Significant Vasodilator Effect Research Articles

Assessment of Renal Hemodynamic Effects of Nesiritide in Patients With Heart Failure Using Intravascular Doppler and Quantitative Angiography

We evaluated the magnitude and site of action of the nesiritide mediated renal vasodilatory effect in patients with heart failure (HF). Nesiritide, a recombinant human B-type natriuretic peptide is approved for the treatment of acute decompensated HF and has been shown to exert favorable hemodynamic, neurohormonal, and symptomatic effects. The renal effect of nesiritide in HF patients has not been well defined. In 15 patients with acute decompensated HF, intravascular Doppler and quantitative angiography of the renal artery were used to assess the effect of nesiritide on renal artery diameter and velocity time integral as well as renal blood flow and vascular resistance. Nesiritide was administered intravenously at a standard dose of 2 microg/kg bolus followed by a continuous infusion at a rate of 0.01 microg/kg/min. Assessment of nesiritide effect was made at 15 min. Nesiritide infusion was associated with a significant central hemodynamic effect including a fall in mean pulmonary artery pressure (36 +/- 12 mm Hg to 31 +/- 13 mm Hg, p < 0.001), mean pulmonary capillary wedge pressure (21 +/- 2 mm Hg to 15 +/- 10 mm Hg, p < 0.001), and systemic vascular resistance (1,995 +/- 532 dynes s cm(-5) to 1,563 +/- 504 dynes s cm(-5), r < 0.001), and an increase in cardiac output from 3.9 +/- 1.2 l/min to 4.6 +/- 1.6 l/min (p = 0.001). Nesiritide was also associated with a significant vasodilatory effect on the large conductance renal arteries resulting in an increase in renal artery diameter from 6.2 +/- 0.7 mm to 6.7 +/- 0.8 mm (p < 0.001). At the same time, there was a concomitant fall in mean renal artery pressure (99 +/- 17 mm Hg to 89 +/- 13 mm Hg, p = 0.002) and renal blood flow velocity time integral (27 +/- 15 cm/beat to 23 +/- 15 cm/beat, p = 0.008) and, therefore, no significant change in renal blood flow or renal vascular resistance. The nesiritide effect on the renal circulation in patients with HF is complex, with a marked vasodilatory action on the large, conductance renal arteries but a concomitant fall in velocity time integral and no effect on renal vascular resistance or renal blood flow. Lack of increase in renal blood flow may be due to a fall in renal blood pressure or an intrarenal vasoconstrictive effect.

Exercise Training-Associated Changes in Arterial Stiffness and Endothelium-Derived Vasoactive Factors

Age- and lifestyle-related arterial stiffening is a well-established independent cardiovascular risk factor. Previous studies have investigated the effects of exercise training on arterial stiffness. Aerobic exercise training reduces arterial stiffness. On the other hand, muscle-strengthening exercise, such as weight training, may stiffen central elastic arteries. However, the mechanism underlying exercise training-associated changes in arterial stiffness has not been fully elucidated. Adaptations of arteries to exercise training may, at least partly, be regulated by local factors. We have focused on endothelium-derived vasoactive factors, such as nitric oxide (NO) and endothelin (ET)-1, because the endothelium regulates vascular tone. NO has a significant vasodilatory effect, and ET-1 is a potent vasoconstrictor. Both factors have been reported to be affected by exercise training. This article reviews literature investigating the effects of exercise training on arterial stiffness and the role of endothelium-derived factors. We discuss here the role of endothelial function in exercise training-induced changes in arterial stiffness.

Effects of big endothelin-1 in comparison with endothelin-1 on the microvascular blood flow velocity and diameter of rat mesentery in vivo

