vasoconstriction by an increased cytosolic sodium concentration, inhibition of the Na+,Ca2+ exchanger, and activation of transplasma membrane calcium influx through potential dependent calcium channels.

Rationale and Objectives: The authors determine flow characteristics and pressure gradients of different stents and stent grafts in an in vitro flow-model., Methods: Five vascular stents (Memotherm, Cragg, two Palmaz P308, Strecker, and Wall) and one stent graft (Cragg EndoPro System 1), equal in length (60 mm) and diameter (10 mm), were deployed in a closed flow-model. The inner diameter of the tube measured 9 mm. Flow at 1.5 L/min, 6 L/min, and 10 L/min was simulated. Flow patterns were visualized by anionic particles illuminated with two Helium-Neon lasers. Laminary flow characteristics and pre-/poststent pressure gradients were determined in either expanded stent, 25% stenosis, or 50% stenosis., Results: Stent implantation induced a decrease of laminary flow compared with an unstented tube with and without concentric 25% stenosis (P < 0.01) at all flow rates and an increase of pressure gradients compared with an unstented tube for flow rates greater than 1.5 L/min (P < 0.01) (except for Cragg EndoPro System 1 stent, which revealed an increase of the pressure gradient at a flow rate of 1.5 L/min [P < 0.01]). Memotherm stent permitted maximum of laminary flow at all flow rates and stenoses (expanded: 79.50% at 1.5 L/min to 69.90% at 10 L/min; P < 0.01). Memotherm and Palmaz permitted lowest pressure gradients (P < 0.01). All of the endoprostheses demonstrated laminary flow at 50% stenosis., Conclusions: The investigated stents and stent grafts showed different severity of flow disturbances and pressure gradients at different graded stenoses. Inadequate stent depolyment bears the risk of creating less laminary flow and pathologic pressure gradients. Because flow disturbances and pressure gradients may influence neointimal hyperplasia, stent design and completeness of stent unfolding are important regarding the appearance of postinterventional restenoses.

Background: We administered a specific, nonselective matrix metalloproteinase (MMP) inhibitor (RS-113,456) to examine the effect of MMP inhibition on flow-mediated arterial enlargement in a rodent arteriovenous fistula (AVF) model., Methods: Four groups of male Sprague-Dawley rats were created: sham (sham operated; n = 10), control (2.0 mm left common femoral AVF alone; n = 16), vehicle (AVF plus 0.5 mL vehicle orally twice a day; n = 20), and treatment (AVF plus 25 mg/kg RS-113,456 in 0.5 mL vehicle orally twice a day; n = 16). Heart rate, mean arterial pressure, and body weight were recorded on postoperative days 0, 7, 14, and 21. On day 21, AVF patency was confirmed, the infrarenal aorta and common iliac arteries were exposed, blood flow velocity and external diameter were measured, and wall shear stress (WSS) was calculated. Analysis was performed by paired, two-tailed Student t test, one-way analysis of variance, and the Bonferroni/Dunn procedure for post hoc testing., Results: Heat rate, mean arterial pressure, and weight did not vary at any time between groups. Aortic and left iliac diameter was larger in the AVF groups than in sham groups (P < .001), and control and vehicle groups were larger than treatment groups (P < .0001). Changes in aortic and left iliac flow were also significant (AVF was more than sham and control, and vehicle was more than treatment). No difference in aortic and left iliac artery velocity and WSS or right iliac diameter, velocity, flow, or WSS was observed between groups., Conclusions: MMP inhibition diminishes flow-mediated arterial enlargement in the rat AVF model.

Based on the affinity of alpha1D adrenoceptor subtype for a selective antagonist BMY 7378, we studied its functional role in rabbit thoracic aorta and iliac artery, and evaluated the subtypes of the alpha1-adrenoceptors that are activated by phenylephrine (a full agonist) and tizanidine (a partial agonist). In thoracic aorta, the concentration response curves of phenylephrine and tizanidine were antagonized by BMY 7378 with low potency (pA2 values 6.68+/-0.06 and 6.67+/-0.06, slopes of Schild plot 1.06+/-0.04 and 1.01+/-0.04, respectively). On the other hand, in iliac artery concentration response curves for phenylephrine were potently antagonized by a low concentration of BMY 7378, and the slope (0.75+/-0.02) of the Schild plot was significantly different from unity. In iliac artery, a concentration response curve of tizanidine was antagonized by BMY 7378 with low potency (pA2 value 6.64+/-0.08, slope of Schild plot 1.01+/-0.05). These results suggest that an alpha1D-adrenoceptor subtype contributes to alpha1-adrenoceptor mediating muscle contraction in iliac artery, but not in thoracic aorta of rabbit, and that it is activated by a full agonist phenylephrine but not by a partial agonist tizanidine.

The effect of a negative arterial-portal venous (a-pv) glucose gradient on skeletal muscle and whole body nonhepatic glucose uptake was studied in 12 42-h-fasted conscious dogs. Each study consisted of a 110-min equilibration period, a 30-min baseline period, and two 120-min hyperglycemic (2-fold basal) periods (either peripheral or intraportal glucose infusion). Somatostatin was infused along with insulin (3 x basal) and glucagon (basal). Catheters were inserted 17 days before studies in the external iliac artery and hepatic, portal and common iliac veins. Blood flow was measured in liver and hindlimb using Doppler flow probes. The arterial blood glucose, arterial plasma insulin, arterial plasma glucagon, and hindlimb glucose loads were similar during peripheral and intraportal glucose infusions. The a-pv glucose gradient (in mg/dl) was 5 +/- 1 during peripheral and -18 +/- 3 during intraportal glucose infusion. The net hindlimb glucose uptakes (in mg/min) were 5.0 +/- 1.2, 20.4 +/- 4.5, and 14.8 +/- 3.2 during baseline, peripheral, and intraportal glucose infusion periods, respectively (P < 0.01, peripheral vs. intraportal); the hindlimb glucose fractional extractions (in %) were 2.8 +/- 0.4, 4.7 +/- 0.8, and 3.9 +/- 0.5 during baseline, peripheral, and intraportal glucose infusions, respectively (P < 0. 05, peripheral vs. intraportal). The net whole body nonhepatic glucose uptakes (in mg . kg-1 . min-1) were 1.6 +/- 0.1, 7.9 +/- 1.3, and 5.4 +/- 1.1 during baseline, peripheral, and intraportal glucose infusion, respectively (P < 0.05, peripheral vs. intraportal). In the liver, net glucose uptake was 70% greater during intraportal than during peripheral glucose infusion (5.8 +/- 0.7 vs. 3.4 +/- 0.4 mg . kg-1 . min-1). In conclusion, despite comparable glucose loads and insulin levels, hindlimb and whole body net nonhepatic glucose uptake decreased significantly during portal venous glucose infusion, suggesting that a negative a-pv glucose gradient leads to an inhibitory signal in nonhepatic tissues, among which skeletal muscle appears to be the most important.

