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PubMed1982

Effects of 6-hydroxydopamine pretreatment on in vivo femoral arterial responses to vasodilator agents.

Reserpine has been previously shown to generally enhance femoral arterial vasodilator responses as indicated by increased slopes of regression lines relating decreases in resistance produced by injections of vasodilator agents to resistance prior to the injections. We have examined the same parameters in dogs pretreated with 6-hydroxydopamine. In contrast, 6-hydroxydopamine either decreased (nitroglycerin, adenosine) or had no effect (isoproterenol, acetylcholine) on femoral arterial vasodilator responses. In a second set of animals, reserpine was administered after pretreatment with 6-hydroxydopamine, and reserpine again tended to augment responses to vasodilator agents. These data suggest that reserpine's effects on vasodilator responses may be a direct effect on vascular smooth muscle and was not dependent on its effects on sympathetic innervation of the femoral bed. The decreased vasodilator responses to certain agents induced by 6-hydroxydopamine, in contrast, may have been attributable to loss of a presynaptic component of their mechanism(s) of vasodilator action.

Adenosine↗
PubMed1996

Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus.

Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9 +/- 9.8 years; diabetes duration, 14.9 +/- 7.9 years; glycated hemoglobin, 7.9 +/- 1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 micrograms glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10 +/- 0.52 mm) compared with C (2.89 +/- 0.55 mm, P = 5.0). FMD in IDDM patients was decreased (12.0 +/- 9.1% versus 15.7 +/- 9.5% in C, P = .046), as was GTN-induced vasodilation (14.9 +/- 8.2% versus 18.3 +/- 8.5% in C, P = .045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.

Adult↗
PubMed2004

Soluble guanylate cyclase activator reverses acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs.

BACKGROUND: Inhaled nitric oxide (NO) is a potent and selective pulmonary vasodilator, which induces cGMP synthesis by activating soluble guanylate cyclase (sGC) in ventilated lung regions. Carbon monoxide (CO) has also been proposed to influence smooth muscle tone via activation of sGC. We examined whether direct stimulation of sGC by BAY 41-2272 would produce pulmonary vasodilation and augment the pulmonary responses to inhaled NO or CO. METHODS AND RESULTS: In awake, instrumented lambs, the thromboxane analogue U-46619 was intravenously administered to increase mean pulmonary arterial pressure to 35 mm Hg. Intravenous infusion of BAY 41-2272 (0.03, 0.1, and 0.3 mg x kg(-1) x h(-1)) reduced mean pulmonary arterial pressure and pulmonary vascular resistance and increased transpulmonary cGMP release in a dose-dependent manner. Larger doses of BAY 41-2272 also produced systemic vasodilation and elevated the cardiac index. N(omega)-nitro-l-arginine methyl ester abolished the systemic but not the pulmonary vasodilator effects of BAY 41-2272. Furthermore, infusing BAY 41-2272 at 0.1 mg x kg(-1) x h(-1) potentiated and prolonged the pulmonary vasodilation induced by inhaled NO (2, 10, and 20 ppm). In contrast, inhaled CO (50, 250, and 500 ppm) had no effect on U-46619-induced pulmonary vasoconstriction before or during administration of BAY 41-2272. CONCLUSIONS: In lambs with acute pulmonary hypertension, BAY 41-2272 is a potent pulmonary vasodilator that augments and prolongs the pulmonary vasodilator response to inhaled NO. Direct pharmacological stimulation of sGC, either alone or in combination with inhaled NO, may provide a novel approach for the treatment of pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve.