Synthetic big endothelin-1 (ET-1), a 39-residue precursor of ET-1, has been reported to elicit potent contractile action on helical strip specimens obtained from the porcine coronary artery, but its molar potency was found to be 140-fold lower than that of ET-1 [Saito, Y., Nakao, K., Mukoyama, M., Imura, H., 1990. Increased plasma endothelin level in patients with essential hypertension. N. Engl. J. Med. 322, 205]. It has been hypothesized that the increased rate of production and/or release of ET-1 from the vascular endothelium may contribute to the pathogenesis of hypertension. However, the effects of big ET-1 in comparison with ET-1 on the macrocirculation and microcirculation of the rat mesentery have not been well documented. Thus, our main purpose for this study was to examine the effects of both big ET-1 and ET-1 to clarify the role of phosphoramidon in inhibiting the conversion of big ET-1 to ET-1, by investigating the systemic blood pressure, microvascular blood flow velocity, and diameters of arterioles and venules of the rat mesentery. For this purpose, two groups of experiments were performed. In these experiments, the mesentery was arranged for in situ intravital microscopic observation under transillumination. In the first group of experiments, intravenous cumulative injections of big ET-1 or ET-1 were infused through a catheter inserted into the right jugular vein. Infusion of big ET-1 (1–8 nmol/kg) elicited a long-lasting significant pressor effect. Infusion of big ET-1 (1–2 nmol/kg) elicited a significant dose-dependent increase in the microvascular blood flow velocity both in arterioles (20–30 μm) and venules (30–40 μm). Microvascular diameters exhibited a slight but significant vasodilator effect. However, the infusion of big ET-1 (4–8 nmol/kg) elicited a dose-dependent significant decrease in the blood flow velocities, and diameters returned to control measurements. The administration of ET-1 (0.25–2 nmol/kg) induced a dose-dependent significant decrease in the blood flow velocity of arterioles and venules, and their diameters exhibited a vasoconstrictive effect more prominent in arterioles than in venules. In the second group of experiments, cumulative injections of phosphoramidon (30 mg/kg/10 min) were administered 10 min prior to the infusion of big ET-1. Phosphoramidon significantly suppressed the long-lasting significant pressor effect and significantly inhibited the dose-dependent increase and dose-dependent decrease in the microvascular blood flow velocity produced by big ET-1 in the rat mesenteric microcirculation. This study observed differences in the effects big ET-1 and ET-1 have on the rat mesenteric microcirculation and proposes a possible mechanism explaining these differences. Moreover, phosphoramidon markedly inhibited the conversion of big ET-1 to ET-1 in the rat mesenteric microcirculation, which may suggest an inhibition of the enzyme which converts big ET-1 to ET-1.

Structural Analysis of Protein Kinase A Mutants with Rho-kinase Inhibitor Specificity

Controlling aberrant kinase-mediated cellular signaling is a major strategy in cancer therapy; successful protein kinase inhibitors such as Tarceva and Gleevec verify this approach. Specificity of inhibitors for the targeted kinase(s), however, is a crucial factor for therapeutic success. Based on homology modeling, we previously identified four amino acids in the active site of Rho-kinase that likely determine inhibitor specificities observed for Rho-kinase relative to protein kinase A (PKA) (in PKA numbering: T183A, L49I, V123M, and E127D), and a fifth (Q181K) that played a surprising role in PKA-PKB hybrid proteins. We have systematically mutated these residues in PKA to their counterparts in Rho-kinase, individually and in combination. Using four Rho-kinase-specific, one PKA-specific, and one pan-kinase-specific inhibitor, we measured the inhibitor-binding properties of the mutated proteins and identify the roles of individual residues as specificity determinants. Two combined mutant proteins, containing the combination of mutations T183A and L49I, closely mimic Rho-kinase. Kinetic results corroborate the hypothesis that side-chain identities form the major determinants of selectivity. An unexpected result of the analysis is the consistent contribution of the individual mutations by simple factors. Crystal structures of the surrogate kinase inhibitor complexes provide a detailed basis for an understanding of these selectivity determinant residues. The ability to obtain kinetic and structural data from these PKA mutants, combined with their Rho-kinase-like selectivity profiles, make them valuable for use as surrogate kinases for structure-based inhibitor design.

Ursolic acid mediates the vasorelaxant activity of Lepechinia caulescens via NO release in isolated rat thoracic aorta