We tested the hypothesis that endothelial nitric oxide synthase (eNOS) modulates angiogenesis in two animal models in which therapeutic angiogenesis has been characterized as a compensatory response to tissue ischemia. We first administered L-arginine, previously shown to augment endogenous production of NO, to normal rabbits with operatively induced hindlimb ischemia. Angiogenesis in the ischemic hindlimb was significantly improved by dietary supplementation with L-arginine, compared to placebo-treated controls; angiographically evident vascularity in the ischemic limb, hemodynamic indices of limb perfusion, capillary density, and vasomotor reactivity in the collateral vessel-dependent ischemic limb were all improved by oral L-arginine supplementation. A murine model of operatively induced hindlimb ischemia was used to investigate the impact of targeted disruption of the gene encoding for ENOS on angiogenesis. Angiogenesis in the ischemic hindlimb was significantly impaired in eNOS-/- mice versus wild-type controls evaluated by either laser Doppler flow analysis or capillary density measurement. Impaired angiogenesis in eNOS-/- mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF. Thus, (a) eNOS is a downstream mediator for in vivo angiogenesis, and (b) promoting eNOS activity by L-arginine supplementation accelerates in vivo angiogenesis. These findings suggest that defective endothelial NO synthesis may limit angiogenesis in patients with endothelial dysfunction related to atherosclerosis, and that oral L-arginine supplementation constitutes a potential therapeutic strategy for accelerating angiogenesis in patients with advanced vascular obstruction.

To characterize long-term vascular remodeling associated with neointimal formation in vivo, we established a model of balloon injury in normal chow fed rabbits. The iliac artery was injured by denudation using a 2F embolectomy catheter. Injured vessels were removed after perfusion fixation (90 mm Hg) in situ at 2, 4, 6, and 12 weeks post-injury; control vessels were obtained from 2- and 12-week age-matched, uninjured animals. Intimal growth was observed in all animals post-injury. Intimal area averaged 0.13 +/- 0.02 mm2 2 weeks post-injury and continued to increase at 4 and 6 weeks post-injury; +38% and +77% relative to the 2-week time point, respectively. Medical areas were similar among the 2-, 4-, and 6-week injury groups and the 2- and 12-week control groups. From 6 to 12 weeks post-injury, both intimal and medial areas decreased significantly (30% and 34%, respectively); while lumen area increased 53% from 4 to 12 weeks and overall vessel size (area enclosed by the external elastic lamina) remained the same. These data demonstrate that intimal and medial thinning contribute to long term maintenance of lumen area in response to neointimal formation.

Lumen area, ellipticity, and wall thickness were measured in the aortoiliac bifurcations obtained at autopsy from 14 patients aged between 1 day and 76 years. The method involved freezing pressure-fixed, stained bifurcations on the stage of a refrigerated microtome and then looking at the block face while sections were removed. Area change was normalized over segment length to produce a value of either taper (narrowing, in mm2/mm), or flare (expansion). The aortoiliac bifurcations were divided into three regions based on the area changes: an apical region corresponding to the bifurcation apex (taper = 2.96 +/- 0.80 mm2/mm), a preapical region (flare = 3.58 +/- 0.87 mm2/mm), and the postapical region (flare = 0.82 +/- 0.80 mm2/mm). Preapical lumen ellipticity showed that the anterio-posterior diameter was always less than the lateral diameter, while the degree of ellipticity increased with age. Average circumferential wall thickness, assessed in polar coordinates, decreased between 0 degree (right lateral) and 120 degrees, while a significant increase in wall thickness was present between 120 degrees and 200 degrees. The most striking difference was found in the 1-day-old, which was very thin posteriorly. This detailed geometric analysis of the aortoiliac bifurcation suggests that taper, flare, and variations in both circumferential and longitudinal wall thickness need to be considered when trying to correlate physical factors in the aorta with the precise location of atherosclerotic lesions and wall remodeling.

A surgical study (Bergeron et al., 1991, International Angiology 10(3), 182-186) picked out that re-endothelialization of implanted expandable stents, frequently used to reduce the recurrent stenosis rate after balloon angioplasty, was correct and more rapid in femoro-popliteal arteries (quasi-straight vessels) than in iliac arteries (bifurcated vessels). Since it is now well known that local hemodynamics are considered to be an important atherogenic factor, we decided to compare and optimize the shape of the existing equipment, in order to further give some informations to surgeons about the optimal stenting at the site of bifurcation. Therefore, we studied in vitro (1) the influence of the protruding part of a stent on the flow patterns in the branches of an aorto-iliac bifurcation model, and (2) the possibility of reducing or preventing this impact. Qualitative information was obtained from visualizations in the horizontal median plane of the bifurcation model, while Doppler ultrasonic velocimetry provided quantitative data, at different points of the cardiac cycle. Results showed that a standard stent implanted in a daughter branch of the bifurcation may have a considerable influence on flow behaviour when it is sticking out of the daughter branch. A new design of stent, with a bevelled shape, showed a significant reduction of flow disturbance.

Objective: To describe changes in the maternal cerebral circulation and the external iliac arteries throughout pregnancy and the puerperium using the Laplace transform analysis of Doppler waveforms., Design: A prospective longitudinal study., Setting: Department of Obstetrics and Gynaecology, Nottingham University Hospital., Sample: A cohort of 17 healthy women studied every four weeks from early pregnancy until term and up to three months postpartum. Pre-conception data were available for 10 subjects., Methods: Doppler signals were recorded from the internal carotid, middle cerebral and external iliac arteries. The waveforms were analysed using two different techniques: standard indices (systolic:diastolic ratio, pulsatility and resistance indices) and Laplace transform analysis, an alternative method of waveform shape analysis which may provide additional haemodynamic information., Results: Vessel wall tone decreased at an early stage in pregnancy in the cerebral circulation and in the external iliac artery, but this rose again following delivery. The Laplace transform analysis techniques suggest dramatic eight-fold increases in downstream resistance within the external iliac artery in the second half of pregnancy. An increase in downstream resistance to flow also occurred in the internal carotid artery whereas more stable conditions were noted in the middle cerebral artery., Conclusions: Having a preliminary idea of the normal ranges for the Laplace transform analysis variables during pregnancy in a variety of maternal vessels, haemodynamic changes in pregnancies complicated by conditions, such as pre-eclampsia, can now be studied.

