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PubMed2003

Analysis of endothelium-dependent vasodilation by use of the radial artery pulse wave obtained by applanation tonometry.

OBJECTIVES: To evaluate applanation tonometry as a method to obtain arterial pulse waves suitable for pulse wave analysis of the height of the diastolic inflection point (IP), and to use this technique to study endothelium-mediated vasodilation by evaluation of the contribution of nitric oxide (NO) to the reduction in the height of the IP induced by beta2-adrenergic stimulation. METHODS: The radial artery pulse waveform was recorded by applanation tonometry in young healthy subjects before and after interventions both locally in the forearm and systemically by different vasodilators and vasoconstrictors, and vasodilatation was analysed as a change in the height of the IP. The mechanism behind the reduction in the height of the IP induced by terbutaline was investigated by systemic interventions with both N(G)-monomethyl-l-arginine (l-NMMA) and noradrenaline (NA). RESULTS: Applanation tonometry was a convenient method to obtain radial artery pulse waves of good quality. The reduction in IP was substantially more pronounced when vasodilators were given systemically than when given locally in the forearm, indicating that the effect was obtained through an effect on peripheral pulse wave reflection. Systemically given l-NMMA, but not NA, increased the IP (P<0.05). Systemically given l-NMMA also caused a more pronounced attenuation than NA of the reduction in IP following terbutaline injection (P<0.05). CONCLUSION: Changes in IP following beta2-adrenergic stimulation appears to be a measurement of pulse wave reflection mainly governed by NO. Applanation tonometry and pulse wave analysis is a minimally invasive method suitable to assess endothelium-dependent vasodilation in large-scale studies.

Adrenergic beta-Agonists↗
PubMed1977

Unusual pulmonary vasodilator activity of 13,14-dehydroprostacyclin methyl ester: comparison with endoperoxides and other prostanoids.

Microsomes from stomach fundus and blood vessels transform the endoperoxide, PGH2, into a newly discovered unstable substance, PGI2, that relaxes arterial strips and inhibits platelet aggregation. 13,14-Dehydro-PGI2 methyl ester, a newly synthesized, stable PGI2 analog, was found to have potent vasodilator activity in the feline and simian pulmonary vascular bed. The PGI2 analog decreased lobar arterial perfusion pressure in the intact cat and monkey. Because pulmonary blood flow was held constant and left atrial pressure was unchanged, the decrease in perfusion pressure reflects a decrease in pulmonary vascular resistance. The dilator response was unusual in that it persisted for 10-12 min, whereas the response to PGE1, the only other vasodilator prostaglandin in the mature animal, persisted for only 1-2 min. The dilator response to the PGI2 analog was enhanced when pulmonary vascular resistance was increased. This substance had less effect on cardiac output and aortic pressure than PGE1, whereas it was a more potent pulmonary vasodilator. These data demonstrate that prostacyclin-like substances possess novel vasodilator activity in the pulmonary circulation and suggest a therapeutic use in the treatment of pulmonary hypertensive diseases.

Animals↗
PubMed1997

Coronary vasodilation without myocardial erection. Simultaneous haemodynamic, echocardiographic and arteriographic findings during adenosine and dipyridamole infusion.