We have determined that the methanolic extract of L. caulescens (MELc) produced a significant vasodilator effect in a concentration-dependent and endothelium-dependent manner. This relaxation was blocked by N ω-nitro- l-arginine methylester ( l-NAME), indicating that MELc vasodilator properties are endothelium mediated due to liberation of nitric oxide (NO). In this paper we aimed to corroborate its mode of action. MELc effects on noradrenaline (NA)-induced contraction in isolated rat aortic thoracic rings with endothelium (+ E), in the presence of atropine (0.1 μM) and 1- H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (ODQ, 1 μM) were conducted. MELc relaxation curve was significantly shifted to the right in the presence of ODQ and atropine, thus confirming that its mode of action is related with activation of nitric oxide synthase (NOS) and the consequent increment in NO formation. Bio-guided study of MELc allowed the isolation of ursolic acid (UA, 50 mg) and ursolic–oleanolic acids mixture [UA/OA (7:3), 450 mg]. The relaxant effect of UA (0.038–110 μM) was evaluated in functional experiments. UA induced a significant relaxation in a concentration- and endothelium-dependent manner (IC 50 = 44.15 μM) and did not produce a vasorelaxant effect on contraction evoked by KCl (80 mM). In addition, NA-induced contraction was significantly displaced to the right by UA (30 μM). In order to determine its mode of action, UA-induced relaxant effect was evaluated in the presence of atropine (0.1 μM), indomethacin (10 μM), l-NAME (100 μM) and ODQ (1 μM). Relaxation was blocked by l-NAME and ODQ. On the other hand, UA (3 μM) provoked a significant displacement to the left in the relaxation curve induced by sodium nitroprusside (SNP, 0.32 nM to 0.1 μM), but it was not significant in the presence of Carbamoyl choline (carbachol, 1 nM to 10 μM). These results indicate that UA-mediated relaxation is endothelium dependent, probably due to NO release, and the consequent activation of vascular smooth muscle soluble guanylate cyclase (sGC), a signal transduction enzyme that forms the second messenger cGMP.

Vasorelaxant Effect of Mexican Medicinal Plants on Isolated Rat Aorta

The vasorelaxant effect of methanol extracts (0.86–50 µg/ml) of Iresine calea, Psyttacanthus calyculathus. (DC.) G. Don, Laelia autumnalis. (Lex.) Lindley, Brickellia cavanillesii. (Cass.) Gray, and Lepechinia caulescens. (Ortega) Epling, plant species used in Mexican folk medicine for the treatment of hypertension and related diseases, were evaluated in isolated rat aortic rings. The extracts of I. calea. and P. calyculathus. did not show a vasorelaxant activity on norepinephrine-evoked contraction (NE, 1 × 10−7.5 M) in endothelium-intact (+ E) and endothelium-denuded (− E) rat aorta rings. On the other hand, L. autumnalis. and B. cavanillesii. induced a concentration-dependent and endothelium-independent relaxation on rat aorta. However, the methanol extract of L. caulescens. produced a significant vasodilator effect in a concentration-dependent and endothelium-dependent manner. In order to determine the mode of the vasorelaxant action evoked by L. caulescens., the extract was evaluated in the presence of L-NAME (inhibitor of nitric oxide synthase at 1 × 10−4 M) and indomethacin (inhibitor of cyclooxygenases at 1 × 10−5 M). Relaxation was blocked by L-NAME, indicating the extract vasodilating properties are endothelium mediated due to liberation of nitric oxide.

Sodium nitroprusside decreases leukocyte adhesion and emigration after hemorrhagic shock.

The adhesion of polymorphonuclear leukocytes to the capillary endothelium is one of the key events in the pathophysiology of hemorrhagic shock. We studied sodium nitroprusside (SNP) for its ability to modulate leukocyte-endothelial cell interactions induced by hemorrhagic shock and reinfusion of blood by using intravital microscopy of the rat mesentery. Administration of SNP at a dose of 0.1 microg x kg(-1) x min(-1) infusion neither significantly decreased mean arterial blood pressure nor significantly altered bleedout volumes in hemorrhagic rats, indicating that SNP at this dose did not modify the severity of the shock protocol. Resuscitation from 1 h of hemorrhagic shock (mean arterial blood pressure approximately 45 mm Hg) significantly increased the number of adherent and emigrated leukocytes in the rat mesenteric microcirculation. However, infusion of SNP, started 15 min before hemorrhage, and continued over the entire experimental period, markedly reduced the leukocyte adhesion after reinfusion and emigration during hemorrhagic shock and after reinfusion. We concluded that the nitric oxide donor SNP is effective at reducing the leukocyte-endothelial interaction after blood reinfusion after hemorrhagic shock in rats. The i.v. infusion of 0.1 microg x kg(-1) x min(-1) of sodium nitroprusside, a dose that does not exert a significant vasodilator effect, reduces leukocyte adhesion and emigration after hemorrhagic shock.

