Search

The growing computing power offered by technical advances has allowed deep learning models to be applied in various fields of healthcare and medical research, including imaging analysis, text mining, and omics studies. This article explores the basic mechanism of artificial neural networks (ANNs), and upon which explains the architecture of popular supervised learning methods such as deep neural networks (DNNs), convolutional neural networks (CNNs), and recurrent neural networks (RNNs), as well as unsupervised learning methods including variations of autoencoders, restricted Boltzmann machines (RBM), and Deep Belief Nets (DBN). Important features of each architecture are explained, such as the convolution layer and pooling layers of CNNs and the recurrent structure of RNNs. These features have optimized their corresponding models to perform different tasks ranging from image processing to textual analysis. The unique advantages of different forms of neural networks have allowed deep learning tools to become the state-of-the-art in various research studies and medical fields. The construction of various architectures is often completed through deep learning frameworks, which provide powerful built-in libraries and ease of use. Several popular deep learning frameworks including TensorFlow, PyTorch, and others are introduced and compared. Further, the article reviews the current obstacles met by deep learning approaches, including computation and interpretability limitations. Nevertheless, improvements and hardware optimization intending to overcome these challenges are emerging rapidly, offering a promising path to more effective implementation of deep learning in the healthcare industry.

The maximum output power of GaN-based high-electron mobility transistors is limited by high channel temperature induced by localized self-heating, which degrades device performance and reliability. Chemical vapor deposition (CVD) diamond is an attractive candidate to aid in the extraction of this heat and in minimizing the peak operating temperatures of high-power electronics. Owing to its inhomogeneous structure, the thermal conductivity of CVD diamond varies along the growth direction and can differ between the in-plane and out-of-plane directions, resulting in a complex three-dimensional (3D) distribution. Depending on the thickness of the diamond and size of the electronic device, this 3D distribution may impact the effectiveness of CVD diamond in device thermal management. In this work, time-domain thermoreflectance is used to measure the anisotropic thermal conductivity of an 11.8 μm-thick high-quality CVD diamond membrane from its nucleation side. Starting with a spot-size diameter larger than the thickness of the membrane, measurements are made at various modulation frequencies from 1.2 to 11.6 MHz to tune the heat penetration depth and sample the variation in thermal conductivity. We then analyze the data by creating a model with the membrane divided into ten sublayers and assume isotropic thermal conductivity in each sublayer. From this, we observe a two-dimensional gradient of the depth-dependent thermal conductivity for this membrane. The local thermal conductivity goes beyond 1000 W/(m K) when the distance from the nucleation interface only reaches 3 μm. Additionally, by measuring the same region with a smaller spot size at multiple frequencies, the in-plane and cross-plane thermal conductivities are extracted. Through this use of multiple spot sizes and modulation frequencies, the 3D anisotropic thermal conductivity of CVD diamond membrane is experimentally obtained by fitting the experimental data to a thermal model. This work provides an improved understanding of thermal conductivity inhomogeneity in high-quality CVD polycrystalline diamond that is important for applications in the thermal management of high-power electronics.

Changes in maternal catecholamines that accompany the onset of labor analgesia include a decrease in epinephrine (EPI) but no change in norepinephrine (NE). Because EPI exerts predominantly beta-adrenergic, and NE predominantly alpha-adrenergic effects in circulating concentrations, we hypothesized that these changes could lead to uterine arteriole vasoconstriction.Uterine microvessels (73-120 microm internal diameter, n = 18) were harvested from near-term pregnant Sprague-Dawley rats, isolated and studied in a pressurized no-flow state with video microscopy. Drugs were applied extraluminally to the superfusion reservoir and the steady-state vessel diameter recorded. Dose-response curves were constructed for NE with and without the addition of the alpha-adrenergic antagonist prazosin, EPI (after 20%-30% preconstruction with the thromboxane analog U46619) with and without the addition of the beta-adrenergic antagonist propranolol, and NE in the presence of 10(-8) M EPI. Washout experiments modeled the changes in circulating maternal catecholamines observed during onset of analgesia: 10(-8) M EPI and 10(-6.5) M of NE (the EC50) were added simultaneously, then washed with NE only, and then with the beta2-adrenergic agonist terbutaline and NE. The washout protocol was repeated in the presence of propranolol.NE caused dose-dependent vasoconstriction (P0.0001), which was blocked by prazosin (P0.0001). EPI, added to U46619-preconstricted microvessels, caused vasodilation at lower concentrations and vasoconstriction at higher doses (P0.0001). Propranolol converted this response to monophasic dose-dependent vasoconstriction (P0.0001). Pretreatment of nonprecontracted vessels with EPI, 10(-8) M, significantly attenuated NE-induced vasoconstriction (P0.0001). In washout experiments, removal of EPI with continued presence of NE resulted in vasoconstriction that was reversed by terbutaline. Propranolol blocked the effect of both EPI and terbutaline.The results demonstrate that EPI, in concentrations found in the plasma of laboring women, vasodilates uterine resistance vessels and attenuates NE-induced vasoconstriction. This observation may have implications for changes in uterine blood flow that may accompany the onset of labor analgesia in human parturients, as effective analgesia is accompanied by an acute decrease in circulating EPI levels.

The sleep-promoting effect of the pineal hormone melatonin in humans is known for decades. However, the mechanisms of this phenomenon remain obscure, mainly due to lack of a simple, genetically tractable, animal model. We now report that melatonin promotes sleep-like state in a diurnal lower vertebrate, zebrafish (Danio rerio), and this effect is mediated through activation of specific melatonin membrane receptors. Furthermore, our data show that the sleep-like state in zebrafish has fundamental similarities with sleep in mammals, including characteristic postures, elevated arousal threshold to sensory stimulation and a compensatory rest rebound following rest deprivation, and can be induced by conventional hypnotics, diazepam and sodium pentobarbital. Collectively, these data indicate that melatonin is evolutionary conserved sleep-promoting agent in diurnal species and suggest that zebrafish provide an efficient animal model for studying the molecular mechanisms of sleep regulation and for screening new types of hypnotic medications.

On ne sait pas comment les effets des variations de capacitance vasculaire (arterielle par rapport a veineuse), induites par le NP (nitroprussiate), se repartissent. Nous avons evalue les pressions veineuses et arterielles ileales canines ainsi que les volumes vasculaires (boucle isolee) totaux (scintigraphie), avant et durant une perfusion de NP. Le taux de NP suffisant pour diminuer la pression de perfusion de 30% a augmente le volume vasculaire total a 111 ± 3% (ET) par rapport au volume temoin (p < 0,01). L'augmentation du debit pour retablir la pression de perfusion a augmente le volume d'un autre 4% (p < 0,01). Supposant un modele a deux compartiments et tenant compte des donnees de la litterature scientifique, les variations de la capacitance veineuse ont ete estimees et comparees a celles de la capacitance arterielle. Durant une perfusion a debit constant, le NP a augmente le volume veineux de 10,0% (par rapport a 18,1% pour le volume arteriel). Lorsque le debit a ete augmente pour retablir la pression, le volume veineux a augmente d'un autre 3,7% (par rapport a 2,6% pour le volume arteriel). Supposant un rapport volume arteriel-veineux initial de 133/1033, l'augmentation a pression constante du volume veineux a ete, au total, environ 4 fois plus forte que l'augmentation arterielle. Ainsi, durant la perfusion de NP, l'augmentation du volume vasculaire a ete principalement induite par des augmentations actives, de meme amplitude, des capacitances veineuses et arterielles (c.-a-d. des deplacements vers la droite des relations pression-volume). Toutefois, etant donne que le volume veineux est tellement plus important que le volume arteriel, l'augmentation de volume veineux induite par le NP a ete plus forte.