AIM: The aim of this study was to evaluate simultaneously echocardiographic, haemodynamic and angiographic changes that occur during adenosine and dipyridamole infusion, in patients with one-vessel coronary artery stenosis. This would assess whether deterioration in left ventricular haemodynamics during vasodilator agent infusion is influenced by vasodilation per se, or the development of myocardial ischaemia. METHODS AND RESULTS: We performed adenosine (140 micrograms.kg-1.min-1 over 4 min) and dipyridamole (up to 0.84 mg.kg-1 over 10 min) stress echocardiography tests, together with angiographic and haemodynamic assessment, in 26 patients undergoing elective coronary angioplasty. In 12 of 26 patients, adenosine and dipyridamole tests were repeated 24 h after angioplasty. The criterion for echocardiography test positivity was the appearance of a new transient regional wall motion abnormality. Coronary angiograms were analysed with quantitative coronary arteriography. Adenosine and dipyridamole induced regional dysfunction in 18/26 (69%) and 14/26 (54%) patients before angioplasty, respectively (P = ns). In the echocardiography-positive patients, the percent diameter stenosis was significantly (P < 0.05) tighter stenosis than in the echocardiography-negative patients (adenosine, 66.6 +/- 8.3% vs 58.0 +/- 8.9%; dipyridamole, 69.2 +/- 7.1% vs 57.7 +/- 7.6%). During both tests, left ventricular end-diastolic pressure significantly increased (P < 0.05) in echocardiography-positive patients (adenosine, 9.8 +/- 2.7 mmHg to 13.5 +/- 4.1 mmHg; dipyridamole, 10.1 +/- 2.8 mmHg to 14.1 +/- 4.3 mmHg), but not in echocardiography-negative patients. In the patients who had undergone successful angioplasty (reduction to < 50% diameter stenosis), both adenosine and dipyridamole confirmed the arteriographic success of the procedure (echocardiography negative in all patients). In this group of patients, no significant change was observed in left ventricular end-diastolic pressure during adenosine or dipyridamole infusion. CONCLUSIONS: Intravenous infusion of either adenosine or dipyridamole was accompanied by an obvious increase in left ventricular end-diastolic pressure only in patients with induced wall motion abnormalities. Coronary vasodilation per se has no significant effect on left ventricular end-diastolic pressure when no ischaemia is induced, disproving any clinically significant 'erectile' and adverse effects of coronary vasodilation per se.

Adenosine↗
PubMed1996

Isoflurane-induced coronary vasodilation is preserved in reperfused myocardium.

Isoflurane causes vasodilation in the coronary circulation. The present study evaluated whether this action is preserved after a brief coronary occlusion followed by reperfusion. Fourteen open-chest dogs anesthetized with fentanyl and midazolam were studied. The left anterior descending coronary artery was perfused via an extracorporeal system with normal arterial blood or with arterial blood equilibrated with 1.4% (1 minimum alveolar anesthetic concentration [MAC]) isoflurane. Coronary perfusion pressure was maintained at 90 mm Hg. Coronary blood flow (CBF) was measured with a Doppler flow transducer. Steady-state changes in CBF during isoflurane, and during intracoronary infusions of acetylcholine (Ach; 20 micrograms/min), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP; 80 micrograms/min), an endothelium-independent vasodilator, were compared in normal myocardium and in myocardium subjected to 15 min of ischemia (due to cessation of perfusion) followed by 30 min of reperfusion. Ischemia-reperfusion had no significant effect on the increases in CBF by isoflurane (421% +/- 88% vs 388% +/- 84%) or SNP (115% +/- 18% vs 135% +/- 19%), whereas it attenuated these increases in CBF by Ach (232% +/- 38% vs 143% +/- 21%). In conclusion, a brief period of myocardial ischemia followed by reperfusion did not affect the coronary vasodilating effects of isoflurane and SNP, although it blunted these effects of Ach. The present findings provide further evidence suggesting that the ability of isoflurane to relax coronary vascular smooth muscle is independent of the nitric oxide-cyclic guanosine monophosphate pathway.

Acetylcholine↗
PubMed1997

A comparative study of the vasodilator effects of prostaglandin E1 in patients with pulmonary hypertension after mitral valve replacement and with adult respiratory distress syndrome.