Studies utilizing systemic administration of alpha-adrenergic antagonists have failed to demonstrate sympathetic vasoconstriction in working muscles during dynamic exercise. The purpose of this study was to examine the existence of active sympathetic vasoconstriction in working skeletal muscles by using selective intra-arterial blockade. Six mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and with a catheter in one femoral artery. All dogs ran on a motorized treadmill at three intensities on separate days. After 2 min, the selective alpha 1-adrenergic antagonist prazosin (0.1 mg) was infused as a bolus into the femoral artery catheter. At mild, moderate, and heavy workloads, there were immediate increases in iliac conductance of 76 +/- 7, 54 +/- 11, and 22 +/- 6% (mean +/- SE), respectively. Systemic blood pressure and blood flow in the contralateral iliac artery were unaffected. These results demonstrate that there is sympathetic vasoconstriction in active skeletal muscles even at high exercise intensities.

Background: Acute flow-induced arterial dilation is mediated by nitric oxide (NO). The role of NO in chronic flow-induced adaptive enlargement is unknown. We assessed the role of NO in arterial adaptation to increased blood flow (BF)., Methods: Iliac artery BF was increased in adult male rats by creating a left femoral arteriovenous fistula. Left iliac BF and diameter were measured, and wall shear stress was calculated. The effect of the NO synthase inhibitor N omega-nitro-L-arginine-methyl ester (L-NAME) was studied in arteriovenous fistula rats divided into three groups (group 1, vehicle, group 2, 0.5 mg/ml; group 3, 2 mg/ml) in drinking water. Arterial diameter, blood pressure, and medial cell density were assessed after 21 days. Left iliac cyclic guanosine monophosphate content was measured in an additional group of animals., Results: BF and wall shear stress in the left iliac artery increased fourfold immediately after arteriovenous fistula. Arterial enlargement was evident after 7 days, and wall shear stress normalized after 42 days. Flow-induced arterial enlargement was inhibited by both low- and high-dose L-NAME compared with control (analysis of variance p < 0.05). Blood pressure was elevated only in animals treated with high-dose L-NAME. Left iliac cyclic guanosine monophosphate content was lower in rats treated with L-NAME than in the control group (p < 0.05)., Conclusions: NO suppression by L-NAME inhibits flow-induced iliac artery enlargement in rats. This finding suggests that NO plays a role in flow-induced arterial remodeling.

It is well known that hemoglobin binds nitric oxide (NO) and produces a pronounced vasoconstriction in isolated arteries. However, it is debatable whether such an effect takes place in whole animals, because hemoglobin also catalyzes the formation of prostaglandins from arachidonic acid. Short-term studies were performed to evaluate the effects induced by intravenous infusion of cross-linked hemoglobin (XL-Hb) on blood pressure (BP) and renal, iliac, and mesenteric flows, and on renal function in six anesthetized dogs. A similar volume-matched expansion with 6% dextran was used as a control (n = 6). Glomerular filtration rate (GFR), urinary flow, and total and fractional sodium excretion were measured before and after XL-Hb or dextran infusion to evaluate possible renal function changes. XL-Hb administration resulted in a 29% elevation in BP and a significant decrease of blood flow (30-37%) to the three vascular beds. XL-Hb did not alter GFR or sodium excretion, despite the increase in BP. In contrast, the administration of dextran did not significantly alter BP but induced a significant increase (6-13%) of blood flow in the three vascular beds. These changes were accompanied by threefold increases in urinary flow and sodium excretion without alterations in GFR. The binding effect of XL-Hb on NO was studied in isolated renal arteries in organ chambers. These in vitro studies showed that XL-Hb blunted the endothelium-mediated vasodilator response to calcium ionophore A-23187 and to acetylcholine. Our results demonstrate that XL-Hb administration is followed by hypertension, vasoconstriction, and blunted natriuresis. All these effects are compatible with the scavenging effect on NO attributed to XL-Hb.

We compared dynamic contrast-enhanced three-dimensional time of flight (3DTOF) magnetic resonance angiography (MRA) with two-dimensional time of flight (2DTOF) MRA with cardiac compensated fast gradient recalled echo (C-MON) and conventional angiography (CA) when it was available. C-MON re-orders the normal data acquisition to minimize ghosting artifacts generated by pulsatile flow. The initial phase of the study involved optimization of parameters and comparison C-MON with no C = MON in eight patients and volunteers. The final phase of the study involved 53 patients who were imaged with contrast-enhanced 3DTOF MRA and 2DTOF MRA with C-MON. Thirty of these patients also had CA. In the initial phase, 2DTOF MRA with C-MON was found to be equal (n = 3) or superior (n = 5) to 2DTOF without C-MON. In the final phase, the agreement among all imaging modalities varied from substantial to almost perfect (Cohen's kappa = .6-.83). The lowest agreement was using 2DTOF to evaluate the external iliac segments. The among suggested treatments varied from substantial to almost perfect for all imaging modalities (Cohen's kappa = .73-93). The diagnostic efficacies of 2DTOF with C-MON and contrast-enhanced 3DTOF were high overall, with the lowest value being a specificity of 63% for one reader in the evaluation of an external iliac segment using 2DTOF. In summary, 2DTOF with C-MON helped to eliminate artifacts due to pulsatility in the iliac arterial segments. In our experience, both dynamic contrast-enhanced 3DTOF MRA and 2DTOF MRA with C-MON performed well in the evaluation of the iliac arteries. Both studies have high interobeserver agreement and high diagnostic efficacy. Contrast-enhanced 3DTOF MRA should be reserved for situations in which the iliac vessels are extremely tortuous or occluded or the external iliac segments are poorly seen.

Vasoconstriction caused by iodinated contrast media (CM) has been considered specific for the renal artery only. We examined the vascular effect of CM in rabbit carotid, aorta, renal, iliac, mesenteric and celiac arteries and found that other arteries also respond with a contraction to CM. Isolated arterial rings were exposed to diatrizoate (high osmolar CM), iohexol (low osmolar CM) or glucose solution, and the isometric contraction response was expressed as percentage of an initial KCl control contraction. Diatrizoate evoked contractions of 82% (carotid), 63% (aorta), 30% (renal), 24% (iliac), 28% (mesenteric) and 18% (celiac), respectively. Iohexol caused contractions of 31% (carotid), 24% (aorta), 15% (renal) and 14% (iliac), whereas the mesenteric and celiac arteries were relaxed by iohexol. A high osmolar glucose solution elicited contractions of 78%, 77%, 11%, 27%, 3% and 5%, respectively, in the arteries. CM have contraction potency in arterial vasculature other than the renal artery.