This study was performed to assess the effects of subacute sepsis in rats on the in vitro reactivity of arterioles (internal diameter, 100-150 microm) to alpha1- and alpha2-adrenergic stimulation and to angiotensin II. Male Sprague-Dawley rats were rendered septic by intraperitoneal implantation of a gelatin capsule containing sterile rat feces and 1 x 10(6) viable colony forming units of Escherichia coli. Control rats underwent sham laparotomy and implantation of a gelatin capsule containing only sterile feces. In vitro reactivity of arterioles from mesentery and skeletal muscle were studied 48 h later in a pressurized (50 mmHg) no flow state using videomicroscopy. Subacute sepsis decreased the contractile response of nonprecontracted microvessels from both anatomical sites to phenylephrine (both p < .01 versus control) and blunted the relaxation response to staurosporine (both p < .01), an inhibitor of protein kinase C. The small contraction to angiotensin II of mesenteric vessels was inhibited by sepsis (p < .05) but was unaltered in the skeletal muscle microcirculation. In the precontracted mesenteric microvessels from septic rats, endothelium-dependent relaxation to clonidine and to adenosine 5'-diphosphate were decreased (both p < .01 versus control), whereas in skeletal muscle microvessels, clonidine and adenosine 5'-diphosphate elicited constriction (both p < .01). Relaxation to the endothelium independent vasodilators sodium nitroprusside and pinacidil was preserved across all vessels. In conclusion, mesenteric and skeletal muscle microvascular responses to angiotensin II and alpha1- and alpha2-adrenergic stimulation are altered in subacute sepsis. This may in part lead to systemic hypotension and altered organ perfusion during states of chronic sepsis.

Background. Cardiopulmonary bypass (CPB) is associated with alterations in the regulation of organ perfusion and vascular permeability. The purpose of this study was to examine the effects of hypothermic CPB on the regulation of the skeletal muscle microcirculation and the modulating influence of the priming solution. Methods. Sheep were placed on hypothermic CPB with a prime of either Pentastarch hydroxylethyl starch (HS) solution (n = 7), a solution in which HS is conjugated with deferoxamine (n = 7), or Ringer's lactate solution (n = 7). Sheep were placed on hypothermic CPB (27°C) for 90 minutes while the heart was protected with cold blood cardioplegia. Sheep were then separated from CPB and perfused for an additional 3 hours off CPB. Hemodynamics and total water content were measured. Results. In vitro relaxation responses of gracilis muscle arterioles (70 to 180 μm) to the endothelium-dependent agent acetylcholine, the endothelium-independent cyclic GMP-mediated vasodilator sodium nitroprusside, the β-adrenergic agonist isoproterenol, and the adenylate cyclase activator forskolin were studied. No statistically significant hemodynamic differences were observed between groups. However, weight gain was significantly less when the priming solution was HS or HS-deferoxamine compared to when Ringer's lactate was used. Skeletal muscle arteriolar relaxations to the endothelium-dependent vasodilator acetylcholine and the βadrenergic agonist isoproterenol were impaired after CPB in the HS and Ringer's lactate groups. Acetylcholine response was preserved in the HS-deferoxamine group, whereas the response to isoproterenol remained impaired. The responses to sodium nitroprusside and forskolin were similar in all groups. Conclusions. Skeletal muscle microvascular endothelium-dependent relaxation and β-adrenergic relaxation are reduced after CPB using either a crystalloid or HS prime. Skeletal muscle microvascular endothelial dysfunction may be attributable to oxygen-derived free radical-mediated injury, whereas altered β-adrenergic regulation is attributable to mechanisms other than the generation of oxygen-derived free radicals during CPB.

We compared the effect of hypermagnesium and hyperkalemic crystalloid cardioplegia on beta-adrenoceptor-mediated and endothelium-dependent relaxation and myogenic responses of coronary arterioles. Pigs were placed on cardiopulmonary bypass. Hearts were arrested with cold hypermagnesium (25 mM Mg2+, hyper-Mg, n = 12) or hyperkalemic (25 mM K+, hyper-K, n = 12) crystalloid cardioplegia for 1 hr. Hearts of selected pigs (n = 6 in each group) were then reperfused for 1 hr. In vitro relaxation responses of acetylcholine-pre-contracted arterioles were studied in a pressurized no-flow state with video-microscopy. Relaxation of pre-contracted coronary microvessels (70-150 microns) to isoproterenol (beta-adrenergic agonist) and forskolin (adenylate cyclase activator) was preserved after cardioplegia using a hyper-Mg solution. In contrast, responses were impaired to isoproterenol [P0.01 (two-factor ANOVA) vs. controls, n = 6] and forskolin (P0.01) after hyper-K cardioplegia. After 1 hr of reperfusion, relaxation responses to isoproterenol and forskolin were partially recovered. Hyper-Mg cardioplegia and post-cardioplegic reperfusion did not affect receptor-mediated endothelium-dependent relaxation to ADP, non-receptor-mediated endothelium-dependent relaxation to A23187, and endothelium-independent relaxation to nitroprusside. However, responses to ADP (P0.01) and A23187 (P0.05) were selectively impaired after hyper-K cardioplegia. Myogenic contraction was impaired after either hyper-Mg or hyper-K cardioplegia. Left ventricular systolic pressure, coronary blood flow, and +dP/dt were similar after hyper-Mg or hyper-K cardioplegia. These results suggest that hyper-Mg cardioplegia is superior to hyper-K cardioplegia in terms of preserving beta-adrenoceptor-mediated and endothelium-dependent regulation of the coronary microcirculation, yet it has minimal if any additional beneficial effect on preserving myogenic responses or myocardial contractile function.