UNLABELLED: To determine whether the vasodilator effects of prostaglandin E1 (PGE1) differ according to the etiology and pathophysiology of pulmonary hypertension, we studied 30 patients with pulmonary hypertension after mitral valve replacement (MVR) (n = 16) or with the adult respiratory distress syndrome (ARDS) (n = 14). PGE1 was administered to decrease the mean pulmonary artery pressure to below 30 mm Hg in both groups. Cardiac index and oxygen delivery tended to increase, whereas mean systemic artery pressure, mean pulmonary artery pressure, systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) significantly decreased in both groups. A vasodilatory index was defined in this study to allow evaluation of vasodilation relative to PGE1 dose: systemic vasodilatory index (VIs) = SVRI change/PGE1 dose; and pulmonary vasodilatory index (VIp) = PVRI change/PGE1 dose. The VIp was similar in both groups, but the VIs was significantly greater in the ARDS group compared with the MVR group (13.3 +/- 7.8 vs 4.8 +/- 5.1, P < 0.01). A good correlation was found between the pretreatment intrapulmonary shunt fraction (Qs/Qt [%]) value and PGE1 extraction rate in the lung (r = 0.60), and between the pretreatment Qs/Qt value and PGE1 concentration in the radial artery (r = 0.65) in an additional 15 patients. We conclude that the vasodilator effects of PGE1 on the pulmonary circulation are similar in the two groups, whereas the vasodilator effects on the systemic circulation are significantly greater in the ARDS group and that significant reduction in VIs in the ARDS group was associated with decreased PGE1 extraction in the lung. IMPLICATIONS: Pulmonary hypertension after mitral valve replacement, or with adult respiratory distress syndrome, is a major medical problem. The authors found that administration of prostaglandin E1 significantly dilated the pulmonary circulation with a concomitant decrease in pulmonary artery pressure. Because the systemic vasodilatory effect was greater in the adult respiratory distress syndrome group, the authors concluded that prostaglandin E1 concentrations in the systemic circulation depend on the severity of lung injury.

Adult↗
PubMed1999

Arteriolar and venular vasodilating properties of benidipine hydrochloride, a 1,4-dihydropyridine Ca2+ antagonist with long-lasting action, assessed in rat mesenteric microcirculation.

To obtain direct and visible evidence of the arteriolar vasodilating action in vivo of benidipine hydrochloride, a long-lasting and light-resistant Ca2+ antagonist of the 1,4-dihydropyridine type, we continuously recorded changes in the diameter of mesenteric arterioles (10-40 microm) and venules (20-40 microm) in anesthetized agent-injected Wistar rats by means of digital image processing combined with videomicroscopy. Benidipine injected intravenously brought about a depressor response, and this response persisted much longer than that induced by nifedipine. Benidipine produced a dose-dependent arteriolar vasodilation and a decrease in the blood-flow velocity. It also relaxed the venules during the depressor response, which relaxation was more prominent 1-2 h after the administration. In pithed rats, both pressor response and arteriolar constriction induced by norepinephrine were prevented by benidipine. Benidipine also inhibited adenosine diphosphate (ADP)-induced interruption of arteriolar blood flow. These results suggest that benidipine produced vasodilation in vivo at both the arteriolar and venular levels. The ability of benidipine to prevent microcirculatory disturbance and to produce arteriolar and venular vasodilation seem to account for its long-lasting Ca2+-antagonistic antihypertensive action.

Adenosine Diphosphate↗
PubMed1999

The role of adenosine in insulin-induced vasodilation.

It was previously shown that systemic hyperinsulinemia induces vasodilation in human skeletal muscle. The mechanism mediating this vasodilation is not yet completely clarified. Based on data from animal experiments, we hypothesized that stimulation of the adenosine receptor is involved in insulin-induced vasodilation. To test this hypothesis, a 105-min hyperinsulinemic euglycemic clamp was performed in three groups of eight healthy volunteers. In group 1, placebo was infused into the left brachial artery (experimental forearm). In the second and third group, respectively, draflazine (an adenosine-uptake blocker) and theophylline (an adenosine-receptor antagonist) were administered by intrabrachial infusion. Forearm blood flow (FBF) was measured by venous-occlusion plethysmography, both at the experimental and the control forearms. The percentage decrease in flow ratio (FBF experimental arm/control arm) in the draflazine group was significantly less pronounced than that in the placebo group, whereas the percentage decrease in flow ratio was larger in the theophylline group. These results demonstrate that the insulin-induced increase in blood flow in the experimental arm was more pronounced at the site of adenosine-uptake blockade by draflazine, whereas this was reduced during adenosine-receptor antagonism by theophylline. Our observations are compatible with the hypothesis that insulin-induced vasodilation is mediated by the release of adenosine.