To determine whether reductions in regional myocardial perfusion at reduced coronary arterial pressures reliably indicate maximal vasodilation of the distal vasculature, coronary autoregulation was studied in open-chest dogs at heart rates of approximately 60 beats/min, a level at which metabolic demand, time-averaged systolic compressive forces, and transmural vasodilator reserve approximate those found under usual resting conditions. Circumflex pressure was controlled with a programmable pressure source. Regional circumflex inflow was 0.56 +/- 0.04(SEM) ml . min-1 . g-1 when circumflex pressure equaled spontaneous aortic pressure and fell to 0.34 +/- 0.02 ml . min-1 . g-1 when circumflex pressure was reduced to 35 mm Hg. Reductions were similar in each myocardial layer, with endocardial flow falling from 0.68 +/- 0.04 to 0.39 +/- 0.03 ml . min-1 . g-1. During adenosine-induced vasodilation at 35 mm Hg, full-thickness and endocardial flows rose to 0.92 +/- 0.08 and 1.07 +/- 0.10 ml . min-1 . g-1, respectively. When coronary pressure was reduced to 25 mm Hg and autoregulation was again operative, full-thickness and endocardial flows fell to 0.28 +/- 0.03 and 0.28 +/- 0.04 ml . min-1 . g-1. During adenosine vasodilation at 25 mm Hg endocardial flow did not increase significantly but epicardial reserve remained present. These results indicate that significant reductions in regional myocardial perfusion can occur before pharmacologic vasodilator reserve is exhausted. In the absence of tachycardia, endocardial vasodilator reserve can persist to coronary pressures less than 35 mm Hg, but is ordinarily exhausted before epicardial vasodilator reserve.

Animals↗
PubMed1986

Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans.

An ideal coronary vasodilator for studying coronary flow reserve in humans would rapidly produce maximal coronary vasodilation, be short acting to permit repeated measurements, and not alter systemic hemodynamics. The two commonly used vasodilators (dipyridamole and meglumine diatrizoate) do not satisfy these criteria; meglumine diatrizoate does not produce maximal hyperemia and dipyridamole has a long duration of effect (greater than 30 min). In this study we used a subselective coronary Doppler catheter to measure the dose-response kinetics of a shorter acting vasodilator, intracoronary papaverine. In 10 patients with normal coronary vessels, the maximal vasodilator response to papaverine was compared with that to intravenous dipyridamole (0.56 mg/kg infused over 4 min) and intracoronary meglumine diatrizoate. The increase in coronary blood flow velocity after the maximal dose of papaverine (4.8 +/- 0.4 peak/resting velocity ratio, mean +/- SEM) was nearly identical to that seen after infusion of dipyridamole (4.8 +/- 0.6) and was significantly greater than that after meglumine diatrizoate (3.1 +/- 0.2, p less than .01). At maximal hyperemia, mean arterial blood pressure fell 9 +/- 2% (mean +/- SEM) after intracoronary papaverine, 8 +/- 4% after dipyridamole, and 3 +/- 3% after meglumine diatrizoate. The dose-response kinetics of intracoronary papaverine were studied in 13 patients with normal coronary arteries. In the left coronary artery, maximal vasodilation (5.4 +/- 0.6) was achieved with 8 mg in six of eight patients and with 12 mg in all patients. In the right coronary artery, maximal vasodilation (4.8 +/- 0.7) was achieved with 6 mg in four or five patients and with 8 mg in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Flow Velocity↗
PubMed1989

Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents.

The use of pharmacologic agents in the treatment of pulmonary hypertension has not proved to be uniformly successful or predictable. One possible reason for the vagaries in response is that the pulmonary vascular lesions are not consistent. We examined the relation between the structure of the pulmonary resistance vessels in unexplained (primary) pulmonary hypertension and the response to pulmonary vasodilators. Our study involved 19 patients with clinically unexplained pulmonary hypertension (mean pressure, 59 +/- 14 mm Hg). After characterizing them clinically and performing control hemodynamic measurements, we determined the acute effects of a series of vasodilator agents that have different mechanisms of action. In 16 patients, lung biopsy material was related to the hemodynamic studies; in nine patients, including six who had undergone open lung biopsy, the hemodynamic studies were related to the pathologic changes found at autopsy. Histologic specimens from all 19 patients were evaluated qualitatively and sorted into three subsets of hypertensive pulmonary arteriopathy: medial hypertrophy (with minimal intimal proliferation), arteriopathy with plexiform lesions (associated predominantly with concentric laminar intimal proliferation and fibrosis), and arteriopathy with microthrombotic lesions (associated predominantly with eccentric intimal proliferation and fibrosis). The 16 lung biopsies were also quantitated by morphometric techniques. Using a decrease in calculated pulmonary vascular resistance of more than 30% accompanied by a decrease in mean pulmonary arterial pressure of at least 10% to define vasodilation, only four patients were responders. The patients varied considerably in their responses to different vasodilator agents. Patients with similar clinical and hemodynamic profiles differed considerably with respect to the nature of their pulmonary vascular obstructive lesions and their responses to vasodilator agents. Qualitative histologic examination of lung tissue did not provide a basis for predicting how individual patients would respond to vasodilator agents. However, quantitative morphologic analysis of the initial open lung biopsy specimens did prove helpful in predicting acute responsiveness to vasodilator agents and the subsequent clinical course of these patients with unexplained (primary) pulmonary hypertension. An intimal area of more than 18% of the vascular cross-sectional area had an 85% predictive value for identifying the patients who did poorly during the first 36 months of follow-up.