Background: Monoclonal anti-rabbit platelet glycoprotein (GP) IIb/IIIa antibody (AZ1) was adsorbed onto cellulose polymer-coated intracoronary stents to enhance their thromboresistance. We evaluated the antithrombotic efficacy of AZ1 antibody-eluting stents., Methods and Results: Twenty-three polymer-coated stents with AZ1 antibody bound by passive adsorption (AZ1-eluting) were compared with 23 control polymer-coated stents adsorbed with either no antibody (base-polymer, n = 12) or isotype-matched irrelevant antibody (anti-CMV-eluting, n = 11) by implantation into balloon-damaged, flow-reduced iliac arteries of New Zealand White rabbits. In 13 animals (acute group), flow measurements were made with transit-time flow probes and platelet adhesion was ascertained by use of 111In-labeled autologous platelets. In the other 10 animals (chronic group), stent occlusion was assessed macroscopically after they were killed 28 days after stenting. Arteries with AZ1-eluting stents had significantly less platelet deposition (15.8 +/- 4.5 x 10(7)) than either base-polymer (32.1 +/- 4.3 x 10(7)) or anti-CMV-eluting (35.2 +/- 8.8 x 10(7)) controls (ANOVA, P < .0001). Compared with base-polymer or anti-CMV-eluting controls, arteries with AZ1-eluting stents showed a marked reduction in cyclic blood flow variation (P < .0001) and a significantly greater mean blood flow 2 hours after stent deployment (P < .0001). There was a significant improvement in the patency rate of AZ1-eluting stents compared with controls at both 2 hours (92% versus 46%, P = .034) and 28 days (100% versus 40%, P = .015)., Conclusions: Platelet GP IIb/IIIa antibody eluting from polymer-coated stents reduces platelet deposition, improves blood flow, virtually abolishes cyclic flow variation, and improves patency rates after stent implantation in a rabbit iliac artery model. Its potential for reducing stent-related thrombosis in humans warrants further evaluation.

The insulin-like growth factor-I (IGF-I) and its receptors are widely distributed in peripheral vascular tissue, yet their role in the regulation of blood pressure and blood flow remains unknown. This study investigated the effect of IGF-I on blood pressure and selected regional blood flow in normal Wistar rats anesthetized with chloralose/urethane. The femoral artery was cannulated and used to monitor arterial blood pressure. Electromagnetic flow probes were placed around the left common iliac artery, left renal artery, and the superior mesenteric artery, and used to measure blood flow. IGF-I (2.6 micrograms, 5.1 or 10.3 nmol/animal Iv) was injected as a bolus into the femoral vein. Following the injection of IGF-I (10.3 nmol), we observed a significant decrease of plasma glucose (57%) and a significant decrease of mean arterial pressure (MAP) that continued to decline throughout the 60-min experimental period. IGF-I (5.1 nmol) significantly decreased blood glucose by 44% and decreased the MAP by 14% with a nadir at 15 min and recovery after 60 min. A smaller dose of IGF-I (2.6 nmol) did not significantly decrease the blood glucose but resulted in a slight but significant decrease in MAP. The heart rate was increased by 10.3 and 5.1 but not 2.5 nmol of IGF-I. IGF-I (10.3 nmol) was associated with regional vascular responses with a preferential increase in flow of the iliac and superior mesenteric vessels, measured as vascular conductance. IGF-I (5.1 and 2.6 nmol) increased preferentially renal vascular conductance. Preinfusion with L-NAME, a nitric oxide inhibitor, inhibited the effects of IGF-I on flow. We conclude that IGF-I can selectively dilate vascular beds leading to a decrease in blood pressure and that the response to IGF-I is mediated by nitric oxide.

Experimental studies on the hypogastric arteries' ligation have pointed out significant changes in the vascular pattern correlated with the time past from the ligation, ligatured vessels, health condition of the patient. They consist in changes in the territory of distribution and the appearance of new anastomosis, that have been grouped in: anastomosis between the central and the peripheral part of the artery or its branches, between the peripheral and the aortic branches, between the uterine artery and subcutaneous abdominal artery, aortico-ovarian and reno-ovarian anastomosis. Based on studies of the vascular pattern in postsurgical state we may conclude;--the ligatured artery gives off more collateral branches than the non-ligatured one;--the vascular network in the ischemic territory is larger in postsurgical than in presurgical state and comes to normal in about 10-20 days;--the ligation of all genital arteries does not result in complete ischemia;--it is impossible to approach all the genital arterial sources, so hysterectomy remains the last choice;--in women with no obstetrical history the ligation does not affect the reproductive potential;--during pregnancy or in postpartum the ligation of the proximal part may stop the haemorrhage, but it results in infertility.

Severe local and systemic complications may occur after revascularization of extremities exposed to prolonged complete or incomplete ischaemia. These complications may be reduced by controlling the reperfusate and the circumstances of the reperfusion period. Ten adult German domestic pigs were exposed to 6 h of incomplete limb ischaemia by occlusion of the left iliac artery. To simulate the clinical situation of embolectomy, the occlusive snares were released after the ischaemic period in five pigs and normal blood flow developed with systemic pressure (uncontrolled reperfusion). In the other five pigs, a controlled reperfusate was delivered at controlled pressure before establishing normal blood reperfusion (controlled reperfusion). At the end of the observation period (90 min after start of reperfusion), the group with controlled reperfusion had a lower mean(s.e.m.) tissue water content (81.8(0.7) versus 84.3(0.7) per cent, P < 0.05, a greater increase in tissue adenosine 5'-triphosphate compared with values at the end of ischaemia (6.2(1.5) versus -2.5(1.8) mumol per g protein, P < 0.03), a higher tissue pH (7.2(0.1) versus 6.8(0.1), P < 0.03), a smaller temperature decrease (0.3(0.2) versus 1.2(0.3) degrees C, P < 0.05), lower concentrations of creatine kinase (355.0(87.5) versus 624.4(73.4) units/l, P < 0.05) and lactate dehydrogenase (LDH) (369.5(42.5) versus 538.4(39.2 units/l, P < 0.03) in the femoral vein blood and lower LDH concentrations (356.5(48.9) versus 546.0(37.8 units/l, P < 0.03) in central venous blood. These data indicate that severe local and systemic damage occurs with uncontrolled (normal blood) reperfusion even after incomplete limb ischaemia, and that these changes can be reduced by delivering a controlled reperfusate under controlled conditions.