Adenosine↗
PubMed2001

Nitric oxide-dependent vasodilation and the regulation of arterial blood pressure.

Conflicting evidence has been reported on the hypothesis that vascular nitric oxide (NO) release is modulated by autonomic influences. Another controversial question is whether an insufficient degree of NO-dependent vasodilation may play a contributory role in the genesis of arterial hypertension. To address these questions we evaluated NO-dependent vasodilation in conscious rats subjected to various experimental manipulations that interfere with autonomic function: chronic chemical sympathectomy (CCSx), acute ganglionic blockade (AGx) and chronic sinoaortic denervation (CSAD). Experiments were also carried out on 6- and 12-week-old spontaneously hypertensive rats (SHR) (i.e. during the pre-hypertensive and the early established hypertensive stage) and in age-matched Wistar-Kyoto (WKY) rats. Nitric oxide-dependent vasodilation was quantified from the extent of blood pressure (BP) elevation in response to acute inhibition of NO synthesis by L-nitromonomethyl-L-arginine (L-NMMA). Chronic chemical sympathectomy was produced by repeated 6-hydroxydopamine injections; AGx was induced by hexamethonium infusion; and CSAD was obtained by aortic nerve section and carotid sinus wall stripping. Nitric oxide synthesis inhibition by L-NMMA was followed by a marked BP elevation in all groups. Rats with CCSx, Agx or CSAD never showed reduced BP responses to L-NMMA compared to intact, control rats. Neither 6- nor 12-week-old SHR had attenuated pressor responses to L-NMMA compared to age-matched WKY rats. In conclusion, the data indicate that (i) in unanaesthetized quietly-behaving rats there is no significant modulation of NO release by autonomic influences and (ii) young SHR have unimpaired NO-dependent vasodilation so it is unlikely that a deficit of vascular NO release plays any etiologic role in the BP elevation of this experimental model.

Animals↗
PubMed1996

Endotoxin-induced inhibition of mesenteric vasodilator responses to acetylcholine, bradykinin, and post-occlusion hyperemia in anesthetized rats.

The effects of endotoxin (20 mg kg-1 i.p.) on the mesenteric vascular responses to acetylcholine, bradykinin, sodium nitroprusside, and to transient occlusion of the superior mesenteric artery were examined in rats anesthetized with pentobarbitone. Mesenteric vasodilator responses to close arterial injections of acetylcholine and bradykinin were reduced at 1.5 h after endotoxin and almost abolished by 4 h; responses to sodium nitroprusside were unaffected. Occlusion of the superior mesenteric artery for 30, 60, or 120 s produced, on release of the occlusion, a time-dependent vasodilator response in the mesenteric circulation (post-occlusion hyperemia). This hyperemia was markedly reduced by nitro-L-arginine methyl ester (L-NAME); L-NAME did not modify acetylcholine-induced vasodilation. Endotoxin-pretreatment did not modify mesenteric post-occlusion hyperemia 1.5 h after administration but markedly reduced the response by 2.5 h. The administration of L-NAME to endotoxin-treated rats did not further attenuate the hyperemic responses. Mesenteric vasoconstrictor responses to phenylephrine were not modified by endotoxin, although systemic pressor responses to this agent were impaired. We concluded that endotoxin impairs endothelium and nitric oxide-dependent vasodilator responses in the mesenteric circulation.

Acetylcholine↗
PubMed2002

Aging impairs endothelium-dependent vasodilation in rat skeletal muscle arterioles.