Patients who undergo cardiopulmonary bypass frequently have neuropsychologic dysfunction. This study was undertaken to determine whether altered cerebral perfusion and vascular responses may in part lead to these neuropsychologic changes. Pigs were placed on normothermic cardiopulmonary bypass for 2 hours. Basal cerebral blood flow and in vivo responses to administration by internal carotid artery of neuronally released vasoactive substances were evaluated before and 5 to 15 minutes after termination of cardiopulmonary bypass. Another group of pigs were placed on cardiopulmonary bypass for 2 hours and then perfused off bypass for 1 additional hour. In vitro responses of cerebral arterial microvessels (100 to 175 μm) from both groups were examined in a pressurized (40 mm Hg) no-flow state with videomicroscopy. Vessels from uninstrumented pigs served as control preparations for in vitro studies. Cerebrovascular resistance and cerebral perfusion were maintained constant during cardiopulmonary bypass and after separation from bypass. The internal carotid artery infusion of acetylcholine (cholinergic agonist) caused increased internal carotid artery blood flow before cardiopulmonary bypass but decreased blood flow after cardiopulmonary bypass. After 2 hours of cardiopulmonary bypass, the increase in internal carotid artery blood flow induced by isoproterenol (a β-adrenoceptor agonist) was reduced, whereas the response to sodium nitroprusside (a guanylate cyclase activator) was unchanged. In vitro acetylcholine-induced microvascular vasodilation was converted to a contractile response and isoproterenol elicited less relaxation after 2 hours of cardiopulmonary bypass. One hour of cerebral perfusion after cardiopulmonary bypass caused a further reduction in isoproterenol-induced relaxation but had no further effect on the cholinergically mediated response. In vitro relaxation responses to sodium nitroprusside and forskolin (an adenylate cyclase activator) were similar in all experimental groups, suggesting that second-messenger mechanisms remain intact after normothermic cardiopulmonary bypass. In conclusion, basal cerebrovascular resistance and internal carotid artery blood flow are maintained if the systemic circulation and pressure are supported with fluid administration after cardiopulmonary bypass. Agonist-induced vasodilation of cerebral microvessels to cholinergic and β-adrenoceptor stimulation are selectively impaired after normothermic cardiopulmonary bypass, whereas second-messenger mechanisms remain intact. (J Thorac Cardiovasc Surg 1996;112:450-61)

Vascular endothelial growth factor (VEGF) is a potent mitogen capable of stimulating angiogenesis. We examined the effect of VEGF administration in a model of chronic porcine myocardial ischemia. Nineteen pigs were instrumented with proximal left circumflex coronary artery (LCX) Ameroid constrictors. In eight animals VEGF (2 microgram) with heparin (50 U) was administered extraluminally to the LCX myocardium with an osmotic pump for 4 wk and 11 other animals served as controls. VEGF-treated animals demonstrated higher flow in the LCX territory during both rest and pacing compared with untreated controls (rest: 1.35 +/- 0.1 vs. 0.80 +/- 0.09 ml.min-1.g-1; pacing; 2.01 +/- 0.37 vs. 1.01 +/- 0.07 ml.min-1.g-1, P < 0.05, VEGF vs. controls). The observed improvement in regional coronary flow in VEGF-treated animals resulted in better preservation of endothelium-dependent microvessel relaxation as well as fractional LV shortening in the LCX territory during pacing in the VEGF-treated than in control animals (controls: 7.1 +/ 2.6 vs. 3.6 +/- 2.0%, rest vs. pacing; VEGF: 6.9 +/- 2.9 vs. 6.3 +/- 2.9%, rest vs. pacing). We conclude that VEGF administration in a gradual coronary occlusion model in pigs results in improvement of coronary flow and preservation of regional hemodynamics in the compromised myocardium.

A novel aspect of the pharmacodynamic action of nitroglycerin is that it is a potent dilator of larger coronary arteries, yet it dilates smaller coronary microvessels submaximally and only in high concentrations. We sought to determine whether this property was shared by other organic nitrates. The effects of two mononitrates. SPM-4744 and SPM-5185 (the latter of which possesses a thioester in its structure), on coronary microvessels of different sizes were studied. Large (200-microns diameter) and small ( < 100-microns diameter) porcine coronary microvessels were studied in vitro while pressurized in a no-flow state. After constriction with the thromboxane analogue U46619, maximal dilations (as a percent of preconstricted tone at the highest applied concentration, 10 microM) of small coronary microvessels were 18 +/- 3 and 16 = 2% in response to SPM-4744 and SPM-5185, respectively. The dilations of larger coronary microvessels to SPM-4744 and SPM-5185 were 55 +/- 5 and 43 +/- 6%, respectively (both p < 0.001 vs. the small vessel responses). This pattern of differential vasodilatation of large and small coronary microvessels was similar to that produced by nitroglycerin. In contrast, sodium nitroprusside produced equivalent degrees of vasodilation of small and large coronary microvessels. Additional experiments demonstrated that both SPM compounds produced dilation of the coronary microcirculation in isolated rat heart and relaxed isolated segments of rat aortic rings only in high ( > or = 1 microM) concentrations. These data demonstrate that the organic mononitrates are similar to nitroglycerin in their selectivity for larger coronary microvessels and produce only minimal dilation of coronary microvessels < 100 microM in diameter.

Cardiopulmonary bypass (CPB) is often followed by pulmonary hypertension, but the effects of extracorporeal circulation on vascular reactivity remain largely unknown. In this study, the influence of total CPB (t-CPB) on beta-adrenergic and cholinergic receptor-mediated pulmonary microvascular responses was examined. Sheep were placed on t-CPB without ventilation. After 90 min, sheep were separated from t-CPB and the lungs were perfused normally for 60 min. Pulmonary artery infusion of acetylcholine (muscarinic cholinergic agonist, ACh) increased pulmonary vascular resistance significantly more and isoproterenol (beta-adrenergic agonist, Iso) decreased pulmonary vascular resistance less after than before t-CPB. The response to sodium nitroprusside (SNP, guanylate cyclase activator) was similar before and after t-CPB. Relaxations (in vitro) of isolated pressurized (20 mmHg) microvessels to Iso and ACh were markedly reduced after t-CPB. Treatment with NPC-15669 (N-[9H-(2,7,-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine) did not affect these changes in vessel reactivity, although leukocyte sequestration in the lungs was reduced with the drug. The in vitro response to forskolin (adenylate cyclase activator) and SNP was similar before and after t-CPB. Complement-activated serum caused microvessels to contract in response to ACh, but it had no effect on Iso, forskolin, or SNP responses, suggesting that activation of the alternate complement pathway causes a selective reduction in endothelium-dependent relaxation. We conclude that t-CPB impairs cholinergic and beta-adrenergic pulmonary vascular responses due to effects at the level of the transmembrane receptor or coupling to the second messenger systems.