Adolescent↗
PubMed1995

Selective impairment of vagally mediated, nitric oxide-dependent coronary vasodilation in conscious dogs after pacing-induced heart failure.

BACKGROUND: Activation in conscious dogs of the carotid chemoreflex or cardiac receptors results in coronary vasodilation that is mediated by a vagal cholinergic mechanism. Our previous study showed that the coronary vasodilation following activation of carotid chemoreflex is also mediated by nitric oxide (NO). In addition, NO production is depressed after the development of heart failure. Therefore, we hypothesized that the coronary vasodilation after activation of reflexes that elicit efferent vagal coronary vasodilation would be blunted in conscious dogs after pacing-induced heart failure due to the disappearance of NO. METHODS AND RESULTS: Mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and left circumflex coronary blood flow (CBF). Without the heart rate controlled, intra-atrial injection of veratrine (4 micrograms/kg) caused bradycardia (-36 +/- 3 beats per minute). With the heart rate controlled, veratrine increased CBF in a dose-dependent manner: for example, 4 micrograms/kg of veratrine increased CBF by 54 +/- 5% from 38 +/- 4.9 mL/min (P < .05). The increases in CBF induced by veratrine were markedly blunted by nitro-L-arginine (NLA). Activation of carotid chemoreflex by nicotine increased CBF by 121 +/- 9% from 32 +/- 4 mL++/min (P < .05) with the heart rate controlled and caused bradycardia (-32 +/- 5 beats per minute) without the heart rate controlled. After the development of heart failure, in response to activation of carotid chemoreflex or cardiac receptors the coronary vasodilation was almost abolished (CBF increased by only 23 +/- 8% or 11 +/- 3%, P < .05 compared with control). There still was a marked bradycardia after injections of nicotine or veratrine (-50 +/- 11 or -48 +/- 7 beats per minute). CONCLUSIONS: Our results indicate that vagally mediated coronary vasodilation is selectively attenuated in conscious dogs after pacing-induced heart failure, whereas the vagally mediated bradycardia is preserved. Since muscarinic receptor-induced coronary vasodilation is mediated by NO, the disappearance of NO from blood vessels leads to a defect in the integrated neural regulation of coronary blood flow and myocardial function during heart failure.

Acetylcholine↗
PubMed1998

Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension.

BACKGROUND: Essential hypertension is associated with impaired endothelium-dependent vasodilation. Inactivation of endothelium-derived nitric oxide by oxygen free radicals participates in endothelial dysfunction in experimental hypertension. To test this hypothesis in humans, we evaluated the effect of antioxidant vitamin C on endothelium-dependent responses in essential hypertensive patients. METHODS AND RESULTS: In 14 healthy subjects (47.1+/-4.8 years; blood pressure, 120.6+/-4.5/80.9+/-3.5 mm Hg) and 14 essential hypertensive patients (47.3+/-5.1 years; blood pressure, 153.9+/-7.1/102.3+/-4.1 mm Hg), we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg x 100 mL(-1) x min(-1)) or sodium nitroprusside (1, 2, and 4 microg/100 mL forearm tissue per minute), an endothelium-dependent and -independent vasodilator, respectively, in basal conditions and during infusion of intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). In hypertensive patients but not in control subjects, vitamin C increased (P<0.01) the impaired vasodilation to acetylcholine, whereas the response to sodium nitroprusside was unaffected. Moreover, in another 14 hypertensive patients (47.1+/-5.2 years; blood pressure, 155.2+/-6.9/103.7+/-4.5 mm Hg), the facilitating effect of vitamin C on vasodilation to acetylcholine was reversed by N(G)-monomethyl-L-arginine (100 microg/100 mL forearm tissue per minute), a nitric oxide synthase inhibitor, suggesting that in essential hypertension superoxide anions impair endothelium-dependent vasodilation by nitric oxide breakdown. Finally, because in adjunctive 7 hypertensive patients (47.8+/-6.1 years; blood pressure, 155.3+/-6.8/103.5+/-4.3 mm Hg), indomethacin (50 microg/100 mL forearm tissue per minute), a cyclooxygenase inhibitor, prevented the potentiating effect of vitamin C on vasodilation to acetylcholine, it is possible that in essential hypertension a main source of superoxide anions could be the cyclooxygenase pathway. CONCLUSIONS: In essential hypertensive patients, impaired endothelial vasodilation can be improved by the antioxidant vitamin C, an effect that can be reversed by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. These findings support the hypothesis that nitric oxide inactivation by oxygen free radicals contributes to endothelial dysfunction in essential hypertension.