Blood flow capacity in skeletal muscle declines with age. Reduced blood flow capacity may be related to decline in the maximal vasodilatory capacity of the resistance vasculature. This study tested the hypothesis that aging results in impaired vasodilatory capacity of first-order (1A) arterioles isolated from rat-hindlimb locomotory muscle: 1A arterioles (90-220 microm) from gastrocnemius and soleus muscles of young (4 mo) and aged (24 mo) Fischer-144 rats were isolated, cannulated, and pressurized via hydrostatic reservoirs. Vasodilatory responses to increasing concentrations of ACh (10(-9) to 10(-4) M), adenosine (ADO, 10(-10) to 10(-4) M), and sodium nitroprusside (SNP, 10(-10) to 10(-4) M) were evaluated at a constant intraluminal pressure of 60 cmH(2)O in the absence of flow. Flow-induced vasodilation was also evaluated in the absence of pressure changes. Responses to ADO and SNP were not altered by age. Endothelium-dependent vasodilation induced by flow was significantly reduced in arterioles from both gastrocnemius and soleus muscles. In contrast, endothelium-dependent vasodilation to ACh was reduced only in soleus muscle arterioles. These results indicate that aging impairs vasodilatory responses mediated through the endothelium of resistance arterioles from locomotory muscle, whereas smooth muscle vasodilatory responses remain intact with aging. Additionally, ACh-induced vasodilation was altered by age only in soleus muscle arterioles, suggesting that the mechanism of age-related endothelial impairment differs in arterioles from soleus and gastrocnemius muscles.

Acetylcholine↗
PubMed2003

Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction.

In estrogen-depleted [i.e., ovariectomized (Ovx)] animals, an endothelium-derived hyperpolarizing factor (EDHF)-like mechanism may arise to, at least partially, replace endothelial nitric oxide (NO) synthase (eNOS)-derived NO in modulating cerebral arteriolar tone. Additional findings show that eNOS expression and function is restored in estrogen-treated Ovx female rats, while the nascent EDHF-like activity disappears. Because NO has been linked to repression of EDHF activity in the periphery, the current study was undertaken to examine whether the nascent EDHF role in cerebral vessels of Ovx females relates to a chronically repressed eNOS-derived NO-generating function. We compared the effects of chronic NOS inhibition with Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 mg. kg-1. day-1 for 3 wk) on EDHF-mediated pial arteriolar vasodilation in anesthetized intact, Ovx, and 17beta-estradiol-treated (0.1 mg. kg-1. day-1 ip, 1 wk) Ovx (OVE) female rats as well as in male rats that were prepared with closed cranial windows. In the chronic NOS inhibition groups, pial arteriolar responses were monitored in the absence (all groups) and presence (females only) of indomethacin (Indo; 10 mg/kg iv). Finally, the gap junction inhibitory peptide Gap 27 (300 muM) was applied to block EDHF-related vasodilation. NO donor (S-nitroso-N-acetyl-penicillamine) responses were similar in all rats studied. Acetylcholine (ACh) reactivity was virtually absent in control Ovx rats and chronically NOS-inhibited intact female, OVE, and male rats. However, a partial recovery of ACh reactivity was seen in L-NAME-treated Ovx females. In addition, in the presence of L-NAME, a normal CO2 reactivity was observed in all females, whereas a 50% reduction in CO2 reactivity was seen in males. In intact and OVE rats, both chronic and acute (NG-nitro-L-arginine suffusion) NOS inhibition, combined with Indo, depressed ADP-induced dilation by > or =50%, and subsequent application of Gap 27 had no further effect on ADP-induced vasodilation. ADP reactivity was retained in Ovx rats after combined chronic NOS inhibition and acute Indo, but was attenuated significantly by Gap 27. In males, Gap 27 had no effect on arteriolar reactivity. Taken together, our data demonstrate that in the cerebral microcirculation, NO does not have an inhibitory effect on EDHF production or action. The increased EDHF-like function in chronic estrogen-depleted animals is not due to eNOS deficiency, suggesting a more direct effect of estrogen in modulating EDHF-mediated cerebral vasodilation.

Acetylcholine↗
PubMed2005

Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease.