The effects of endothelin-1 on ischaemia-induced ventricular arrhythmias in rat isolated hearts

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1–10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K +) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K + (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21–30-min post-occlusion period. Furthermore, in hearts perfused with low K + solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.

Nitric oxide synthase inhibition attenuates vasoactive response to spinal cord stimulation in an experimental cerebral vasospasm model.

The basic mechanism of delayed cerebral vasospasm following subarachnoid haemorrhage (SAH) has been intensively investigated. It is thought that nitric oxide (NO) is a basic mediator of the cerebral vasodilator mechanism. Previous clinical and experimental studies have shown a cerebral vasodilator effect of high cervical spinal cord stimulation (SCS) however, the mechanism of this effect is still controversial. We investigated the contribution of the vasodilator effect of NO to this mechanism in an experimental SAH model using rabbits. Four experimental groups, were designated: Group 1. Cerebral blood flow (CBF) was evaluated by transcranial Doppler ultrasonography (TDU) in 8 rabbits. Group 2. In 4 animals, intracisternal saline injection and cervical epidural electrode placement without SCS were performed before TDU. Group 3. TDU was performed before and after SCS on the fourth day of SAH in 8 rabbits. Group 4. In 8 animals, N-Nitro-L-Arginine Methyl Esther (L-NAME) was administered intracisternally on the fourth day of SAH, at a dose of 0.6 mg/kg, 45 minutes before SCS. CBF parameters, obtained via measurements or calculations from TDU data, were compared. The occurrence of vasospasm after SAH was demonstrated with significant changes in TDU parameters (high peak systolic velocity and positive values of the degree of stenosis). In all SAH animals, SCS resulted in significant vasodilation. Even after the injection of L-NAME, SCS still had a significant vasodilatory effect in SAH animals, but there was also a significant difference in CBF parameters in the SCS-only group when compared with the L-NAME treatment before SCS group. The mechanism of the cerebral vasodilatory effect of SCS remains controversial. Our results revealed the contribution of a neurohumoral effect which can be partially prevented by use of an NO synthase inhibitor.

S-Nitroso-N-acetylpenicillamine (SNAP) during hemorrhagic shock improves mortality as a result of recovery from vascular hyporeactivity.

Nitric oxide donors are protective against hemorrhagic shock (HS). However, no detailed investigation has been performed. We investigated this mechanism using S-nitroso-N-acetylpenicillamine (SNAP). HS (mean arterial pressure: 40 mm Hg) was induced in 20 dogs. Sixty min after HS, the animals were treated with saline (Cont-Gr: n = 7) or SNAP; 5 microg. kg(-1). 10 min(-1) followed by 5 microg. kg(-1). h(-1) (SNAP-Gr: n = 7). After another 60 min, the shed blood was reinfused. Reactivities to noradrenalin (NA), changes in hemodynamics, the plasma catecholamines, and nitric oxide derivatives were determined. In Cont-Gr, 3 dogs died at 90, 98, and 102 min after HS. In Cont-Gr, % changes of systolic arterial blood pressure to 1 and 2.5 microg/kg of NA after the recovery from HS decreased from 23.7% +/- 4.1% (before HS) to 6.5% +/- 0.6% and from 50.1% +/- 7.7% (before HS) to 14.5% +/- 2.6%, respectively (P < 0. 01). In SNAP-Gr, reactivity to NA was maintained. At 120 min after HS, mean arterial pressure and cardiac output in SNAP-Gr increased but not in Cont-Gr. Plasma catecholamine levels in SNAP-Gr were suppressed compared with those of Cont-Gr. In conclusion, a small dose of SNAP during HS decreased the mortality of the dogs. This might have been caused in part by residual vascular hyporeactivity. The administration of a small dose of S-nitroso-N-acetylpenicillamine (a nitric oxide donor), a dose which did not exert a significant vasodilator effect, was administered during hemorrhagic shock in dogs. S-nitroso-N-acetylpenicillamine improved the vascular hyporeactivity to noradrenaline and decreased the mortality rate.