IGF-1 and its receptors have been identified in many tissues including the central nervous system (CNS). We have previously demonstrated that injection of insulin directly into the cerebral ventricles (ICV) is followed by a drop in mean arterial pressure (MAP) associated with an increase in skeletal muscle blood flow. Given the similarities between the IGF-1 and insulin molecules and their respective receptors, we have investigated the effect of ICV administration of IGF-1 on systemic blood pressure and blood flow in selected vascular beds. ICV cannulas were implanted into normal rats and the animals were allowed to recover for 3 to 4 days. The femoral artery and vein were cannulated for blood pressure monitoring and blood sampling and blood flow probes placed around the iliac, the renal and the superior mesenteric artery were used to assess regional blood flow. ICV injection of IGF-1 resulted in a significant decrease in MAP with a nadir at 15 minutes and a gradual return to baseline by 60 minutes; heart rate increased 40 minutes after the injection. IGF-1 significantly enhanced vascular flow and conductance in the iliac, but not in the renal and superior mesenteric arteries. The effects of IGF-1 were much smaller than those observed previously with equimolar amounts of insulin. We conclude that IGF-1 can decrease MAP by selectively increasing blood flow to skeletal muscle through a direct action on the central nervous system.

The present study was undertaken in anaesthetized pigs to determine the primary reflex effects of gastric distension on the peripheral circulation. Changes in blood flow in the splenic, superior mesenteric, left renal and left external iliac arteries were assessed using electromagnetic flowmeters during distension of a balloon in the stomach, performed at constant aortic blood pressure and heart rate, with 0.6 l of Ringer solution (mean gastric transmural pressure of about 12 mmHg). In fourteen pigs, a decrease in splenic, renal and iliac flows and variable changes in mesenteric flow were obtained. A decrease in mesenteric flow and more marked decreases in the other flows occurred in response to the distension after the administration of propranolol or butoxamine. In five pigs, the vasoconstrictive responses were graded by step increments in gastric distending volume from 0.4 to 0.8 l. The above responses were abolished by the administration of phentolamine (eight pigs) and by bilateral cervical vagotomy (six pigs). The results showed that innocuous distension of the stomach in anaesthetized pigs reflexly caused vasoconstriction in the splenic, renal and iliac vascular beds; vasoconstriction also occurred in the mesenteric vascular bed but only after beta-blockade. These reflex responses were mediated by sympathetic mechanisms which involved both alpha and beta vascular adrenoceptors and their afferent limb was in the vagal nerves.

Background: After experimental angioplasty, partial or complete reendothelialization of the denuded surface occurs; the function of the regenerated endothelium has, however, been shown to be abnormal. Basic fibroblast growth factor (bFGF) is mitogenic for endothelial cells in vitro and in vivo. We investigated whether chronic administration of bFGF in a rabbit model of balloon denudation might not only improve endothelial regrowth but also restore normal physiological responses to endothelium-dependent agonists., Methods and Results: Thirty-nine New Zealand White rabbits underwent balloon denudation of the right iliac artery. Twenty rabbits received intravenous administration of bFGF (2.5 micrograms twice a week for 2 weeks). Nineteen rabbits receiving saline injections served as controls. Animals were killed on day 28 for assessment of reendothelialization and neointimal thickening and for analysis of in vitro vasoreactivity. Animals in the bFGF group had a significantly (P<.005) greater degree of reendothelialization than controls (115 +/- 13 versus 55 +/- 6 mm2). Neointimal thickening was similar in the two groups. Four weeks after denudation, endothelium-independent responses did not differ significantly between the two groups. In contrast, the maximal endothelium-dependent acetylcholine-induced relaxation of the bFGF-treated animals (Emax, 40 +/- 7%) was significantly greater than that of the control group (Emax, 11 +/- 9%; P<.05)., Conclusions: Systemic administration of bFGF restores, in large part, the responses of previously denuded arterial segments to endothelium-dependent vasodilators. Angiogenic growth factors may help to reestablish normal endothelial cell function in patients who have undergone angioplasty.

One limitation encountered using high frequency intravascular ultrasound (IVUS) is the echogenicity of blood, which increases dramatically at frequencies of 20-40 MHz. Because of the higher velocity of moving blood particles, the echo pattern of flowing blood shows more variations in time than that of the wall. To investigate the time-varying characteristics of the blood scattering measurements were performed on the radiofrequency (RF) data collected in vivo from five pig experiments. After positioning the echo catheter inside the iliac artery, an M-mode sequence of 30 RF traces was acquired at a high pulse repetition rate (5 kHz). The RF correlation time was measured on the regions of blood and the arterial wall. Two processing techniques, temporal averaging and correlation, were tested for suppression of the blood echo intensity. The correlation time Tc measured in the blood region was approximately 1 ms, which was shorter than that measured in the wall region (Tc >> 6 ms). The correlation values calculated in a small window showed a large variation in the blood region while the wall region produced a constant high output. After processing eight consecutive RF traces (delta T = 200 microseconds), the temporal averaging method results in a 50% intensity reduction in the blood region. Using the correlation output as a weighting function, the blood echo intensity can be further reduced to only 10% of its original value. Application of the RF correlation processing to a cross-sectional image data demonstrates the feasibility of this technique to remove most of the blood echoes and enhance the image contrast of the luminal interface.

The physiology of the pelvic territory after the ligation of the hypogastric arteries may be resumed in the following phenomena: the absence of bleeding, absence of ischemia and changes in pelvic vascular pattern. The hemostatic effect is noticed immediately after ligation, when the bleeding is considerably diminished, permitting to finish the surgical act. The blood pressure has been measured before ligation, immediately and it increases after five minutes due to the changes in local characteristic impedance. The impedance profile is in concordance with geometrical modification of the microvascular network made to prevent the ischemia. The increase in blood pressure five minutes after ligation is the result of the anastomosis between the ischiatic artery and other branches of the hypogastric artery, remaking the capillary bed in the pelvic territory.