Adenosine is a key myocardial metabolite that elicits coronary vasodilation in a variety of pathophysiological conditions. We examined the mechanism of adenosine-induced vasodilation in coronary arterioles from patients with heart disease. Human coronary arterioles (HCAs) were dissected from pieces of the atrial appendage obtained at the time of cardiac surgery and cannulated for the measurement of internal diameter with videomicroscopy. Adenosine-induced vasodilation was not inhibited by endothelial denudation, but A(2) receptor antagonism with 3,7-dimethyl-1-propargylxanthine and adenylate cyclase (AC) inhibition with SQ22536 significantly attenuated the dilation. In contrast, A(1) receptor antagonism with 8-cyclopentyl-1,3-dipropylxanthine significantly augmented the sensitivity to adenosine. Moreover, dilation to A(2a) receptor activation with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine hydrochloride was reduced by the A(1) receptor agonist (2S)-N(6)-(2-endo-norbornyl)adenosine. The nonspecific calcium-activated potassium (K(Ca)) channel blocker tetrabutylammonium attenuated adenosine-induced dilation, as did the intermediate-conductance K(Ca) blocker clotrimazole. Neither the large-conductance K(Ca) blocker iberiotoxin nor small-conductance K(Ca) blocker apamin altered the dilation. In conclusion, adenosine endothelium independently dilates HCAs from patients with heart disease through a receptor-mediated mechanism that involves the activation of intermediate-conductance K(Ca) channels via an AC signaling pathway. The roles of A(1) and A(2) receptor subtypes are opposing, with the former being inhibitory to AC-mediated dilator actions of the latter. These observations identify unique fundamental physiological characteristics of the human coronary circulation and may help to target the use of novel adenosine analogs for vasodilation in perfusion imaging or suggest new strategies for myocardial preconditioning.

Adenosine↗
PubMed2005

Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species.

Insulin resistance (IR) and associated hyperinsulinemia are major risk factors for coronary artery disease. Mechanisms linking hyperinsulinemia to coronary vascular dysfunction in IR are unclear. We evaluated insulin-induced vasodilation in isolated small coronary arteries (SCA; approximately 225 microm) of Zucker obese (ZO) and control Zucker lean (ZL) rats. Vascular responses to insulin (0.1-100 ng/ml), ACh (10(-9)-10(-5) mol/l), and sodium nitroprusside (10(-8)-10(-4) mol/l) were assessed in SCA by measurement of intraluminal diameter using videomicroscopy. Insulin-induced dilation was decreased in ZO compared with ZL rats, whereas ACh and sodium nitroprusside elicited similar vasodilations. Pretreatment of arteries with SOD (200 U/ml), a scavenger of reactive oxygen species (ROS), restored the vasorelaxation response to insulin in ZO arteries, whereas ZL arteries were unaffected. Pretreatment of SCA with N-nitro-L-arginine methyl ester (100 micromol/l), an inhibitor of endothelial nitric oxide (NO) synthase (eNOS), elicited a vasoconstrictor response to insulin that was greater in ZO than in ZL rats. This vasoconstrictor response was reversed to vasodilation in ZO and ZL rats by cotreatment of the SCA with SOD or apocynin (10 micromol/l), a specific inhibitor of vascular NADPH oxidase. Lucigenin-enhanced chemiluminescence showed increased basal ROS levels as well as insulin (330 ng/ml)-stimulated production of ROS in ZO arteries that was sensitive to inhibition by apocynin. Western blot analysis revealed increased eNOS expression in ZO rats, whereas Mn SOD and Cu,Zn SOD expression were similar to ZL rats. Thus IR in ZO rats leads to decreased insulin-induced vasodilation, probably as a result of increased production of ROS by vascular NADPH oxidase, leading to decreased NO bioavailability, despite a compensatory increase in eNOS expression.

Acetylcholine↗
PubMed2005

Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training.