S-nitroso-N-acetylpenicillamine (SNAP) During Hemorrhagic Shock Improves Mortality as a Result of Recovery From Vascular Hyporeactivity

Nitric oxide donors are protective against hemorrhagic shock (HS). However, no detailed investigation has been performed. We investigated this mechanism using S-nitroso-N-acetylpenicillamine (SNAP). HS (mean arterial pressure: 40 mm Hg) was induced in 20 dogs. Sixty min after HS, the animals were treated with saline (Cont-Gr:n = 7) or SNAP; 5 μg · kg−1 · 10 min−1 fol- lowed by 5 μg · kg−1 · h−1 (SNAP-Gr:n = 7). After another 60 min, the shed blood was reinfused. Reactivities to noradrenalin (NA), changes in hemodynamics, the plasma catecholamines, and nitric oxide derivatives were determined. In Cont-Gr, 3 dogs died at 90, 98, and 102 min after HS. In Cont-Gr, % changes of systolic arterial blood pressure to 1 and 2.5 μg/kg of NA after the recovery from HS decreased from 23.7% ± 4.1% (before HS) to 6.5% ± 0.6% and from 50.1% ± 7.7% (before HS) to 14.5% ± 2.6%, respectively (P < 0.01). In SNAP-Gr, reactivity to NA was maintained. At 120 min after HS, mean arterial pressure and cardiac output in SNAP-Gr increased but not in Cont-Gr. Plasma catecholamine levels in SNAP-Gr were suppressed compared with those of Cont-Gr. In conclusion, a small dose of SNAP during HS decreased the mortality of the dogs. This might have been caused in part by residual vascular hyporeactivity. Implications The administration of a small dose of S-nitroso-N-acetylpenicillamine (a nitric oxide donor), a dose which did not exert a significant vasodilator effect, was administered during hemorrhagic shock in dogs. S-nitroso-N-acetylpenicillamine improved the vascular hyporeactivity to noradrenaline and decreased the mortality rate.

Reactivity of Small Intramyocardial Arteries from Atherosclerotic and Non-Atherosclerotic Human Hearts

Little is known about how the vascular reactivity of the coronary microcirculation is affected by upstream atherosclerotic disease. We have examined, with a wire myograph, the responses of intramyocardial arteries from hearts in which the epicardial vessels were either free of atherosclerotic lesions (non-diseased group) or were affected by atherosclerosis (diseased group). Vasodilator responses of preconstricted vessels to substance P (84.1 ± 12.6 compared to 42.0 ± 19.7%) were less in vessels from the diseased group (p < 0.05). In contrast, the relaxation to bradykinin (70.2 ± 21.2 compared to 100.6 ± 7.9%) was increased in vessels from the diseased group (p < 0.05). The dilator responses to acetylcholine, adenosine diphosphate, histamine and sodium nitroprusside showed no significant differences between arteries from each group. 5-Hydroxytryptamine was without any significant vasodilator effect in arteries from either group. Assessment of contractile function revealed that the responses to 5-hydroxytryptamine, acetylcholine, U46619, endothelin-1 and L-N^G-monomethylarginine in each group were not significantly different. Histamine, noradrenaline and dopamine were without any significant contractile response. These results demonstrate that upstream atherosclerosis does not confer any global impairment of endothelium-dependent vasorelaxant responses or smooth muscle hyperreactivity to vasoconstrictors in the arteries that penetrate the myocardium.

Effect of calcitonin gene-related peptide on delayed cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits

Calcitonin gene-related peptide (CGRP) is an intrinsic vasodilatory substance contained in perivascular nerve fibers of intracranial arteries. It is suggested that CGRP plays a role in cerebral vasospasm after subarachnoid hemorrhage (SAH). An experimental SAH was produced by intracisternal injection of arterial blood in rabbits. The animals were treated with intrathecal administration of CGRP solution 3 days after SAH. The degree of vasospasm and the effect of CGRP were evaluated angiographically by measuring the basilar artery diameter. The basilar artery constricted to 73.0% of the pre-SAH values 3 days after SAH. Fifteen minutes after injection of 10(-10) mol/kg CGRP, the basilar artery dilated to 117.1% (n = 8), which was significantly larger than 67.1% in the vehicle group (n = 8) (p < 0.01). The significant vasodilatory effect of CGRP, compared with the vehicle group, lasted for 6 hours. Intrathecal administration of CGRP has therapeutic potential for treating cerebral vasospasm.