A new intraoperative method for blood flow measurement, ultrasonic transit-time flowmetry, was validated regarding its variation and error of measurement. Both common iliac arteries of five piglets were dissected under inhalation anaesthesia. Three probes, calibrated by the manufacturer, were used. Variability was evaluated by repeated measurements from the native artery and under exsanguination controlled with a withdrawal pump. The errors of measurement were calculated by comparing the flow with the exsanguinated volume by time. For each vessel 34-36 separate exsanguinations were carried out, with flow ranging from 10 to 500 ml/min. The coefficients of variation for the two 5 mm probes measured from the native artery were 3.8% and 4.2%, and 4.5% for the 3 mm probe. With the use of the withdrawal pump the coefficients were 2.5%, 2.2% and 2.1%, respectively. The two 5 mm probes showed a mean error of measurement of 0.7% (95% confidence interval (CI) was -10.4 to 13.25) and -11.4% (95% CI -20.6 to -1.1), while the error for the 3 mm probe was 3.4% (95% CI -18.1 to 14.0). The small variation of all probes indicated a good reproducibility. With accurate calibration of the probes, ultrasonic transit-time flowmetry appears to be a valid and adequate method for clinical use.

Background: Vascular tone is a determinant of conduit artery distensibility. The aim of this study was to establish whether endothelium-derived relaxing factor (EDRF) influences the distensibility of conduit arteries and whether endothelium-mediated increases in distensibility are impaired in chronic heart failure (CHF)., Methods and Results: Conduit artery distensibility was measured by two methods in healthy subjects and in nine patients with CHF caused by dilated cardiomyopathy. In the first method, pulse-wave velocity (PWV) was measured in the right common iliac artery at rest and during local infusions of acetylcholine (10(-7) to 10(-5) mol/L) or adenosine (2 x 10(-7) to 2 x 10(-5) mol/L), with correction for systemic effects. Acetylcholine induced concentration-dependent local reductions of PWV in healthy subjects (-5%, -15%, and -26%) but not in CHF patients (3%, 1%, -4%, P < .01), whereas adenosine induced similar reductions of PWV in healthy subjects and CHF patients. In the second method, brachial artery diameter, blood flow, and blood pressure were measured noninvasively by high-resolution ultrasound, continuous-wave Doppler, and photoplethysmography during reactive hyperemia in the hand and after sublingual glyceryl trinitrate (GTN, 400 micrograms). Hyperemic flow, similar in healthy subjects and CHF patients, was associated with increases in diameter and distensibility in healthy subjects (8.8% and 18.4%, respectively) but not in CHF patients (0.3% and -4.5%), whereas GTN induced similar effects in healthy subjects and CHF patients., Conclusions: These data indicate that conduit artery distensibility is increased by acetylcholine and increased blood flow in healthy subjects but not in CHF patients, whereas the effects of adenosine and GTN on distensibility are preserved in CHF patients. This implies that EDRF-mediated increases in distensibility are impaired in CHF patients, thus adding to cardiac work.

Phase contrast flow velocity measurements were performed in six healthy volunteers and 30 patients with arteriosclerotic disease. The iliac arteries were investigated in 8 cases and the femoral arteries in 28 cases. In the first 24 patients, 16 evenly distributed data sets were acquired during one cardiac cycle. In the last 12 patients, a trigger pulse followed by the acquisition of 30 evenly distributed data sets was applied every second heart beat. This procedure allowed data to be acquired over a full heart cycle without any acquisition gap. The measured flow velocities were displayed as function of time. Systolic acceleration, postsystolic deceleration and pulsatility of flow velocity were calculated and compared with stenosis grades determined from DSA angiograms. Flattening of the flow velocity patterns was found to correlate with the local severity of arteriosclerotic disease.

Instrumentation for the real-time clinical measurement of pulse wave velocity (PWV) from intra-arterial pressure waveforms is presented. This time delay between pressure waveforms (obtained from two intra- arterial catheter-mounted transducers 5 cm apart) is calculated by a transputer using multiple comparisons between discrete sections of the waveforms. The method is validated by analysis of digital and analogue signals with known time delays and is used to measure changes in PWV in the right common iliac artery (RCIA) during infusions of acetylcholine (2.4, 24 and 240 micrograms ml-1) in six healthy subjects. The system measures the delay between digitally shifted triangular waveforms and pressure waveforms to a precision of about 50 microseconds, and it is superior to measurements performed by hand using a high-performance digital storage oscilloscope. When used to measure the effects of acetylcholine on the RCIA, dose-dependent reductions in PWV are recorded (-85%, -11.6%, -14.5%). It is concluded that the instrumentation enables PWV to be measured with high accuracy and precision in real time, if the pressure signals are of high fidelity and the relative amplification of the signals is carefully balanced.

Background: Fibronectin (FN), a component of the extracellular matrix, influences cellular migration and differentiation. It is a prominent component of the extracellular matrix of normal arteries and is thought to play an important role in the pathogenesis of restenosis after angioplasty. FN exists in multiple forms that arise from a single RNA transcript that can be alternatively spliced. EIIIA- and EIIIB-containing FN mRNAs predominate in the embryo, whereas in the adult, most of the normal tissue FN lacks these domains. Since few data were available concerning pattern of expression of the different alternatively spliced forms of FN mRNA in arteries after endoluminal injury, we analyzed the expression of EIIIA and EIIIB FN isoforms at different times after experimental angioplasty., Methods and Results: The spatial and temporal alterations in FN expression were studied in an in vivo model of endothelial denudation in the rabbit aorta and iliac artery by a combination of immunochemistry and in situ hybridization methods. Alternatively spliced forms of FN EIIIA and EIIIB were detected in the media and the adventitia of both types of vessels 24 to 48 hours after injury. Two weeks after injury, EIIIA and EIIIB mRNAs were found to accumulate within the luminal layers of the neointima. The cellular form of FN protein was not found until 2 weeks after the injury and accumulated in the inner part of the neointima., Conclusions: These data demonstrate that FN upregulation is an early and long-lasting process after arterial injury. These results suggest that the induction of the embryonic FN isoforms may be involved in the restenotic process that follows balloon denudation of arteries.

