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* Clinical Question Are angiotensin-converting enzyme inhibitors effective in decreasing mortality and morbidity in patients with heart disease but without heart failure or systolic dysfunction? * Bottom Line ACE inhibitors [...]

Whether or not a cyclosporine A (CsA)‐free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty‐four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid‐to‐femoral pulse‐wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin‐1 (ET‐1), thiobarbituric acid‐reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow‐up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET‐1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA‐free regimen based on SRL reduces aortic stiffness, plasma endothelin‐1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

In this paper, we describe a simple new design for the application of controlled, top-hat profiled wall shear stress forces in a way that is independent of hydrostatic pressure and oxygen tension, based on a rotating wall vessel system. This system has been applied to the culture of rat coronary endothelial cells obtained with a Langendorff-derived procedure isolation. Endothelial cells are immunopurified on the basis of RECA expression, and conservation of endothelial phenotype has been assessed on the basis of morphology, RECA and von Willebrand factor expressions and diI-Ac-LDL uptake. Shear stress induced by the rotating wall vessel was measured using a mathematical formula specifically designed for this type of model, and its impact on coronary endothelial cells was evaluated. Shear stress produced cell orientation parallel to the flux direction, elevated NO production and decreased monocyte adhesion. Cells were kept viable and functional for at least 4 days under shear. This simple design allows the handling and management of numerous vials in parallel and appears to be suitable for large-scale studies of both the acute and chronic impact of modulation of the physico-chemical environment on endothelial cell physiology and function.

A successful global vector field reconstruction from physiological signals is obtained for the first time. Data are generated by blood pressure and arterial diameter oscillations by using an arterial catheter with pressure transducer and an ultrasonic echo-tracking system, respectively. Results lead to the unambiguous evidence that such biological systems are characterized by a low-dimensional deterministic dynamical behavior. It is shown that a physiological system can be modelled from the knowledge of its behaviour only, as this has yet been done for theoretical systems and for laboratory designed experiments.

BACKGROUND: An altered arterial nitric oxide (NO) pathway could partly explain the damage to arteries observed in haemodialyzed (HD) patients. The present study was designed to non-invasively evaluate the NO pathway of peripheral conduit arteries in HD patients. METHODS: Twelve normotensive, non-diabetic HD patients treated with erythropoietin and 12 matched healthy controls (C) were included in the study. The effect of endogenous release of NO was assessed by measuring the flow-dependent vasodilatation of the radial artery (post-ischaemic hyperaemia), and the response to exogenous NO assessed using sublingual glyceryl trinitrate administration (GTN). RESULTS: Radial artery diameter (echo-tracking), radial blood flow (RBF: Doppler) and mean arterial pressure (Finapres) were identical at baseline in HD patients and in healthy subjects. The flow-dependent vasodilatation of the radial artery was decreased in HD patients (C: 9 +/- 1% vs HD: 3 +/- 05%, P < 0.05). The decrease in radial vascular resistance (C: -44 +/- 4% vs HD: -24 +/- 2%, P < 0.05) and the increase in radial diameter (C: 31 +/- 2% vs HD: 25 +/- 2%, P < 0.05) after GTN administration were less in HD patients than in controls. The ratio between the increase in diameter after hyperaemia to the increase in diameter after GTN, was also diminished in HD patients (C: 30 +/- 3% vs HD: 13 +/- 2%, P < 0.001). CONCLUSIONS: The flow-dependent vasodilatation of peripheral conduit arteries is altered in HD patients and is associated with a slight but significant decrease in the vasodilating response to exogenous NO. These results suggest, in the absence of changes in basal radial vascular resistance and arterial diameter, more a decrease in endothelial NO bioavailability, than an increase in basal vascular tone.

We studied the effects of verapamil and diltiazem on regional myocardial blood flow (RMBF, tracer microspheres) and function during ischemia in 18 open-chest dogs. Instrumentation included left ventricular and aortic pressure transducers, an electromagnetic flowmeter, and a hydraulic occluder on the circumflex coronary artery; sonocardiometry measured shortening of severely ischemic, moderately ischemic, and nonischemic subendocardial segments (L). Measurements were made in the control state, 10 min after subtotal coronary stenosis, and 10 min later in control (n = 6, group I), verapamil-treated (0.3 mg/kg i.v.) (n = 6, group II), and diltiazem-treated (0.3 mg/kg i.v.) (n = 6, group III) dogs. The effects of coronary stenosis were similar in all three groups and after 20 min of coronary stenosis there were no further modifications of any parameter in group I. Verapamil and diltiazem produced similar reductions in heart rate and mean aortic pressure. In severely ischemic zones, RMBF was similarly decreased [0.22 ± 0.03–0.12 ± 0.04 ml/min/g, p < 0.01 (verapamil) and 0.21 ± 0.02–0.12 ± 0.02 ml/min/g, p < 0.01 (diltiazem)] without any change in function. In moderately ischemic zones, verapamil did not modify RMBF and function while diltiazem increased RMBF from 0.43 ± 0.05 to 0.96 ± 0.18 ml/min/g (p < 0.05) and L from 3.5 ± 1.2 to 6.2 ± 1.2 (p < 0.05). In nonischemic zones, although RMBF was increased by 42.9 ± 13.6 (p < 0.05) with verapamil and 156.9 ± 33.8 (p < 0.01) with diltiazem, L remained unchanged. Thus, (a) diltiazem and verapamil, although increasing flow, do not affect function in nonischemic areas; (b) diltiazem and verapamil exert almost no effects either on flow or on function in severely ischemic areas; and (c) while verapamil shows no effects on flow and function, diltiazem increases both parameters in marginal areas demonstrating its ability to preserve the viability of this zone.