Renal vasodilatory effect of endothelial stimulation in patients with chronic congestive heart failure

Objectives. This study sought to examine the vasodilatory response of the renal circulation to endothelial stimulation in patients with chronic heart failure.Background. Renal blood flow is often reduced in patients with chronic congestive heart failure and may lead to deterioration of renal function. Stimulation of renal endothelium has been shown to cause renal vasodilation in animals and in isolated human renal artery. The vasoregulatory role of the renal endothelium in patients with heart failure has not been evaluated.Methods. Renal vasodilatory effect of endothelial stimulation with acetylcholine was assessed and compared with that of endothelial-independent vasodilation with nitroglycerin. Both drugs were infused into the main renal artery. Renal artery cross-sectional area was measured with intravascular ultrasound and renal blood flow velocity with the aid of an intravascular Doppler technique.Results. Both drugs caused a significant and comparable increase in renal artery cross-sectional area (maximal increase [mean ± SE] 14 ± 5% with acetylcholine, 15 ± 5% with nitroglycerin; both changes <0.05 vs. baseline). Acetylcholine also caused a significant reduction in renal vascular resistance (maximal reduction 55 ± 6%) and increase in renal blood flow (maximal increase 136 ± 54%). In contrast, nitroglycerin administration showed no significant effect on renal vascular resistance and blood flow.Conclusions. Stimulation of endothelium-derived nitric oxide with acetylcholine results in a significant vasodilatory effect on both conductance and resistance renal blood vessels and leads to a marked reduction in renal vascular resistance and enhancement of renal blood flow. Nitroglycerin, an exogenous nitric oxide donor, caused a selective vasodilatory effect on renal conductance but not on resistance blood vessels and failed to increase renal blood flow. These data suggest the possibility that stimulation of endogenous nitric oxide production in the kidney could be used as a therapeutic target for enhancement of renal flow in patients with heart failure.

Effects of inhaled prostacyclin as compared with inhaled nitric oxide in a canine model of pulmonary microembolism and oleic acid edema

Recently, it has been shown that the inhalation of nitric oxide (NO) and of prostacyclin (PGI2) elicits selective pulmonary vasodilation in a canine model of pulmonary hypertension induced by hypoxic pulmonary vasoconstriction. The present study was designed to investigate whether inhaled NO or PGI2-aerosol, respectively, is also effective in decreasing pulmonary artery pressure in a canine model of acute pulmonary microembolism and oleic acid edema. Prospective, randomized, cross-over design. University animal research laboratory. Eight anesthetized, mechanically ventilated dogs (28 +/- 1 kg). Acute pulmonary microembolization (PME) was induced using glass microbeads (mean diameter: 100 microns) and 0.01 mL/kg of oleic acid. Subsequently, inhaled PGI2 (concentration: 10 micrograms/mL) or NO (50 ppm), respectively, was randomly administered for 15 minutes each and then withdrawn. Central hemodynamics (heart rate [HR], cardiac output [CO], stroke volume [SV], mean arterial pressure [MAP], systemic vascular resistance [SVR], mean pulmonary artery pressure [PAP], pulmonary vascular resistance [PVR]) and gas exchange (PaO2/FIO2 ratio, intrapulmonary shunt [Qs/Qt], alveolar-arterial oxygen difference, [AaDO2]) were assessed. Measurements were performed at control, after PME, and during administration of PGI2 and NO, respectively. PME induced a significant increase (p < 0.001) of MAP (+9%), PAP (+68%), and PVR (+163%), whereas HR, CO, and SV remained unchanged and lung function deteriorated. Inhalation of NO slightly decreased PAP (-10%; p < 0.05) and PVR (-26%; p < 0.01) and improved AaDO2 and PaO2/FIO2. In contrast, inhalation of PGI2 had no consistent effect on pulmonary vascular tone or gas exchange. The data demonstrate that inhaled NO may elicit selective pulmonary vasodilation and improve gas exchange in a canine model of pulmonary microembolism and respiratory insufficiency. However, the degree of these effects was relatively small. The aerosolization of PGI2 under conditions of positive-pressure ventilation did not exert a significant vasodilatory effect on pulmonary vessels and did not improve pulmonary gas exchange in this model.