Background Cardiopulmonary bypass (CPB) and cardioplegia are associated with systemic hypotension and altered vascular responses, suggesting a defect in the smooth muscle control of vascular tone. Previous studies demonstrated alteration in neurohumoral control of the systemic and coronary circulation after CPB and cardioplegia; however, effects of CPB and cardioplegia on the intrinsic control of the vascular smooth muscle, especially in the coronary microcirculation, remain to be determined. Methods and Results Pigs were placed on CPB. Selected hearts were arrested with a cold, hyperkalemic ([K + ]=25 mmol/L) crystalloid cardioplegic solution for 1 hour. In another group, hearts were arrested and then reperfused with warm blood for 1 hour. Coronary arterioles (70 to 149 μm) were studied in a pressurized, no-flow state with video microscopy. Myogenic reactivity was examined to stepwise increases in intraluminal pressure from 10 to 100 mm Hg. The vessel diameter was normalized to the diameter at 50 mm Hg after application of papaverine (10 −4 mol/L). Myogenic reactivity of vessels from noninstrumented control pigs was not altered after mechanical denudation of the endothelium or pretreatment with N G -nitro- l -arginine or indomethacin. In vessels from control pigs and vessels from the CPB group, myogenic contraction was observed with pressures >40 mm Hg. However, CPB significantly decreased intrinsic tone as the pressure-diameter relation shifted upward ( P N G -nitro- l -arginine, suggesting an increased basal release of nitric oxide. Cardioplegic arrest, with or without reperfusion, decreased myogenic contraction to pressures >40 mm Hg ( P P Conclusions The result of the present study suggests that coronary microvascular myogenic reactivity and the intrinsic tone are reduced after hyperkalemic cardioplegia and that CPB preserves myogenic reactivity but reduces the intrinsic tone of the vascular smooth muscle.

The effect of chronic, collateral-dependent perfusion on beta-adrenergic coronary microvascular responses was examined. Ameroid constrictors were placed on the proximal left circumflex (LCx) coronary artery in 16 pigs. In 8 pigs, heparinized saline containing vascular endothelial growth factor (VEGF) was administered into the perivascular space of the proximal LCx artery using an implanted osmotic pump. After 5-7 weeks, coronary arterial microvessels (70-150 microns) were studied in a pressurized (40 mm Hg) no-flow state with video-microscopy. beta-Adrenoceptor-mediated relaxations of isolated microvessels from the collateral-dependent LCx region to isoproterenol (P0.01) were markedly reduced, as were those to the adenylate cyclase activator forskolin (P0.01), compared to the respective response of vessels from the normally perfused left anterior descending artery region. Responses to the Gs-protein activator NaF showed a similar trend, but the differences were not significant. Chronic treatment with VEGF normalized responses to isoproterenol, NaF, and forskolin in the collateral-dependent LCx region. Blood flow in the LCx region increased in both control (P0.01) and VEGF-treated (P0.05) groups during rapid atrial pacing. The absolute increase in LCx blood flow was greater in the VEGF group than in the control group at rest (P0.05), but not during rapid pacing. Thus, beta-adrenergic microvascular relaxation is impaired in the collateral-dependent coronary microcirculation. The periadventitial delivery of VEGF improves myocardial perfusion to the collateral-dependent area and preserves beta-adrenergic-mediated relaxation of microvessels in the collateral-dependent myocardium.

To examine the acute effect of cocaine on the coronary microcirculation and whether chronic cocaine administration with or without a concomitant high-cholesterol diet affects beta-adrenoceptor and endothelial functions in the coronary microcirculation.Prospective experimental study.Laboratory and animal research facility.Yorkshire pigs.Pigs were fed a high (2%)-cholesterol diet or a regular diet for 3 months. Animals in both groups received cocaine chronically (7 mg/kg/day, IM). Control animals were fed a regular diet.Responses of the porcine coronary arterioles (90 to 190 microns in diameter) were examined in vitro in a pressurized (40 mmHg) no-flow state using a video-imaging apparatus. Acute application of cocaine caused a significant contraction with a mean maximal diameter decrease of 14% +/- 5%, which was markedly reduced by muscarinic blockade but not significantly affected by alpha 1-adrenergic blockade. Lidocaine or procainamide had no vasoconstrictor effect. Chronic exposure of animals to cocaine diminished contractile responses to cocaine and reduced relaxation responses to the nonselective beta-adrenergic receptor agonist isoproterenol. Phenylephrine caused a minimal (4%) contraction of vessels in all groups. Chronic cocaine administration with concomitant high-cholesterol feeding attenuated endothelium-dependent relaxations to serotonin, whereas endothelium-dependent relaxations to bradykinin were unaffected. Endothelium-independent relaxations to sodium nitroprusside were similar in all groups.These results suggest that cocaine can exert a direct vasoconstrictor effect on the porcine coronary microcirculation via a muscarinic mechanism. Chronic exposure to cocaine significantly decreases beta-adrenoceptor-mediated relaxation and blunts endothelium-dependent relaxation to a small degree.

Previous studies have shown an increase in left atrial plasma thromboxane (TBX) level and associated increase in lung injury parameters after total cardiopulmonary bypass (t-CPB) but not after partial cardiopulmonary bypass (p-CPB). We used dazmegrel to study the effect of TBX synthesis inhibition on lung injury after t-CPB compared with p-CPB. Sheep were placed on t-CPB without ventilation and with pulmonary artery occlusion (n = 7) or p-CPB with ventilation and an unrestricted pulmonary artery (n = 7). All sheep were treated with dazmegrel. After 90 minutes we separated the sheep from CPB. Plasma TBX, platelets, white blood cells, protein concentration, lung lymph protein, flow, and pulmonary vascular resistance were measured before and after CPB. Lung biopsies were also obtained. Minimal derangement of these pulmonary parameters was seen after either p-CPB or t-CPB. Inhibition of TBX synthesis virtually eliminated the lung injury previously reported after t-CPB, when compared with p-CPB. Clearly TBX has an important role in mediating lung injury after t-CPB.

To define relative changes in intestinal vascular capacitance, we developed a model that allowed us to construct intestinal vascular pressure-volume relationships (PVR). Thirteen alpha-chloralose-anesthetized and splenectomized dogs were studied using a pneumatic constrictor and a small catheter to change and measure portal venous pressure. A small lead sheet was placed beneath the abdominal wall. Relative changes in intestinal blood volume (IBV) were determined by in vivo blood pool scintigraphy with 99mTc-labeled erythrocytes and were expressed as percentages corrected for specific activity and abdominal wall radioactivity. PVRs were constructed using data recorded during graded inflations of the portal venous constrictor. The abdominal wall contributed 32.4 +/- 7.7% (SD) of the total counts. During a 4-h control period, PVRs varied by no more than 6% (of IBV). In the isolated intestinal circulation, the change in IBV was precisely proportional to the volume of blood added, indicating that this method can detect very small changes in volume (< or = 5 ml). Nitroglycerin (25 micrograms.kg-1.min-1) increased capacitance by 20%. Although it measures only relative changes, the model is stable and sensitive, provides reproducible measurement of intestinal PVRs, and, with adaptation, may prove useful in patient studies.