The effects of PK 11195, a peripheral benzodiazepine receptor antagonist (200 mg orally), of nicardipine (20 mg orally), of their combination, and of a placebo on brachial and carotid arteries, diameters, and flows were determined and compared over a period of 8 h after drug intake during a double-blind and cross-over study performed on six healthy volunteers. Simultaneously, plasma concentrations of both drugs were measured. PK 11195 significantly increased carotid and more markedly brachial arteries, flows (20 and 39, respectively), and diameters (4 and 7, respectively) and de-creased forearm vascular resistance. Thus, PK 11195 preferentially affected the resistance vascular beds where it dilated both large arteries and arterioles. The intensity and duration of the peripheral vasodilating effects of PK 11195 were similar to those of nicardipine. Simultaneous administration of PK 11195 and nicardipine abolished al-most all the peripheral vasodilating effects of both drugs. This finding, which was not related to a pharmacokinetic interaction between PK 11195 and nicardipine, demonstrates that in humans a functional antagonism develops between these two drugs at the vascular level.

The effects of three doses (4, 8, and 16 mg) of perindopril, a new angiotensin I converting enzyme inhibitor, on systemic blood pressure, heart rate, brachial and carotid artery flow and diameter (assessed by the pulsed Doppler technique), forearm vascular resistance, plasma converting enzyme and renin activities, and plasma aldosterone were investigated in the normal volunteer and compared with those of a placebo over a 24-h period following oral drug intake in a double-blind, crossover trial. Perindopril dose-dependently decreased plasma converting enzyme activity, an effect that peaked at 3–4 h and persisted up to at least 48 h. Plasma renin activity increased for 12 h and plasma aldosterone was slightly decreased. Systemic blood pressure and heart rate were not drug-affected but perindopril dose-dependently augmented brachial and carotid artery flow, indicating an increase in peripheral arterial compliance. These vasodilating effects, which lasted up to 10 h after drug intake, affected both large arteries and arterioles, the latter being more sensitive, however, and were more marked in the muscular resistance vessels.

The systemic and regional haemodynamic and cardiac effects of two oral doses (100 and 300 mg) of a new sulphone-indolizine calcium antagonist SR 33 557 (SR) and a placebo were non invasively investigated in a double-blind, cross-over study in 6 healthy male volunteers.

The ß-adrenoceptor blocking effects and pharmacokinetics of bornaprolol (FM 24), a new ß-adrenoceptor blocking agent, have been compared with those of propranolol and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate, systolic and diastolic blood pressures and peak expiratory flow rate were measured at rest and at the end of 3 min vigorous exercise on a bicycle ergometer, before and 2, 24 and 48 h after single oral doses of bornaprolol (120, 240 and 480 mg) and propranolol (40, 80 and 160 mg). Plasma renin activity at rest and the plasma concentrations of the two drugs were determined. Bornaprolol significantly reduced resting heart rate, dose-dependently lowered exercise-induced tachycardia and decreased peak expiratory flow rate and plasma renin activity. In addition, exercise-induced tachycardia was significantly reduced by bornaprolol up to 48 hours after drug intake (pharmacodynamic half-life approximately 63–86 h) and there was a correlation between this reduction and the log plasma bornaprolol concentration over the 48-h period. Thus, bornaprolol behaved in man as a non-cardioselective and long-lasting ß-adrenoceptor blocking drug, probably devoid of intrinsic sympathomimetic activity.

The effect of oral diltiazem 120 mg, on the responses to baroreflex activation and deactivation by phenylephrine and nitroglycerin, respectively, were investigated in normotensive subjects, with simultaneous measurement of plasma catecholamine levels. Diltiazem significantly reduced the tachycardia induced by bolus injections of nitroglycerin and abolished the concomitant increase in plasma noradrenaline. It also significantly decreased the bradycardiac response to phenylephrine infusion. Diltiazem reduced, although not significantly so, the bradycardia induced by boluses of phenylephrine. The overall reduction in baroreflex sensitivity, which might contribute to the limited tachycardiac effect of diltiazem in man, is consistent with the drug-induced attenuation of the sympathetic and also of the parasympathetic components of the baroreceptor reflex.