To determine whether uterine blood flow was reduced and indexes of pelvic blood flow distribution altered in normotensive pregnancy at high (3,100 m) compared with low altitude (1,600 m), we measured uterine, common iliac, and external iliac artery blood flow velocities and diameters in women during pregnancy and again postpartum. Pregnancy increased uterine artery diameter, blood flow velocity, and volumetric flow at both altitudes. Uterine artery blood flow velocity was greater (69.0 +/- 2.2 vs. 59.4 +/- 3.0 cm/s; P < 0.005) but diameter was smaller at 3,100 m than at 1,600 m (2.5 +/- 0.3 mm vs. 3.4 +/- 0.2 mm; P < 0.005), resulting in volumetric flow that was one-third lower at week 36 of pregnancy (203 +/- 48 vs. 312 +/- 22 ml/min, respectively; P < 0.01). Pregnancy increased common iliac blood flow velocity and decreased external iliac artery blood flow velocity at both altitudes. The uterine artery received a smaller percent of common iliac flow at 3,100 than at 1,600 m (46 +/- 7 vs. 74 +/- 6%; P < 0.005). Gestational age was similar but birth weight was lower at 3,100 m than at 1,600 m. Among subjects at 1,600 m, variation in uterine blood flow velocity correlated positively with infant birth weight. We concluded that reduced uterine blood flow and altered pelvic blood flow distribution during pregnancy at high altitude likely contributed to the altitude-associated reduction in infant birth weight.

Background: The presence of smooth muscle fibers on the wall of large arteries would suggest that arterial compliance might change in response to vasoactive substances. The purpose of this study is to determine the basal level of vasomotor tone in these arteries in a commonly used animal preparation and to learn whether the compliance of large conductance arteries can be altered in vivo by vasoactive agents., Methods: Proximal iliac arterial compliance was measured in 7 pentobarbital-anesthetized pigs, before and during local infusions of adenosine and norepinephrine. Luminal area was measured every forty milliseconds by means of a 30 MHz intravascular ultrasound catheter and an automatic edge detection program. Simultaneous high-fidelity pressure measurements were obtained by means of a catheter-tipped pressure microtransducer positioned at the origin of the iliac artery. Linear regression analysis of the area/pressure relationship in two consecutive cardiac cycles (systolic phase only) was performed before and during adenosine and norepinephrine infusions. The slope of the area/pressure regression line was defined as an index of arterial compliance. Measurements after three minutes of infusions of adenosine (5-5000 micrograms/minute) and norepinephrine (0.001-10 micrograms/minute) were compared with the control measurements., Results: Even at the highest infusion rate, adenosine did not significantly increase arterial compliance as compared with baseline (25 +/- 7 vs 19 +/- 4 mm2/mmHg x 10(-3), respectively, P = ns). In contrast, norepinephrine decreased arterial compliance as compared with the second baseline control (13 +/- 3 vs 20 +/- 3 mm2/mmHg x 10(-3), respectively, P < 0.01)., Conclusions: In this animal model with pentobarbital anesthesia, arterial compliance may be modified more by the acute infusion of norepinephrine than by adenosine in large conductance arteries such as the proximal iliac. Thus, in this preparation, smooth muscle tone tends to be minimal and arterial compliance near maximal (ie, mostly a passive phenomenon). However, in response to norepinephrine, arterial compliance can decrease significantly as smooth muscle tone increases. Intravascular ultrasound allows continuous and accurate monitoring of these changes of arterial dimensions, suggesting that this technique may be useful in the evaluation of pharmacologically induced changes in the compliance of large arteries by vasoactive agents.

Magnetic resonance (MR) flow measurements were obtained in six healthy volunteers and 30 patients with arteriosclerotic disease with a 1.5-T imager and a pulse sequence for flow quantification based on flow-induced phase shifts. The iliac arteries were investigated in eight and the femoral arteries in 28 subjects. A trigger pulse, followed by the acquisition of 30 evenly distributed data sets, was applied every second heartbeat, thus eliminating any acquisition gap in a full heart cycle. For quantitative analysis, flow velocity was plotted as a function of time. Systolic acceleration, postsystolic deceleration, and pulsatility of flow were calculated and compared with stenosis grades determined from recent intraarterial digital subtraction angiograms. The flattening of the temporal flow patterns correlated with local severity of vascular occlusive disease.

Rationale and Objectives: Electromagnetic flowmeters have been used for many years as a standard method to determine blood flow in animal models. The use of a modified probe to measure electromagnetic induction in response to an external, large direct current (DC) field magnetic resonance (MR) imaging system was investigated., Methods: Extracted sheep iliac vessels were inserted into a pumped saline circuit with a modified probe and placed into a 2.0-T MR research imaging system. Voltage readings were collected at various flow rates ranging from 100 to 400 ml/min. Actual flows were measured with a graduated cylinder., Results: A correlation of .937 (p < .001) was observed between the measured voltage changes and the actual flows. Baseline drift was also linear and within specified limits., Conclusion: The results indicate that electromagnetic induction in a conductive fluid can be accurately measured using electrodes and an MR imaging system and that this technique provides possible opportunities for in situ flow measurements in humans.

The spontaneous variability of heart rate and arterial blood pressure was investigated in chloralose-anesthetized dogs with the left iliac vascular bed mechanically uncoupled from the central circulation. Electrocardiogram, mean arterial pressure (ABP), iliac perfusion and venous pressures, and flow (FLOW) were recorded for 5 min in steady state. Autoregressive spectral and cross-spectral analyses and digital filtering were performed. The variation coefficient (VC%), calculated from the overall variance of each signal, was 5-7%, with the exception of perfusion pressure (VC% = 1%). The frequency-related percentage of total variance was distributed among three frequency bands: two were < 0.20 Hz [lower (F1) and higher (F2; low-frequency range = F1 + F2)], and one was > 0.20 Hz (respiratory, F3). F3 was not always present in RR, which, however, oscillated also in F1 and F2, although with limited amplitude; ABP showed large respiratory and low-frequency oscillations; the FLOW oscillations were in the low-frequency range. Cross-spectral analysis showed high squared coherence in the relevant frequency bands between variables in the three couples: RR-ABP, RR-FLOW, and ABP-FLOW. Changes in RR preceded changes in ABP and in FLOW by > or = 3 s, whereas FLOW was approximately in phase opposition to ABP. It was concluded that, in the chloralose-anesthetized dog, 1) arterial pressure and heart rate oscillate with frequencies corresponding to those described in conscious humans, 2) low-frequency arterial pressure oscillations are due to changes in peripheral vascular resistance, and 3) peripheral vascular resistance does not display respiratory oscillations. Furthermore it was suggested that oscillations of vasomotor tone are generated by a rhythm of central origin and that F1 and F2 oscillations may recognize a common mechanism.

Dopplerometric investigation of pelvic arteries was carried out in 30 women without gynecologic diseases, in 51 patients with internal endometriosis, and 48 ones with uterine myomas. Internal endometriosis of the uterus was found to be characterized by specific qualitative changes in spectral curves of bloodstream velocity in the internal iliac and uterine arteries. Moreover, progressive changes in spectral curves related to dissemination of endometrioid heterotopias were revealed. In patients with uterine myomas combined with internal endometriosis disorders of peripheral circulation typical of endometriosis predominated.