Total cardiopulmonary bypass with associated reduced pulmonary blood flow causes significant alterations of endothelium-dependent pulmonary microvascular responses after resumption of normal perfusion. To determine if this change in pulmonary vascular reactivity may influence the responses of pulmonary arterioles to protamine and histamine, we examined isolated pulmonary microvessels after cardiopulmonary bypass. Sheep were heparinized, cannulated, and placed on either total bypass without ventilation or partial bypass (70% of baseline pulmonary arterial flow) with continued ventilation. After 90 minutes, sheep were separated from cardiopulmonary bypass and the lungs were perfused normally for 60 minutes. Vessels from noninstrumented sheep were used as controls. Peripheral pulmonary arterioles (90 to 190 microns) were cannulated, pressurized (20 mm Hg) in a no-flow state, and examined with video microscopy. After precontraction of vessels with the thromboxane A2 analog U46619 by 18% to 25% of the baseline diameter, vasoactive agents were applied. Protamine sulfate, histamine, heparin, and the protamine-heparin complex caused significant dose-dependent relaxations of control pulmonary microvessels. These relaxation responses were substantially reduced or converted to contractile responses in endothelium-denuded vessels, which suggests that these relaxations are mediated through endothelium-dependent mechanisms. After partial bypass, responses to protamine and histamine were slightly reduced compared with the respective responses of control vessels, whereas the relaxation to protamine-heparin complex was not significantly altered. After total bypass, relaxation responses to protamine and protamine-heparin complex were markedly reduced, whereas histamine induced contraction of pulmonary microvessels. Endothelium-independent relaxation to sodium nitroprusside was not affected by partial cardiopulmonary bypass and was slightly reduced after total bypass. A reduced direct vascular relaxation response to protamine and increased contractile response to histamine (or other humoral substances released during the systemic administration of protamine sulfate) may contribute to the elevation of pulmonary vascular resistance during infusion of protamine after cardiopulmonary bypass.

The purpose of the present study was to examine whether adrenoceptor-mediated responses of porcine coronary resistance arteries are affected by cardioplegic arrest under conditions of extracorporeal circulation (cardiopulmonary bypass; CPB). Pigs were placed on CPB. The hearts were arrested with a cold hyperkalemic crystalloid cardioplegic solution for 1 h, then were reperfused for 1 h. In vivo and in vitro beta-adrenoceptor-mediated responses were compared before CPB and 2 min and 1 h after initiation of reperfusion. In vitro responses were studied in a pressurized no-flow state with video microscopy. Isoproterenol (0.02 micrograms.kg-1.min-1, intracoronary) increased coronary blood flow by 100 +/- 32% (P < 0.001) before CPB and cardioplegic arrest, 17 +/- 7% 2 min postcardioplegia (P < 0.01), and 71 +/- 9 (P < 0.001) after 1 h of reperfusion. Relaxation of precontracted microvessels (90-180 micron) to isoproterenol, NaF, forskolin, and adenosine was reduced after cardioplegic arrest (all P < 0.001). After 1 h of postcardiolegia-reperfusion, relaxation responses to forskolin and adenosine were completely restored, whereas the responses to isoproterenol (P < 0.05) and NaF (P < 0.10) were only partially recovered. Cardioplegic arrest and postcardioplegia-reperfusion blunted the alpha 2-adrenoceptor-mediated endothelium-dependent relaxation to clonidine (P < 0.001) but did not affect the minimal (< 4%) contractile response to the alpha 1-adrenoceptor agonist phenylephrine or the relaxation to nitroprusside. These results show that hyperkalemic cardioplegia results in the generalized defect in the beta-adrenoceptor-GS protein-adenylate cyclase pathway, which is significantly restored after reperfusion.

Crystalloid cardioplegia may cause coronary microvascular endothelial dysfunction during cardiopulmonary bypass. The perioperative administration of either adenosine or AICA-riboside (acadesine, 5-aminoimidazole-4-carboxamide-1-ribofuranoside) has been associated with improved myocardial functional preservation and improved coronary blood flow after ischemic arrest. To examine if this enhanced recovery of myocardial function and perfusion may be related to improved endothelial preservation, pigs were placed on cardiopulmonary bypass and the hearts were arrested with plain cold, hyperkalemic (K+ = 25 mmol/L) crystalloid cardioplegia, or cardioplegic solution containing either 0.1 mmol/L adenosine or 50 mumol/L AICA-riboside, which causes the release of endogenous adenosine. AICA-riboside (375 mg) also was infused over 30 minutes before cardioplegia in the later group. After 1 hour of ischemic cardioplegia, hearts were reperfused for 1 hour while the pigs were weaned from cardiopulmonary bypass. Coronary arterioles (90 to 190 microns in diameter) from both subepicardial and subendocardial regions of the left ventricle were studied in vitro in a pressurized, no-flow state with videomicroscopy. After contraction of vessels by 25% to 40% of the baseline diameter, drugs were applied extraluminally. Relaxation of control arterioles to serotonin was slightly greater in vessels from the subendocardial region compared with vessels from the subepicardial region, and subendocardial arterioles were more affected by cardioplegia than were subepicardial vessels. In contrast, relaxations of control microvessels to bradykinin and the calcium ionophore A23187 were similar in the two transmural myocardial regions. Responses to bradykinin and A23187 were significantly and similarly reduced after ischemic arrest with plain crystalloid cardioplegia.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to examine the effects of Escherichia coli endotoxemia on coronary and pulmonary microvascular responses to serotonin (5-HT) and ADP, arterioles (80-190 micros diameter) were isolated from pigs 3 h after administration of E. coli endotoxin (150 micrograms/kg, intravenously over 1 h, n = 8) or Ringer's lactate (control, n = 8). Arterioles were studied in vitro in a pressurized, partially contracted, no-flow state with video-microscopy. Precontracted (30-50% of baseline diameter) control coronary arterioles dilated in responses to either 5-HT (24 +/- 2%) or ADP (89 +/- 2%). These relaxations were partially inhibited by indomethacin, but were markedly reduced with nitric oxide synthase inhibition. After 3 h of endotoxemia, 5-HT caused contraction of coronary arterioles which was inhibited with indomethacin. In the presence of indomethacin, coronary vessels from endotoxic pigs relaxed slightly, but significantly, more to 5-HT than did control vessels exposed to indomethacin. In contrast, the relaxation response to ADP was unchanged following endotoxemia. Precontracted (15-30% of baseline diameter) pulmonary arterioles dilated in response to 5-HT (13 +/- 1%) or ADP (67 +/- 3%). Following 3 h of endotoxemia, the pulmonary arteriolar relaxation induced by 5-HT was reduced, whereas the response to ADP was not altered. In both coronary and pulmonary arterioles, relaxation induced by the endothelium-independent vasodilator, sodium nitroprusside, was unaffected by endotoxemia. Thus, coronary and pulmonary microvascular relaxation response to ADP are minimally affected by 3 h of endotoxemia, but relaxation responses to 5-HT are significantly reduced or converted to contractile responses.

IMPLICATIONS We describe the anesthetic management of a parturient with compound heterozygous medium chain acyl-CoA dehydrogenase deficiency, the most common disorder of fatty acid metabolism.