Acetylcholine↗
PubMed2002

Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance.

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin's effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-L-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Cyclosporine impairs the ability of human platelets to mediate vasodilation.

Cyclosporine causes various platelet abnormalities. Whether it affects the ability of platelets to mediate vasodilation is unknown. Platelets were isolated from healthy volunteers and 13 heart transplant patients on cyclosporine. When perfused through preconstricted normal rabbit carotid arteries, activated platelets from transplant patients failed to cause vasorelaxation, whereas normal platelets produced significant vasodilation (-4.0 +/- 1.9% versus 30 +/- 3% [P < .0001] change in vessel diameter, respectively). When normal platelets were exposed to cyclosporine in vitro, they lost their ability to cause vasodilation in a dose- and time-dependent fashion. However, when activated and perfused through quiescent, N omega-nitro-L-arginine-pretreated arteries, platelets from transplant patients and normal platelets caused similar degrees of vasoconstriction. The amount of adenosine triphosphate in the supernatant from activated cyclosporine-exposed and control platelets was similar (1.7 +/- 0.4 versus 1.5 +/- 0.3 mumol/L [P = NS], respectively). However, concomitant perfusion of activated platelets from transplant patients impaired acetylcholine-mediated, endothelium-dependent vasodilation but perfusion of normal platelets did not. Although cyclosporine-exposed platelets showed an impaired ability to produce vasorelaxation, supernatant from the same platelets caused near normal vasodilation. Human platelets exposed to cyclosporine have an impaired ability to mediated vasodilation. This is not due to increased platelet-mediated vasoconstriction or a decrease in the release of platelet-derived nucleotides but rather to a short-acting compound released by cyclosporine-exposed platelets that interferes with endothelium-dependent vasodilation.

Adenosine Triphosphate↗
PubMed1997

Lacidipine restores endothelium-dependent vasodilation in essential hypertensive patients.

Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to test whether antihypertensive treatment with the calcium antagonist lacidipine can improve endothelium-dependent vasodilation in essential hypertensive patients. In 12 normotensive subjects (mean age, 47.8+/-8.6 years; blood pressure, 118.6+/-4.2/76.7+/-3.9 mm Hg) and 19 hypertensive patients (mean age, 49.4+/-10.2 years; blood pressure; 153.5+/-13.3/101.3+/-6.4 mm Hg), we studied forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute) and bradykinin (5, 15, and 50 ng/100 mL per minute), two endothelium-dependent vasodilators that act through different receptors and signal transduction pathways, and sodium nitroprusside (1, 2, and 4 microg/100 mL per minute), an endothelium-independent vasodilator. In essential hypertensive patients, vascular reactivity was repeated during prolonged (8 weeks of oral treatment at 6 mg/d) lacidipine administration and 2 weeks after withdrawal of chronic (32-week) treatment. Hypertensive patients showed significantly (P<.01) blunted vasodilation in response to acetylcholine (vascular resistance, 31.5+/-4.9 to 7.6+/-2.4 SU) and bradykinin (vascular resistance, 32.3+/-5.8 to 8.5+/-3.0 SU) compared with control subjects (vascular resistance: acetylcholine, 24.3+/-3.9 to 3.7+/-1.2 SU; bradykinin, 24.7+/-0.4 to 4.1+/-1.3 SU), whereas the response to sodium nitroprusside was similar. After either 8 or 32 weeks of lacidipine treatment, the vasodilation in response to acetylcholine (30.6+/-7.7 to 5.7+/-1.5 and 34.3+/-6.6 to 5.9+/-1.9 SU, respectively) and bradykinin (31.3+/-7.2 to 6.4+/-1.6 and 33.7+/-5.4 to 6.1+/-1.5 SU, respectively), but not to sodium nitroprusside, proved to be significantly (P<.05) increased compared with baseline. In essential hypertensive patients, oral treatment with lacidipine increased forearm vasodilation in response to acetylcholine and bradykinin, suggesting that this drug can improve endothelial function in patients with essential hypertension.