Chronic heart failure (CHF) impairs endothelium-dependent vasodilatation of large conductance arteries. We investigated whether a similar reduction also occurs in small arteries, and whether such a reduction can be prevented by the angiotensin converting enzyme inhibitor perindopril (P) in a rat model of CHF (left coronary artery ligation). After 1 month treatment with placebo or P (2 mg/kg/day), rats were anesthetized and arterial pressure, left ventricular end-diastolic pressure, and central venous pressure were measured with a micromanometer. Segments of aorta and mesenteric artery (mean diameter, 281 +/- 8 microns) were then isolated, cannulated, and perfused at constant pressure using an arteriograph. Responses to increasing concentrations of acetylcholine (Ach), nitroprusside, and to 10(-4) mol/L NG-nitro-L-arginine methyl ester (L-NAME) were studied after preconstriction by phenylephrine. Heart failure resulted in a decrease in systolic and diastolic pressures, an increase in left ventricular end-diastolic and central venous pressures, and a significant depression of Ach-induced dilatation of the mesenteric artery (maximal dilatation, from 90 +/- 4% to 63 +/- 4%, P < .05) but not of the aorta (from 56 +/- 8% to 45 +/- 5%, NS) without any modification in the endothelium-independent vasodilatation induced by nitroprusside. In the group treated by the angiotensin converting enzyme (ACE) inhibitor perindopril, systolic and diastolic pressures were slightly decreased, whereas left ventricular end diastolic, central venous pressures, and the endothelium-dependent vasodilating response to Ach were normalized. Responses to L-NAME were not affected by CHF or perindopril. Perindopril also decreased hypertrophy, as evidenced by a significantly lower heart weight in treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of Bay K 8644, aortic constriction, and a placebo on regional myocardial blood flows (RMBFs) and contractile function (RCF) were compared in three groups of open-chest anesthetized dogs during coronary stenosis. Bay K 8644 was investigated in two doses: 0.1 μg/kg, which exhibited no systemic hemodynamic effect, and 1 μg/kg, which significantly increased arterial pressure. Aortic constriction was performed to raise afterload to the same extent as Bay K 8644 1 μg/kg. As compared with placebo, Bay K 8644 0.1 μg/kg, significantly increased coronary resistance, decreased RMBFs without changing RCF in nonischemic myocardial zones, and affected neither RMBFs nor RCF in ischemic zones. In nonischemic myocardium. Bay K 8644 1 μg/kg increased RMBFs without affecting RCF, whereas aortic constriction did not modify RMBFs but decreased RCF. In ischemic myocardium, both Bay K 8644 1 μg/kg and aortic constriction increased RMBFs but did not affect RCF. Thus, the low dose of Bay K 8644 exerts a direct and selective coronary vasoconstrictor effect that has no deleterious consequences on nonischemic RCF. Despite this intrinsic coronary vasoconstrictor effect, the high dose of Bay K 8644 increases RMBFs and maintains RCF in both ischemic and nonischemic zones in relation with the drug-induced increases in coronary perfusion pressure (both zones) and in contractility (nonischemic zones).

The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers.

Summary—The increased sympathetic drive in chronic heart failure (CHF) might provoke vascular adrenoceptor desensitization, which, together with endothelial dysfunction, could contribute to the altered vasomotor tone seen in CHF. We investigated 1) whether CHF alters the responses mediated by α and β adrenoceptors in small and large peripheral arteries, and 2) the effect of angiotensin‐converting enzyme (ACE) inhibition. Rats with CHF (coronary artery ligation) were treated with placebo or the ACE inhibitor lisino‐pril (10 mg/kg/d) starting 7 days after ligation. Responses to phenylephrine (α, agonist), salbutamol (β2agonist) as well as acetylcholine (endothelium‐dependent), were assessed after 3 months in isolated and pressurized segments of the abdominal aorta, the femoral and the mesenteric arteries. In animals with hemodynamic signs of CHF, neither the vasoconstrictor responses to phenylephrine nor the vasodilator response to salbutamol were affected. In contrast, the dilator response to acetylcholine of both small arteries, but not that of the aorta, was impaired. Furthermore, CHF did not modify vessel structure. While lisinopril did not modify the responses to adrenergic agonists, it normalized the response to acetylcholine. Furthermore, ACE inhibition reduced vascular media cross sectional area and collagen density. Thus, the unchanged arterial responsiveness to adrenoceptor agonists does not indicate any vascular adrenoceptor desensitization, while endothelial dependent vasodilation of small arteries is impaired in CHF. ACE inhibition does not modify the response to adrenergic stimuli, prevents endothelial dysfunction and induces both cardiac and vascular remodeling, which probably contribute to the effect ACE inhibitors have on exercise tolerance and survival.

Experiments performed in isolated arteries or in animals suggested that flow-dependent dilation of conduit arteries is mediated through the release of endothelium-derived nitric oxide (NO). The present study was designed to assess whether NO also contributes to flow-dependent dilation of conduit arteries in humans.

Recent experiments demonstrated increased isobaric arterial compliance and distensibility in hypertensive patients, which could be explained by a decrease in arterial wall stress, when assessed at constant pressure. We investigated the effect of hypertension on the mechanical properties of the carotid arterial wall, and especially wall stress, assessed in vivoin spontaneously hypertensive rats (SHR).