Vasodilatory actions of calcitonin gene-related peptide and nitric oxide in parenchymal microvessels of the rat hippocampus

Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent dilators in a variety of vascular beds. Recent evidence suggests that NO may serve as an intermediary messenger for CGRP and/or CGRP may serve as an intermediary messenger for NO in the expression of vasodilation. The present study was designed to provide an initial characterization of the responses to NO and CGRP in parenchymal microvessels and to determine whether NO and/or CGRP act as intermediaries for one another. Microvessels in the parenchyma of in vitro hippocampal slices from rat brain were examined using computer-assisted videomicroscopy. The resting diameter of the microvessels ranged from 9 to 26 μm. Treatment with the nitric oxide synthase inhibitor, N G-nitro-l-arginine ( l-NNA; 100 μM) constricted vessels to 64.2% ± 3.0% of resting luminal diameter. Sodium nitroprusside (SNP; 1 μM), a donor of NO, reversed the l-NNA-induced vasoconstriction by 77.0% ± 15.0%. CGRP alone (10 nM) elicited a small but significant vasodilatory effect on resting vascular tone (2.3% ± 0.6%). In the presence of l-NNA, CGRP elicited a significant dose-dependent vasodilatory response, and 10 nM CGRP elicited a sizeable response, reversing the l-NNA-induced constriction by 84.3% ± 15.5%. This CGRP-induced dilation was inhibited by pretreatment with the CGRP receptor antagonist, CGRP fragment (8–37) (1 μM). In contrast, pretreatment with 1 μM CGRP fragment (8–37) did not attenuate the SNP-induced dilation in the presence of l-NNA. Taken together, these findings demonstrate that CGRP and NO are potent dilators of parenchymal microvessels, and that NO provides a substantial relaxant effect on resting tone. In addition, the results indicate that CGRP is not a necessary intermediary in NO-induced dilation, and that NO is not a necessary intermediary in CGRP-induced dilation in parenchymal microvessels.

Insulin resistance vs. hyperinsulinemia in hypertension: insulin regulation of Ca2+ transport and Ca(2+)-regulation of insulin sensitivity.

Hypertension in obesity and insulin resistance has been attributed to insulin stimulation of sympathetic neural output and renal sodium retention. However, recent data demonstrates a significant vasodilatory effect of insulin and suggests that vascular smooth muscle resistance to this action may instead be the cause of hypertension in insulin resistance. This concept is supported by the observation that pharmacological amplification of peripheral insulin sensitivity results in reduced arterial pressure. Insulin attenuates vasoconstrictor responses to pressor agonists and accelerates vascular smooth muscle relaxation, while these effects are blunted in obesity and insulin resistance. Insulin regulation of vasoconstriction and vascular relaxation appears to be secondary to regulation of intracellular Ca2+ ([Ca2+]i), as insulin attenuates both voltage- and receptor-mediated Ca2+ influx and stimulates both the transcription and activity of Ca(2+)-ATPase in vascular smooth muscle cells. Further, these effects are also blunted in insulin resistance. Although [Ca2+]i plays a poorly understood role in insulin signalling, increases beyond an optimal range results in impaired insulin sensitivity, possibly by Ca(2+)-inhibition of insulin-induced dephosphorylation of insulin-sensitive substrates. Consistent with this concept, ectopic overexpression of the agouti gene in the viable yellow (Avy) mouse results in increased skeletal myocyte [Ca2+]i. Accordingly, increased [Ca2+]i in primary insulin target tissues appears to result in peripheral insulin resistance which then results in aberrant regulation of vascular smooth muscle [Ca2+]i and increases in arterial pressure.

Contribution of potassium to exercise-induced vasodilation in humans.