Acetylcholine↗
PubMed1990

Baroreflex control of the cutaneous active vasodilator system in humans.

Cutaneous arterioles are controlled by vasoconstrictor and active vasodilator sympathetic nerves. To find out whether the active vasodilator system is under baroreceptor control, laser-Doppler velocimetry and the local iontophoresis of bretylium were combined to allow selective study of the active vasodilator system. Each of six subjects had two forearm sites (0.64 cm2) treated with bretylium to abolish adrenergic vasoconstrictor control. Laser-Doppler velocimetry was monitored at those sites and at two adjacent untreated sites. Subjects underwent 3 minutes of lower-body negative pressure (LBNP) and 3 minutes of cold stress to verify blockade of vasoconstrictor nerves. They were then subjected to whole-body heat stress (water-perfused suits), and the 3 minutes of LBNP was repeated. Finally, subjects were returned to normothermia, and LBNP and cold stress were repeated to verify the persistence of blockade. During the application of LBNP in normothermia, cutaneous vascular conductance (CVC) fell at untreated sites by 22.7 +/- 4.7% (p less than 0.01) but was unaffected at bretylium-treated sites (p greater than 0.20). During cold stress, CVC at untreated sites fell by 30.2 +/- 1.7% (p less than 0.01) and at treated sites rose by 0.7 +/- 4.6% (p greater than 0.10). Both control and bretylium-treated sites reflexly vasodilated in response to hyperthermia. With LBNP during hyperthermia, CVC at untreated sites fell by 23.3 +/- 7.1% (p less than 0.05) and at treated sites 17.9 +/- 9.2% (p less than 0.05) with no significant difference between sites (p greater than 0.10). After return to normothermia, neither LBNP application nor cold stress caused CVC to fall at treated sites (p greater than 0.10). Thus, the vasoconstrictor system was blocked by bretylium treatment throughtout the study, whereas the active vasodilator response to heat stress was intact. Because LBNP in hyperthermia induced similar falls in CVC at both sites, we conclude that baroreceptor unloading elicits a withdrawal of active vasodilator tone and that the baroreflex has control of the active vasodilator system.

Adult↗
PubMed1997

Integrin signaling transduces shear stress--dependent vasodilation of coronary arterioles.

A direct relationship exists between shear stress and endothelium-dependent NO-mediated vasodilation of blood vessels. The transduction of shear stress to the biochemical signals resulting in the production of NO is, however, unknown. We tested the hypothesis that integrin binding to Arg-Gly-Asp(RGD) peptide sequences in extracellular matrix proteins is a critical step in initiation of the signaling sequence whereby shear stress activates endothelial tyrosine kinase(s) and induces vasodilation of isolated arterioles. Isolated coronary arterioles were exposed to increasing shear stress under control conditions and in the presence of a synthetic peptide, GRGDNP, to competitively inhibit integrin binding to extracellular matrix proteins containing RGD peptide sequences. Intraluminal GRGDNP (0.1, 0.5, and 1.0 mmol/L) inhibited shear stress-induced vasodilation in a concentration-dependent manner. Application of GRGDNP had no effect on endothelium-dependent relaxation to substance P (10(-12) to 10(-8) mol/L). An inactive structural analogue, GRGESP, did not alter shear stress-induced vasodilation. To further elucidate the integrin involved in shear stress-induced vasodilation, we administered a blocking antibody to the integrin beta 3 chain (F11) and observed significant attenuation of the vasodilation. Shear stress was also associated with an increase in tyrosine kinase activity, as assessed by anti-phosphotyrosine binding. Application of GRGDNP significantly decreased anti-phosphotyrosine binding during shear stress, suggesting a link between tyrosine kinase activation and integrin signaling during this vasodilatory response. Taken together, these results indicate that integrin-matrix interactions, possibly at focal adhesions, are of cardinal importance in the signaling pathway of shear stress-induced vasodilation.