Forearm endothelium-dependent vasodilation is impaired with age in sedentary, but not endurance-trained, men. The purpose of this investigation was to determine whether these age- and physical activity-related differences in endothelium-dependent vasodilation also occur in the leg. Brachial and common femoral arterial blood flow were measured with Doppler ultrasound during increasing doses of acetylcholine (1, 4, and 16 microg.100 ml limb tissue(-1).min(-1)), substance P (8, 31, and 125 pg.100 ml limb tissue(-1).min(-1)), and sodium nitroprusside (0.063, 0.25, and 1 microg.100 ml limb tissue(-1).min(-1)) in 23 healthy men (8 younger sedentary, 8 older sedentary, and 7 older endurance trained). Increases in forearm blood flow to the highest dose of acetylcholine and sodium nitroprusside were smaller (P < 0.05) in older sedentary (841 +/- 142%, 428 +/- 74%) compared with younger sedentary (1,519 +/- 256%, 925 +/- 163%) subjects. Similarly, increases in forearm blood flow to sodium nitroprusside (1 microg.100 ml limb tissue(-1).min(-1)) were smaller (P < 0.05) in older endurance-trained (505 +/- 110%) compared with younger sedentary (925 +/- 163%) subjects. In contrast, no differences in leg blood flow responses to intra-arterial infusions of acetylcholine, substance P, or sodium nitroprusside were noted between subject groups. These results demonstrate that 1) acetylcholine- and sodium nitroprusside-induced vasodilation are attenuated in the forearm vasculature and preserved in the leg vasculature of older sedentary subjects and 2) sodium nitroprusside-induced vasodilation remains attenuated in the forearm vasculature of healthy older endurance-trained men but preserved in the leg vasculature of these men.

Acetylcholine↗
PubMed1992

K+ATP-channel activation causes marked vasodilation in the hypertensive neonatal pig lung.

We studied the potential role of ATP-sensitive potassium (K+ATP) channel activation in mediating pulmonary vasodilation in newborn piglets. Piglet lungs (n = 14, ages 1-4 days) were artificially perfused with recirculating Ringer solution containing bovine serum albumin and statistically inflated using 95% O2-5% CO2. We measured pulmonary arterial pressure (Ppa) and distribution of pulmonary vascular resistance (using double-occlusion method). Under resting conditions (Ppa 13.7 +/- 1.6 cmH2O, mean +/- SE), the K+ATP channel agonist BRL 38227 (lemakalim, 10(-7) and 10(-6) M) caused small dose-dependent pulmonary vasodilation. This response was diminished by the K+ATP-channel blocker glibenclamide (10(-5) M). Pretreatment of lungs with indomethacin (10(-5) M) and N omega-nitro-L-arginine (10(-5) M) to inhibit cyclooxygenase- and nitric oxide (NO)-related vasodilation, respectively, resulted in a marked increase in the baseline Ppa to 85.6 +/- 11.2 cmH2O. Injection of BRL 38227 (10(-7) M and 10(-6) M) in these lungs decreased Ppa to 72.5 +/- 8.5 (P < 0.01) and 19.3 +/- 0.9 cmH2O (P < 0.01), respectively; the corresponding times for half-recovery of Ppa (t1/2R) were 5.7 +/- 4.3 and > 20 min. Glibenclamide (10(-5) M) abolished the response to 10(-7) M BRL 38227 and significantly diminished (P < 0.05) the decreases in Ppa and t1/2R in response to 10(-6) M BRL 38227 but not to acetylcholine (10(-10) M). We conclude that activation of K+ATP channels has a minimal role in maintaining basal pulmonary vasomotor tone but is able to induce marked vasodilation when NO and cyclooxygenase-dependent vasodilatory mechanisms are inhibited.

Adenosine Triphosphate↗
PubMed1993

Abnormal responses to pulmonary vasodilators in conscious dogs after left lung autotransplantation.