It has been postulated that skeletal muscle release of potassium contributes to exercise-induced vasodilation of skeletal muscle arterioles. To determine whether potassium produces muscle arteriolar vasodilation in humans, we measured plethysmographic forearm blood flow and brachial venous potassium concentrations during brachial arterial infusion of potassium (0.6, 3, 6, 15, and 30 mueq.min-1.100 ml forearm volume-1) in nine normal subjects. Infusion of potassium decreased forearm vascular resistance, with an increase in brachial venous potassium of 1 meq/l decreasing forearm vascular tone by 25-30%. We then measured plasma potassium concentrations during forearm and upright bicycle exercise in 15 normal subjects. Forearm exercise at 0.6 W decreased forearm vascular resistance by 83%, whereas brachial venous potassium increased by only 0.5 +/- 0.2 meq/l (both P < 0.05). Maximal bicycle exercise increased systemic potassium concentrations by 1.2 +/- 0.2 meq/l. These findings indicate that potassium produces muscle arteriolar vasodilation in humans and therefore supports the hypothesis that potassium release from exercising muscle contributes to exercise-induced vasodilation. The relatively small change in venous potassium noted during forearm exercise despite marked forearm vasodilation suggests that local potassium release is only a small contributor to exercise-induced vasodilation. However, potassium release during maximal exercise may have significant vasodilatory effects on arterioles both in exercising and nonexercising tissues.

Endothelium dependent vasomotor responses to endogenous agonists are potentiated following ACE inhibition by a bradykinin dependent mechanism

The aim was to investigate the effects of angiotensin converting enzyme inhibition on agonist induced endothelium dependent vasodilatation in vivo. Chronically instrumented conscious dogs (n = 8) were prepared for the measurement of coronary blood flow, diameter of the left circumflex coronary artery, mean arterial blood pressure, and heart rate. Intracoronary infusions of acetylcholine, adenosine, and bradykinin that induced dose dependent increases in coronary blood flow and diameter were performed with and without intracoronary administration of captopril (1 mg.kg-1) and enalapril (0.4 mg.kg-1). The effects were studied of concomitant inhibition of bradykinin actions by the specific B2 kinin antagonist HOE-140 (10(-7) M), NO-synthesis by NG-nitro-L-arginine-methyl ester (L-NAME, 2 x 10(-5) M), or cyclo-oxygenase by indomethacin (10(-7) M) (all intracoronary). Neither captopril nor enalapril had significant vasodilating effect on the coronary vasculature when given alone. In contrast, both ACE inhibitors potentiated the agonist induced increases in coronary blood flow by bradykinin and acetylcholine (p < or = 0.01). HOE-140 strongly antagonised the effects of infused bradykinin and prevented the potentiation of acetylcholine responses by ACE inhibition. L-NAME caused hypertension and bradycardia and abolished the responses to acetylcholine and adenosine, but only partially attenuated the bradykinin induced increases in coronary blood flow. Simultaneous ACE inhibition reduced the hypertensive effect of L-NAME and partially restored the responses to bradykinin. Indomethacin reduced the responses to bradykinin but did not affect acetylcholine and adenosine induced coronary vasodilatation. The potentiation of the response to acetylcholine induced by ACE inhibition was, however, diminished by indomethacin. In the coronary vasculature of the dog, ACE inhibitors enhance vasomotor responses to endothelium dependent agonists by facilitating the release of both NO and PGI2, a mechanism which is coupled to endogenously formed bradykinin. ACE inhibitors may thus mediate their effects in vivo partly by increasing the capacity of the endothelium to release autacoids.

Vasodilator effects of parathyroid hormone, parathyroid hormone-related protein, and calcitonin gene-related peptide in the human fetal-placental circulation.

The purpose of our study was to determine the vasoactivity of calcitonin gene-related peptide (CGRP), parathyroid hormone (PTH), and parathyroid hormone-related protein (PTHrP) in the human fetal-placental circulation in vitro. Dually perfused placental cotyledons from term pregnancies were used in this study. Calcitonin gene-related peptide, PTHrP (both 10(-10)-10(-6) mol/L), and PTH (10(-8)-10(-6) mol/L) demonstrated a significant concentration-dependent vasodilator effect (P = .0007, P = .0172, P = .0063, respectively), following preconstriction with a thromboxane mimetic U46619. The CGRP-1 receptor inhibitor CGRP8-37 (10(-6) mol/L) significantly inhibited (P = .0131) the CGRP-induced vasodilator effect, while the nitric oxide synthesis inhibitor n-nitro-l-arginine showed no inhibitory effect. These results demonstrate the vasodilator effects of CGRP, PTH, and PTHrP in the human fetal-placental circulation. Calcitonin gene-related peptide and PTHrP were of equal potency, and both were approximately 100 times more potent than PTH. This study also suggests the CGRP may exert its vasodilator effect through two classes of receptors in the human placenta and may do so independently of nitric oxide.