Animals↗
PubMed1998

Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation.

Cytochrome P450 epoxygenases convert arachidonic acid into 4 epoxyeicosatrienoic acid (EET) regioisomers, which were recently identified as endothelium-derived hyperpolarizing factors in coronary blood vessels. Both EETs and their dihydroxyeicosatrienoic acid (DHET) metabolites have been shown to relax conduit coronary arteries at micromolar concentrations, whereas the plasma concentrations of EETs are in the nanomolar range. However, the effects of EETs and DHETs on coronary resistance arterioles have not been examined. We administered EETs and DHETs to isolated canine coronary arterioles (diameter, 90.0+/-3.4 microm; distending pressure, 20 mm Hg) preconstricted by 30% to 60% of the resting diameter with endothelin. All 4 EET regioisomers produced potent, concentration-dependent vasodilation (EC50 values ranging from -12.7 to -10.1 log [M]) and were approximately 1000 times more potent than reported in conduit coronary arteries. The vasodilation produced by 14,15-EET was not attenuated by removal of the endothelium and indicated a direct action of 14,15-EET on microvascular smooth muscle. Likewise, 14,15-DHET, 11,12-DHET, 8,9-DHET, and the delta-lactone of 5,6-EET produced extremely potent vasodilation (EC50 values ranging from -15.8 to -13.1 log [M]). The vasodilation produced by these eicosanoids was highly potent in comparison to that produced by other vasodilators, including arachidonic acid (EC50=-7.5 log [M]). The epoxide hydrolase inhibitor, 4-phenylchalone oxide, which blocked the conversion of [3H]14,15-EET to [3H]14,15-DHET by canine coronary arteries, did not alter arteriolar dilation to 11,12-EET; thus, the potent vasodilation induced by EETs does not require formation of DHETs. In contrast, charybdotoxin (a KCa channel inhibitor) and KCl (a depolarizing agent) blocked vasodilation by 11,12-EET and 11,12-DHET. We conclude that EETs and DHETs potently dilate canine coronary arterioles via activation of KCa channels. The preferential ability of these compounds to dilate resistance blood vessels suggests that they may be important regulators of coronary circulation.

8,11,14-Eicosatrienoic Acid↗
PubMed2000

Is the acetazolamide test valid for quantitative assessment of maximal cerebral autoregulatory vasodilation? An experimental study.

BACKGROUND AND PURPOSE: The cerebral vasodilating effect of acetazolamide (ACZ) injection has been used as an index of the autoregulatory vasodilation (or cerebral perfusion reserve). The question of whether the ACZ test assesses the maximal autoregulatory vasodilating capacity is not definitely resolved. The effects of ACZ injection on this reserve at a dose producing maximal vasodilation have never been evaluated and may help to resolve this problem. METHODS: The effect of ACZ injection on cerebral blood flow (CBF) autoregulation was tested in anesthetized rats. A pilot experiment evaluated the dose-effect relationship of injected ACZ, cumulative doses (n=4, group 1), and independent bolus doses (n=6, group 2). CBF was estimated by laser-Doppler flowmetry, and cerebrovascular resistance (CVR) was calculated from mean arterial blood pressure (MABP) and from CBF (expressed as a percentage of baseline CBF). A bolus of ACZ of 21 mg/kg produced the maximal cerebral vasodilation that could be obtained by ACZ administration. In the main experiment, MABP was lowered from 110 to 20 mm Hg by stepwise bleeding in 3 groups of 6 animals treated 10 minutes before bleeding by injection of saline (group 3), 7 mg/kg ACZ (group 4), or 21 mg/kg ACZ (group 5). RESULTS: The CVR-MABP relationship was linear in all groups, indicating that CBF autoregulation was still effective after ACZ administration. CONCLUSIONS: These results indicate that maximal ACZ-induced cerebral vasodilation is not quantitatively equivalent to maximal autoregulatory vasodilating capacity in anesthetized rats.

Acetazolamide↗
PubMed2001

Ceramide reduces endothelium-dependent vasodilation by increasing superoxide production in small bovine coronary arteries.