UNLABELLED: Pregnancy is associated with altered vascular reactivity. However, the effect of pregnancy on the alpha- and beta-adrenergic responses in the uterine microcirculation remains to be determined. In late-pregnant (Day 20-21, n = 6) and virgin (n = 6) Sprague-Dawley rats, uterine radial arterioles (70-120 microm in internal diameter) were isolated. We studied in vitro arteriolar responses in a pressurized, no-flow state with videomicroscopy. alpha(2)-Adrenergic activation relaxed uterine arterioles; this relaxation was increased with pregnancy and was inhibited after endothelial denudation or inhibition of nitric oxide synthase. Pregnancy significantly increased the contractile response to the alpha(1)-adrenoceptor agonist phenylephrine but decreased the relaxation to the beta-adrenoceptor agonist isoproterenol. The contractile response to the protein kinase C activator phorbol ester and relaxation responses to both the adenylate cyclase activator forskolin and the endothelium-independent cyclic guanosine monophosphate-mediated vaso- dilator nitroprusside were preserved. These results suggest that pregnancy enhances the alpha(2)-adrenoceptor-mediated relaxation of uterine arterioles, probably because of an increase in the release of nitric oxide. The alpha(1)-adrenergic response is upregulated, whereas the beta-adrenergic response is impaired, in the uterine microcirculation of pregnant rats. IMPLICATIONS: Both alpha- and beta-adrenergic responses are important mechanisms for the regulation of uteroplacental perfusion. By use of an in vitromicrovascular technique, we have shown pregnancy-associated alteration in adrenergic responses in the uterine microcirculation of the rat.

Clotrimazole (CLT), used in the treatment of patients with sickle cell disease, directly blocks Ca2+-activated K+ (K+INF POS="STACK"Ca) channels in red cells and in portal vein smooth muscle cells by a cytochrome P450(cyt P450)-independent mechanism. Therefore, we examined the effects of CLT on vasomotor tone of coronary arterioles. Rat coronary arterioles (80-180 micro(m) in diameter) were studied in vitro in a pressurized no-flow state with a video microscopy. CLT (0.1 micromol/L) elicited in nonprecontracted vessels a small contraction (10% baseline diameter, P0.05 vs time control), consistent with blockade of a hyperpolarizing K+ channel. However, similar contraction was produced by the cyt P450 blocker 17-octadecynoic acid (17-ODYA, 100 micromol/L), suggesting possible involvement of arachidonate metabolites of cyt P450. In contrast, microvessels precontracted with the thromboxane A2 analog U46619 dilated in response to CLT [90% relaxation of the U46619-induced precontraction at 100 micromol/L (P0.01 vs time control)] and its structural analogs flutrimazole (FLT), UR-4055, UR4057, UR-4058, and UR-4059. This relaxation was cyt P450-independent, since the in vivo CLT metabolite (CLT-carbinol) was equipotent with CLT, and 17-ODYA did not promote relaxation. CLT-induced dilation was not inhibited by the nitric oxide synthase inhibitor NGnitro-l-arginine (100 micromol/L, P0.5) or affected by endothelial denudation (P0.5). Thus, CLT at concentrations1 micromol/L is a potent vasodilator of rat coronary arterioles. This dilation is likely mediated through a vascular smooth muscle mechanism independent of cyt P450 and is not modulated by nitric oxide or by the endothelium. This effect may arise from CLT's reported ability to inhibit voltage-gated Ca2+ channels or to inhibit, in some tissues, Ca2+ release from intracellular stores. The CLT- and FLT-induced relaxation may be a property common to this class of drugs and have clinical applicability.

Cardiopulmonary bypass (CPB) is associated with a generalized defect in the intrinsic control of vascular smooth muscle. To determine if myogenic reactivity of skeletal muscle arterioles was altered by CPB, sheep (n = 7) were placed on hypothermic CPB (27 degrees C) for 90 min and hearts were arrested by cold blood cardioplegia ([K+] = 25 mM) for 60 min. Arterioles (70-180 microns) were isolated from the gracilis muscle before (control) and 15 min after CPB. In vitro arteriolar responses were studied with video-microscopy. Myogenic reactivity was examined to stepwise increases in intraluminal pressure from 10 to 100 mm Hg. Mean arterial pressure was decreased from 80 +/- 15 prior to CPB to 55 +/- 4 mm Hg (P0.01) 15 min after CPB. Myogenic contraction was observed in control vessels and was markedly attenuated by the protein kinase C inhibitor staurosporine (P0.01). CPB decreased myogenic contraction and shifted the pressure-diameter relation upward, suggesting a decrease in the intrinsic tone (both P0.05 vs control). CPB reduced contractile responses to the alpha 1-adrenoceptor agonist phenylephrine from -43 +/- 7% to -23 +/- 5% (P0.01) and the protein kinase C activator 12-deoxyphorbol 13-isobutyrate 20-acetate (phorbol ester) from -64 +/- 6% to -38 +/- 16% (P0.01). CPB-associated decrease in myogenic reactivity of skeletal muscle arterioles is likely due to alterations in protein kinase C and/or downstream signal transduction. This may account in part for reduction in systemic vascular resistance and hypotension associated with CPB.

Background The purpose of the present study was to examine the effects of the cardiac vagal reflex on intestinal vascular capacitance and cardiac filling pressure during experimental acute myocardial infarction (AMI). Methods and Results AMI was induced in anesthetized dogs through injection of microspheres into the left main coronary artery. Intestinal blood volume was measured with blood-pool scintigraphy. Portal venous pressure was varied through graded inflation of a portal venous constrictor to determine the intestinal vascular pressure-volume relation. Induction of AMI decreased intestinal blood volume to 88±3% of the control value ( P P P P P P Conclusions These results suggest that the cardiac vagal reflex modulates the decrease in the intestinal vascular capacitance induced by AMI and modulates ventricular preload through pooling of blood in the intestinal circulation.

Background. The purpose of this study was to determine whether cerebral cortical microvascular responses to platelet-derived vasoactive substances are altered after normothermic cardiopulmonary bypass (CPB), and whether these alterations are modified by moderate hypothermia. Methods. Pigs were placed on normothermic CPB (37°C) for 2 hours and then perfused off CPB with normothermic blood for either 15 minutes (n = 8) or 60 minutes (n = 6). Another group was placed on moderately hypothermic CPB (25°C) for 2 hours and then perfused off CPB at 37°C for 15 minutes (n = 6). Alpha-stat pH management was used. In vitro responses of isolated cortical cerebral arterioles (90 to 170 μ m internal diameter) to platelet-derived vasoactive substances were examined in a pressurized no-flow state with video-microscopy. Microvessels from noninstrumented pigs (n = 14) were used as controls for in vitro studies. Results. Cerebrovascular resistance and internal carotid artery blood flow were similar 15 minutes after CPB in both normothermic and hypothermic groups. However, relaxations of microvessels to adenosine 5′ diphosphate or serotonin were reduced in vessels from both groups. One hour of after CPB cerebral perfusion did not change this pattern of altered vascular reactivity. Hypothermia caused a partial but significant reduction in impairment of responses to adenosine 5′ diphosphate and serotonin. Microvascular relaxation to the endothelium-independent agent sodium nitroprusside and contraction to a thromboxane A 2 analog were similar in all experimental groups, suggesting normal vascular smooth muscle responsiveness. Conclusions. This study demonstrates that normothermic extracorporeal circulation reduces endothelium-dependent relaxation responses to products of platelet activation in the cerebral microcirculation. Moderate hypothermia attenuates the CPB-induced impairment of endothelium-dependent relaxation, but has no effect on baseline cerebral blood flow after rewarming.