We investigated the extent to which left lung autotransplantation (LLA) alters endothelium-dependent (bradykinin and acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilation in the pulmonary circulation of conscious dogs. Continuous left pulmonary vascular pressure-flow (LPQ) plots were generated in conscious dogs 3-4 wk post-LLA and in sham-operated controls. LLA resulted in a marked upward shift in the baseline LPQ relationship compared with the control group (P < 0.01), i.e., LLA caused a chronic increase in pulmonary vascular resistance. The thromboxane analogue, U-46619, was used to acutely preconstrict the pulmonary circulation in control dogs, which shifted the control LPQ relationship to the same position measured post-LLA. Under these circumstances, bradykinin, acetylcholine, and nitroprusside caused pulmonary vasodilation in the control group, whereas these responses were either attenuated or reversed to vasoconstriction post-LLA. After acute preconstriction with U-46619 post-LLA, the pulmonary vasodilator responses to bradykinin and acetylcholine were again attenuated, but the response to nitroprusside was unaltered compared with control. These results indicate that a significant component of the chronic increase in pulmonary vascular resistance post-LLA is passively mediated and does not reflect an active increase in baseline vasomotor tone. Moreover, LLA results in an impairment in endothelium-dependent, but not endothelium-independent, pulmonary vasodilation in conscious dogs.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Adenosine-induced vasodilation: receptor characterization in pulmonary circulation.

Adenosine mediates vascular smooth muscle relaxation in the pulmonary circulation. The A2 receptor has been suggested to mediate adenosine-induced vasodilation (AIV). In this study, the effect(s) of selective adenosine agonist and antagonist on the hypoxic pressor response (HPR) was assessed in the isolated blood-perfused rat lung. Adenosine (0.075-7.5 mM) infusion (0.125 ml/min) into the pulmonary artery dose dependently attenuated the HPR. AIV was mimicked by 10 microM 5'-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist. Adenosine- and NECA-induced vasodilation were attenuated by 67 microM 8-(p-sulfophenyl)theophylline. In contrast, NECA-induced vasodilation was not attenuated by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 microM). At 10 microM, a minimal vasodilatory effect was seen with the nonselective adenosine agonists CV-1808 and N6-(2-phenylisopropyl)adenosine (R-PIA) compared with NECA. The highly selective A2a agonist 2-[p-(2-carboxyethyl)phenyl amino]-5'-N-ethyl carboxamido adenosine (CGS-21680C, 10 microM) and A1 agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 10 microM) had no vasodilatory effect. Neither the K+ channel blockers tetraethylammonium chloride (10 mM) and glibenclamide (100 microM) nor the NO synthase inhibitor N omega-nitro-L-arginine methyl ester attenuated NECA-induced vasodilation. These findings suggest that AIV is mediated via the A2b receptor and that AIV occurs via an NO-independent mechanism.

Adenosine↗
PubMed1996

ATP-sensitive K+ channel opener pinacidil augments beta 1-adrenoceptor-induced coronary vasodilation in dogs.

The opening of ATP-sensitive K+ (K+ATP) channels contributes to the mechanism of metabolic coronary vasodilation. The aim of the present study was to determine whether K+ATP channel opener pinacidil augments coronary vasodilation induced by beta-adrenoceptor stimulation. In anesthetized dogs, coronary vasodilation in response to intracoronary infusion of a beta 1-adrenoceptor agonist denopamine, selective beta 2-adrenoceptor stimulation with isoproterenol after bisoprolol or nitroglycerin was studied before and during simultaneous intracoronary infusion of pinacidil at a dose of 1 microgram/min, which had no effect on basal hemodynamics. Pinacidil augmented the denopamine-induced increase in coronary blood flow (CBF) from 38 +/- 9 to 66 +/- 16% (P < 0.05) but did not affect the denopamine-induced by isoproterenol or nitroglycerin. Thus pinacidil selectively augmented beta 1-adrenoceptor-mediated coronary vasodilation. These observations suggest that the K+ATP channel opener pinacidil may increase myocardial perfusion during metabolic stress associated with beta 1-adrenoceptor stimulation.

Adenosine Triphosphate↗