We compared arterial growth to hemodynamic changes in the perinatal period in lambs. Blood pressure did not change significantly from 120 days gestation to 3 days postpartum, when it was 45.4 +/- 1.9 mmHg; however, pressure rose to 64.8 +/- 2.5 mmHg at 21 days postpartum. Thoracic and abdominal aortic and iliac and carotid arterial blood flows fell > 50% after birth but returned to fetal levels except in the abdominal aorta by 21 days postpartum. Blood flows in mesenteric (BFm) and renal (BFr) arteries increased between 120 days gestation (BFr = 13.4 +/- 1.4; BFm = 41.8 +/- 3.5 ml/min) and 140 days gestation (BFr = 25.9 +/- 1.8; BFm = 189 +/- 18 ml/min) and between 3 and 21 days postpartum (to BFr = 71.1 +/- 14.3; BFm = 334 +/- 59 ml/min). Elastin accumulation accelerated at 140 days gestation in all arteries except the thoracic aorta, in which elastin accumulation was always rapid. Collagen but not DNA accumulation also accelerated in most arteries. Postpartum dexamethasone (0.1 mg/kg twice a day) did not affect abdominal aortic elastin by 10 days of age (23.9 +/- 2.7 vs. 26.4 +/- 4.1 mg for controls); however, dexamethasone upregulated tropoelastin mRNA in fetuses. We hypothesize that cortisol stimulates elastin accumulation in late gestation. Postnatal elastin but neither collagen nor DNA correlated with blood flow changes at birth (r = 0.855, P < 0.05). We infer that accumulation of elastin is sensitive to blood flow rates during perinatal development.

The hemodynamic significance of endothelium-derived relaxing factor (EDRF)-mediated mechanisms in vascular responses to abrupt rat femoral artery occlusion was investigated. Temporary arterial occlusion was produced before and after inhibition of nitric oxide synthase by N omega-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA). Iliac artery blood flow and arterial pressures proximal and distal to the occlusion were measured. Normal vascular compensation included a return of resistance to preocclusion levels and a rise in distal pressure to a plateau within 5 min postocclusion. After treatment with L-NAME and L-NMMA, postocclusion resistance remained elevated by 53 and 36%, respectively. Collateral dilation after occlusion, as indicated by the rise in distal pressure, was prevented by L-NAME but not L-NMMA. Increases in adrenergic tone and mean arterial pressure by phenylephrine did not prevent compensation, suggesting the effects of L-NAME and L-NMMA did not result from elevated sympathetic activation or pressure. The results are consistent with the hypothesis that the stimulated release of endothelium-derived relaxing factor mediates the acute vascular compensation to abrupt arterial occlusion.

Objective: The aim was to study the effects of altered heart rate and vasoactive drugs on the blood velocity patterns in the region of an arterial bifurcation., Methods: Blood velocity profiles were measured in an exposed iliofemoral bifurcation of paced dogs using a pulsed Doppler ultrasound velocimeter with high temporal and spatial resolution., Results: Decrease of the heart rate from 120 beats.min-1 (2 Hz) to 60 beats.min-1 (1 Hz) increased the peak forward velocity (30%), the peak reverse velocity (20%), and the duration of reverse flow (25%). Each drug caused qualitatively similar changes in velocity patterns at both heart rates. The systemic administration of angiotensin II reduced peak forward velocity (-26% at 2 Hz and -33% at 1 Hz) and forward flow duration (-15% at 1 Hz), the peak reverse velocity (-30% at 1 Hz), and reverse flow duration (-20% at 2 Hz and -28% at 1 Hz). Glyceryl trinitrate also reduced the peak forward velocity (-19% at both 2 and 1 Hz) but prolonged forward flow duration (28% at 2 Hz and 17% at 1 Hz) and that of reverse flow (45% at 2 Hz and 24% at 1 Hz), and also decreased the degree of oscillation (-16% at 2 Hz). Barnidipine hydrochloride (a calcium channel antagonist) also increased the duration of forward flow (48% at 1 Hz) and of reverse flow (31% at 2 Hz) but reduced the peak reverse velocity (-29% at 1 Hz) and flow oscillation (-22% at 2 Hz and 20% at 1 Hz)., Conclusions: These dramatic changes in the pattern of blood flow, including alterations in the amplitudes and durations of the different phases of the flow cycle, are expected to have important consequences on the shear dependent responses of endothelial cells in the region of the bifurcation.

This study was designed to assess the physiological consequences of augmented vascularity induced by administration of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, in a rabbit model of hindlimb ischemia. Ten days after excision of the common and superficial femoral arteries from one hindlimb of 24 New Zealand White rabbits, VEGF (n = 15) or saline (control; n = 9) was selectively injected into the ipsilateral internal iliac artery. Limb perfusion was evaluated immediately pre-VEGF (baseline) and again at days 10 and 30. A Doppler guide wire was advanced to the internal iliac artery to record flow velocity at rest and at maximum flow velocity provoked by intra-arterial injection of papaverine. At baseline and at day 10, no differences in flow parameters were observed between the control and the VEGF-treated animals. By day 30, however, flow at rest (P < 0.05), maximum flow velocity (P < 0.001), and maximum blood flow (P < 0.001) were all significantly higher in the VEGF-treated group. These physiological findings complement previous-anatomic studies by providing evidence that a single intra-arterial bolus of VEGF augments flow, particularly maximum flow, in the rabbit ischemic hindlimb. These data thus support the notion that VEGF administration represents a potential treatment strategy for certain patients with lower extremity ischemia.

The possibility of using radiofrequency energy (RFE) to produce a sutureless anastomosis is attractive both to the military surgeon and on the grounds of cost and simplicity. To investigate this, fresh rabbit aorta was divided lengthways into 4 mm strips and apposed, intima-to-itima. A Valleylab Force 30 Electrosurgery machine supplied RFE at 500 kHz. The energy was applied using standard bipolar forceps and 121 attempts were made to weld the tissue. Seventy seven welds resulted of which 36 were able to withstand a distraction force of greater than 0.1N: the strongest weld was disrupted at 0.35N. Intact tissue withstood a distraction force of greater than 2N, whilst sutured joints disrupted at 0.97 N. It is concluded therefore that radiofrequency energy at 500 kHz does not satisfactorily weld vascular tissue.