Background: Total cardiopulmonary bypass, in an ovine model, is associated with increased pulmonary thromboxane A 2 production, cellular sequestration of white cells and platelets, transient pulmonary hypertention, and increased lung lymph flow and lymph protein clearance when compared with respective findings with partial cardiopulmonary bypass. This study evaluates the effect of neutrophil adhesion blockade on lung injury after cardiopulmonary bypass. Methods: Two groups of anesthetized sheep were placed on total cardiopulmonary bypass without assisted ventilation. One group of seven sheep was treated before and during total cardiopulmonary bypass with the neutrophil adhesion blocker NPC 15669. A second group of seven sheep did not receive NPC 15669 treatment before total cardiopulmonary bypass. A third group of seven sheep was treated with NPC 15669 before initiation of partial cardiopulmonary bypass with continued assisted ventilation. Aortic occlusion and hypothermia were not used. After 90 minutes all sheep were separated from cardiopulmonary bypass, with resumption of assisted ventilation and pulmonary arterial flow. After 30 minutes the left atrial pressure was elevated mechanically. Hemodynamics, thromboxane A 2 levels, platelet levels, and white blood cell and plasma protein concentrations were measured before cardiopulmonary bypass and afterwards at four 15-minute intervals. Samples were taken from the right and left atria simultaneously. Lung lymph protein levels and flow were measured before and after cardiopulmonary bypass at two 30-minute intervals. Results: In the total cardiopulmonary bypass group not treated with NPC 15669 signs of lung injury developed after cardiopulmonary bypass. Animals treated with NPC 15669 did not manifest a similar degree of lung injury after either partial or total cardiopulmonary bypass. Increased pulmonary vascular resistance did not develop in treated sheep nor did sequestration of platelets or white blood cells occur. Despite the drug, increased pulmonary capillary permeability after total cardiopulmonary bypass persisted, but was reduced. Conclusions: Compared with unmodified total cardiopulmonary bypass, blockade of neutrophil adhesion with NPC 15669 reduces, but does not entirely eliminate, lung derangement after total cardiopulmonary bypass. (J THORAC CARDIOVASC SURG 1996;111:460-8)

Background Chronic angiotensin-converting enzyme (ACE) inhibition initiated days to weeks after acute myocardial infarction can reduce ventricular dilatation and improve patient survival. However, the effects on coronary vascular and myocardial function of very early ACE inhibitor therapy for acute myocardial infarction remain unresolved. Methods and Results Hemodynamics, segmental shortening, coronary blood flow, and in vitro coronary microvascular relaxation responses were studied in noninstrumented control pigs (n=8) and pigs subjected to 30 minutes of left anterior descending ischemia followed by administration of 30 mL IV normal saline (IR-saline, n=8), 5 mg/kg IV captopril (IR-captopril, n=6), or 1.5 mg/kg IV enalaprilat (IR-enalaprilat, n=6) before 1 hour of reperfusion. Hemodynamics were similar at baseline, end of ischemia, and end of reperfusion. However, coronary blood flow immediately on reperfusion was significantly enhanced in the IR-enalaprilat cohort (59±10 mL/min) compared with the IR-saline group (32±3 mL/min, P P P P P =.95). Endothelium-dependent venular responses to ADP and serotonin were maintained despite ischemia-reperfusion. Endothelium-independent responses to sodium nitroprusside were unaltered in arterioles and venules. Either captopril or enalaprilat restored ADP and A23187 arteriolar responses to control levels and increased bradykinin responses above control levels. Conclusions Brief ischemia followed by reperfusion induces arteriolar microvascular endothelial dysfunction, while venular endothelial function is preserved in this porcine model. ACE inhibition enhances coronary blood flow at the time of reperfusion and can prevent impairment of endothelium-dependent arteriolar responses. However, ACE inhibition does not enhance ventricular segmental shortening acutely despite improved microvascular endothelial function and augmented postischemic coronary blood flow in this model of ischemia-reperfusion.

Background The purpose of this study was to assess the effect of pericardial constraint on the activity of left ventricular (LV) mechanoreceptors with nonmyelinated vagal afferents. Methods and Results Single-unit activity of cervical vagal afferents (conduction velocity, 1.6±0.5 m/s) was recorded in six cats anesthetized with α-chloralose. Discharge frequency during diastole (DF diastole ) and systole (DF systole ) was determined after correction for conduction delay of the nerve action potential. When the pericardium was closed and LV end-diastolic pressure (LVEDP) was ≈5 mm Hg, DF diastole and DF systole were 1.3±1.0 and 0.3±0.1 impulses per second, respectively. Volume expansion increased LVEDP, LV transmural LVEDP, and segment length and was associated with a significant increase in DF diastole . At a given LVEDP, DF diastole was significantly greater in the absence of the pericardium than with the pericardium closed. Removal of the pericardium increased the slope of the relation between DF diastole and intracavitary LVEDP but did not alter the slope of the relations between DF diastole and transmural LVEDP and LV segment length. Conclusions These results suggest that, rather than the absolute value of intracavitary LVEDP, transmural LVEDP and distension appear to be more important determinants of diastolic LV mechanoreceptor activity and that pericardial constraint may attenuate mechanoreceptor activity by limiting cardiac distension.

The purpose of the present study was to examine the role of adenosine triphosphate-sensitive potassium channels in mediating the coronary hyperemic response after crystalloid cardioplegia. Thirteen pigs were placed on normothermic cardiopulmonary bypass support. Hearts were arrested with cold (4 degrees C) crystalloid ([K+] 25 mmol/L) cardioplegic solution for 60 minutes. In seven of these pigs, hearts were then reperfused for 60 minutes with warm blood, and the animal was separated from cardiopulmonary bypass. The in vivo responses to the intracoronary administration of the K+ adenosine triphosphate channel blocker glibenclamide (50 gm/kg per minute) or the K+ adenosine triphosphate channel opener pinacidil (2 gm/kg per minute) were evaluated before cardiopulmonary bypass (baseline) and after 2 minutes and 60 minutes of reperfusion in the cardioplegia-reperfusion group. Under baseline conditions, glibenclamide and pinacidil induced a respective decrease and increase in coronary blood flow and an increase and a decrease in coronary vascular resistance. Coronary responses to glibenclamide and pinacidil were markedly enhanced after 2 minutes or 60 minutes of postcardioplegia reperfusion. In vitro responses of coronary arterioles (90 to 180 microns) were examined in a pressurized, no-flow state with video microscopy. The contractile response of coronary arterioles to glibenclamide and the relaxation response to pinacidil were significantly enhanced 2 minutes or 60 minutes after reperfusion (all p0.05 versus control). The response to pinacidil was markedly inhibited by glibenclamide, which confirms these antagonistic effects on K+ adenosine triphosphate channels. Decreased tissue concentrations of adenosine triphosphate in the coronary arterial smooth muscle and myocardium were observed after cardioplegia and persisted for up to 60 minutes of reperfusion (both p0.05 versus control). These results suggest that coronary hyperemia associated with postischemic cardioplegia is mediated in part by activation of K+ adenosine triphosphate channels in the coronary microcirculation.