Ceramide serves as a second messenger in a variety of mammalian cells. Little is known regarding the role of ceramide in the regulation of vascular endothelial function. The present study was designed to determine whether ceramide affects endothelium-dependent vasodilation in coronary arteries and to explore the mechanism of action of ceramide. In isolated and pressurized small bovine coronary arteries, cell-permeable C(2)-ceramide (10(-)(5) mol/L) markedly attenuated vasodilator responses to bradykinin and A23187 (by 40% and 60%, respectively). In the presence of K(G)-nitro-L-arginine methyl ester, ceramide produced no further inhibition on the vasodilation induced by these vasodilators. Ceramide had no effect on DETA NONOate-induced vasodilation. By use of a fluorescence NO indicator (4,5-diaminofluorescein diacetate), intracellular NO was measured in the endothelium of freshly isolated small coronary arteries. It was found that ceramide significantly inhibited bradykinin-induced NO increase within endothelial cells. However, it had no effect on the activity of arterial or endothelial NO synthase. Pretreatment of the arteries with sodium dihydroxybenzene disulfonate (Tiron, 10(-)(3) mol/L), a cell-permeable superoxide scavenger, or polyethylene glycol superoxide dismutase (100 U/mL) largely restored the inhibitory effects of ceramide on the vasodilation and NO increase induced by bradykinin or A23187. Moreover, ceramide time-dependently increased intracellular superoxide (O(2)(-. )) in the endothelium, as measured by a fluorescent O(2)(-. )indicator, dihydroethidium. These results demonstrate that ceramide inhibits endothelium-dependent vasodilation in small coronary arteries by decreasing NO in vascular endothelial cells and that this decrease in NO is associated with increased O(2)(-. ) but not with the inhibition of NO synthase activity within these cells.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1984

Hemodynamic and metabolic effects of vasodilator therapy for heart failure in acute myocardial infarction.

Hemodynamic effects of vasodilator agents (molsidomine, nitroglycerin, isosorbide dinitrate or prostaglandin I2) were studied in 53 patients with acute myocardial infarction. In 20 of these patients, effect on cardiac metabolism were also studied. Patients were divided into four groups according to the Forrester subset and hemodynamic effects of these agents were evaluated by the cardiac index (CI)-preload (PAEDP) relationship. In patients of Forrester subset II and IV, vasodilators were capable of producing a considerable reduction in preload without a significant decrease in cardiac output. However, in patients of Forrester subset IV, five of six patients had only a minimal improvement in cardiac performance with vasodilator therapy because of a severe pump failure. In these patients, a combination therapy with dopamine was necessary to maintain the cardiac output. In patients with Forrester subset III, vasodilator therapy decreased cardiac index and preload was also reduced. Thus, for these patients vasodilators could not be indicated but volume infusion may be indicated. In patients with Forrester subset I, although vasodilator therapy decreased cardiac output, coronary sinus flow and myocardial oxygen consumption were also decreased, indicating that the vasodilator therapy is also beneficial for patients even without heart failure because of the protective effect of unloading on ischemic myocardium. Three nitrate agents, i.e., molsidomine, nitroglycerin and isosorbide dinitrate, demonstrated the similar effect on hemodynamics; mean blood pressure and PAEDP decreased by 7-10% and 20-29%, respectively, while systemic vascular resistance was not significantly decreased. In contrast to nitrates, PGI2 decreased mean blood pressure and systemic vascular resistance significantly, whereas a decrease in PAEDP was minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1992

Decreased skeletal muscle vasodilation in patients with congestive heart failure.

In congestive heart failure (CHF), excessive vasoconstriction is present, which is due to overactive vasoconstrictor mechanisms although vasodilator mechanisms may be impaired. In the present study, we examined vasodilation in CHF by measuring forearm blood flow with a strain gauge plethysmograph. Patients with CHF had higher forearm vascular resistance than normal control subjects. Patients with CHF had decreased forearm vasodilation in response to intra-arterial infusions of atrial natriuretic peptide (ANP) and acetylcholine, but not in response to sodium nitroprusside or nitroglycerin. Oral captopril did not alter the degree of forearm vasodilation during handgrip exercise. These results suggest that endothelium-dependent and ANP-induced forearm vasodilation is impaired in patients with CHF but the decreased vasodilation is not due to impaired vascular smooth muscle responsiveness to a vasodilator. The renin-angiotensin system does not seem to play a major role in the maintenance of vascular resistance during exercise in CHF.

Acetylcholine↗