Background Vasodilator drugs have variable effects on veins and arteries. However, direct measurements of their effects on the splanchnic veins, perhaps the most important volume reservoir, have not been reported. We assessed the effect of acute heart failure and the subsequent administration of hydralazine, enalaprilat, and nitroglycerin on the splanchnic venous pressure–volume relation in intact dogs. Methods and Results Experimental acute ischemic heart failure was induced in 19 splenectomized dogs by microsphere embolization of the left main coronary artery. Embolization was repeated until left ventricular end-diastolic pressure (LVEDP) reached 20 mm Hg and cardiac output decreased by 50%. The splanchnic vascular pressure–volume relation was determined by radionuclide plethysmography during the control stage, after acute heart failure had been established, and after administration of a vasodilator (hydralazine, enalaprilat, or nitroglycerin) at a dose sufficient to reduce mean aortic pressure by approximately 20%. Induction of acute heart failure was associated with a decrease in the splanchnic vascular volume from 100% to 86±2% and an increase in LVEDP from 6±1 to 21±1 mm Hg ( P P =NS, P P P =NS, P P Conclusions Acute heart failure was associated with a parallel leftward shift of the splanchnic venous pressure–volume relation (venoconstriction). Splanchnic (systemic) venoconstriction may in part explain the increased LVEDP during acute heart failure by displacement of blood to the central compartment. Subsequently administered enalaprilat and, to a greater degree, nitroglycerin produced splanchnic venodilation, thereby lowering LVEDP. Hydralazine had no significant effect on the splanchnic veins and only a modest effect on LVEDP. In this model, splanchnic capacitance changes appear to modulate change in left ventricular preload.

Cardiopulmonary bypass (CPB) and cardioplegia are associated with systemic hypotension and altered vascular responses. Myogenic properties and intrinsic tone of vascular smooth muscle are important mechanisms in the regulation of coronary blood flow and systemic vascular resistance. To examine if CPB and cardioplegic arrest alter myogenic reactivity and the intrinsic tone in the coronary microcirculation, pigs were placed on CPB. Selected hearts (n = 6) were arrested with a cold, hyperkalemic ([K+] = 25 mM) crystalloid cardioplegic solution for 1 hour. In another group (n = 6), hearts were arrested and then reperfused with warm blood for 1 hour, or pigs were placed on CPB without cardioplegia (n = 6). Coronary arterioles were studied in a pressurized, no-flow state with video-microscopy. Myogenic reactivity was examined to stepwise increases in intraluminal pressure from 10 to 100 mmHg. The vessel diameter was normalized to the diameter at 50 mmHg after application of papaverine (10-4 M). In vessels from non-instrumented control hearts (n = 6) and vessels in the CPB group, myogenic contraction was observed with pressures g40 mmHg. However, CPB significantly shifted the pressure-diameter relation upward (p l 005 vs control). suggesting a decrease in the intrinsic tone. Cardioplegic arrest, with or without reperfusion, decreased myogenic reactivity with an upward displacement of the pressure-diameter relation (both p l 0.05 vs control). Myogenic reactivity of the control vessel was not altered after mechanical denudation of the endothelium, or following pretreatment with NG-nitro-L-arginine or indomethacin. However, blockade of the ATP-sensitive potassium channel by glybenclamide significantly attenuated the cardioplegia-induced decrease in myogenic reactivity (p l 0.05). These results suggest that coronary microvascular myogenic reactivity and the intrinsic tone are reduced following hyperkalemic cardioplegia, and that CPB alone preserves myogenic reactivity but reduces the intrinsic tone of the vascular smooth muscle. Download : Download high-res image (71KB) Download : Download full-size image

The effect of chronic, periadventitial administration of basic (b) fibroblast growth factor (FGF) on endothelial dysfunction in the collateral-dependent and normally perfused coronary microcirculation was examined. Ameroid constrictors were placed on the proximal left circumflex coronary artery (LCX) in 23 pigs. In 11 pigs, bFGF was released from calcium alginate microcapsules into the perivascular space of the proximal left anterior descending coronary artery (LAD) and LCX. After 5-8 wk, coronary arterial microvessels (80-170 microns) were studied in a pressurized (40 mmHg) no-flow state with video microscopy. Receptor-mediated endothelium-dependent relaxations to ADP and serotonin were reduced while contraction to acetylcholine was enhanced in the collateral-dependent LCX microvessels of non-bFGF-treated control hearts. Relaxation of vessels to the non-receptor-mediated, endothelium-dependent agent A-23187; endothelium-independent relaxation to nitroprusside; and contraction to KCl were similar in all groups. Chronic treatment with bFGF normalized responses to ADP, serotonin, and acetylcholine in the collateral-dependent LCX region but had no effect on the responses of vessels in the normally perfused LAD region. Arteriolar density in the collateral-perfused LCX region of bFGF-treated hearts was markedly increased (4-fold compared with that in untreated hearts, suggesting a link between the angiogenic effect of bFGF and its action on endothelial preservation. Thus the periadventitial, sustained delivery of bFGF preserves receptor-mediated, endothelium-dependent responses in the collateral-dependent LCX region but has no effect on responses of microvessels in the normally perfused LAD region or on non-receptor-mediated endothelium-dependent relaxation.

To examine the effect of crystalloid cardioplegia on the different β-adrenoceptor subtypes in the coronary microcirculation, we compared microvascular responses before and after cardioplegic arrest. Pigs were placed on cardiopulmonary bypass and hearts were arrested with cold hyperkalemic crystalloid solution. After 1 hour, hearts were reperfused for 1 hour. In vitro coronary arteriolar responses to isoproterenol and the adenylate cyclase activator forskolin were studied in a pressurized, no-flow state with a video-microscopy. After contraction of vessels by 25% to 50% of the baseline diameter, drugs were applied extraluminally. Isoproterenol-induced relaxation of vessels in the presence of ICI-118,551 (s2-blocker) was significantly less than that of vessels in the presence of atenolol (s1-blocker). Thus, coronary microvascular relaxation to isoproterenol is primarily due to s2-adrenoceptor stimulation. Crystalloid cardioplegia reduced relaxations to s1- or s2-stimulation and to forskolin. Following reperfusion, the relaxation responses to forskolin and s1- or s2-adrenergic stimulation were completely restored. Cardioplegic arrest and reperfusion blunted endothelium-dependent relaxation to adenosine 5′-diphosphate, whereas endothelium-independent relaxation to sodium nitroprusside was not affected. Therefore, the present study demonstrates that crystalloid cardioplegia reduces the s1- and s2-adrenoceptor-mediated and cyclic AMP-dependent relaxation in the coronary microcirculation. The cardioplegia-induced alteration in the coronary microvascular s-adrenergic mechanism may be responsible for episodic coronary spasm and altered myocardial perfusion following cardiac surgery.