Systemic Vasodilator Response Research Articles

2477 Targeting pulsatile load to increase exercise capacity and quality of life after TAVR for severe aortic stenosis

OBJECTIVES/SPECIFIC AIMS: The objective of the study is to test the effect of oral inorganic nitrate on the primary outcomes of exercise capacity and quality of life in patients who have undergone TAVR for severe aortic stenosis. We will also test the effect of the study drug on various physiology endpoints, including systemic vasodilator response to exercise, LV diastolic function and myocardial strain, late systolic LV load and pulsatile arterial wave reflections. METHODS/STUDY POPULATION: This is a randomized double-blind crossover clinical trial, in which 24 subjects who underwent TAVR for severe AS 3 or more months before enrollment will receive the following 2 interventions, in randomized order: (1) Potassium nitrate (KNO3), at a dose of 12–18 mmol/day by mouth for ~4 weeks, or (2) Potassium chloride (KCl), at a dose of 12–18 mmol/day by mouth for ~4 weeks. A 1-week washout period will be introduced between the 2 interventions. RESULTS/ANTICIPATED RESULTS: We hypothesize that sustained oral administration of potassium nitrate will lead to improvement of exercise capacity and quality of life in this population.DISCUSSION/SIGNIFICANCE OF IMPACT: His study will have a significant impact on assessment and management of patients after TAVR. We will gain a better understanding of physiologic abnormalities leading to exercise intolerance after TAVR. In addition, there are currently no proven therapies that improve exercise capacity in this population.

Vasodilator responses to acetylcholine are not mediated by the activation of soluble guanylate cyclase or TRPV4 channels in the rat

The effects of 1H-[1,2,4]-oxadizaolo[4,3-]quinoxaline-1-one (ODQ), an inhibitor of the activation of soluble guanylate cyclase (sGC) on responses to NO donors acetylcholine (ACh) and bradykinin (BK) were investigated in the pulmonary and systemic vascular beds of the rat. In these studies the administration of ODQ in a dose of 5 mg/kg iv attenuated vasodilator responses to five different NO donors without inhibiting responses to ACh and BK in the systemic and pulmonary vascular beds of the rat. Vasodilator responses to ACh were not inhibited by l-NAME or the transient receptor vanilloid type 4 (TRPV4) antagonist GSK-2193874, which attenuated vasodilator responses to the TRPV4 agonist GSK-1016790A. ODQ did not inhibit vasodilator responses to agents reported to act in an NO-independent manner or to vasoconstrictor agents, and ODQ did not increase blood methemoglobin levels, suggesting that off target effects were minimal. These results show that ODQ in a dose that inhibited NO donor-mediated responses did not alter vasodilator responses to ACh in the pulmonary and systemic vascular beds and did not alter systemic vasodilator responses to BK. The present results indicate that decreases in pulmonary and systemic arterial pressures in response to ACh are not mediated by the activation of sGC or TRPV4 channels and that ODQ can be used to study the role of the activation of sGC in mediating vasodilator responses in the rat.

Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat

Cardiovascular responses to the tyrosine kinase inhibitor imatinib were investigated in the rat. Intravenous injections of 0.3-30 mg/kg imatinib produced small decreases in pulmonary arterial pressure, larger dose-dependent decreases in systemic arterial pressure, and no change or small increases in cardiac output, suggesting that the systemic vasodilator response is more pronounced under baseline conditions. When pulmonary arterial pressure was increased with U-46619 or N(ω)-nitro-L-arginine methyl ester (L-NAME), intravenous injections of imatinib produced larger dose-dependent decreases in pulmonary arterial pressure. Imatinib attenuated the acute hypoxic pulmonary vasoconstrictor response. Vasodilator responses to imatinib were not inhibited by meclofenamate, glybenclamide, or rolipram, suggesting that cyclooxygenase, ATP-sensitive K(+) (KATP) channels, and cAMP were not involved in mediating the response. In a 21-day prevention study, imatinib treatment (50 mg/kg ip) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and small vessel remodeling induced by monocrotaline. Imatinib reduced PDGF receptor phosphorylation and PDGF-stimulated thymidine incorporation in rat pulmonary artery smooth muscle cells. These data suggest that the beneficial effect of imatinib in pulmonary hypertension may involve inhibition of PDGF tyrosine kinase receptor-mediated effects on smooth muscle cell proliferation and on vasoconstrictor tone. These results indicate that imatinib has nonselective vasodilator activity in the pulmonary and systemic vascular beds similar to the Rho kinase inhibitor fasudil and the calcium entry antagonist isradipine. The present results are consistent with the hypothesis that imatinib may inhibit a constitutively active tyrosine kinase vasoconstrictor pathway in the pulmonary and systemic vascular beds in the rat.

Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase activator, BAY 60–2770, are not dependent on endogenous nitric oxide or reduced heme

4-({(4-Carboxybutyl)[2-(5-fluoro-2-{[4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}methyl)benzoic acid (BAY 60-2770) is a nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) that increases the catalytic activity of the heme-oxidized or heme-free form of the enzyme. In this study, responses to intravenous injections of the sGC activator BAY 60-2770 were investigated under baseline and elevated tone conditions induced by the thromboxane mimic U-46619 when NO synthesis was inhibited by N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), when sGC activity was inhibited by 1H-[1,2,4]-oxadizaolo[4,3]quinoxaline-1-one (ODQ), an agent that oxidizes sGC, and in animals with monocrotaline-induced pulmonary hypertension. The intravenous injections of BAY 60-2770 under baseline conditions caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and no change or small increases in cardiac output. Under elevated tone conditions during infusion of U-46619, intravenous injections of BAY 60-2770 caused larger decreases in pulmonary arterial pressure, smaller decreases in systemic arterial pressure, and increases in cardiac output. Pulmonary vasodilator responses to BAY 60-2770 were enhanced by L-NAME or by ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside. ODQ had no significant effect on baseline pressures and attenuated pulmonary and systemic vasodilator responses to the sGC stimulator BAY 41-8543 2-{1-[2-(fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5(4-morpholinyl)-4,6-pyrimidinediamine. BAY 60-2770 and sodium nitroprusside decreased pulmonary and systemic arterial pressures in monocrotaline-treated rats in a nonselective manner. The present data show that BAY 60-2770 has vasodilator activity in the pulmonary and systemic vascular beds that is enhanced by ODQ and NOS inhibition, suggesting that the heme-oxidized form of sGC can be activated in vivo in an NO-independent manner to promote vasodilation. These results show that BAY 60-2770 and sodium nitroprusside decreased pulmonary and systemic arterial pressures in monocrotaline-treated rats, suggesting that BAY 60-2770 does not have selective pulmonary vasodilator activity in animals with monocrotaline-induced pulmonary hypertension.

Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

BAY 41-8543 is a nitric oxide (NO)-independent stimulator of soluble guanylyl cyclase (sGC). Responses to intravenous injections of BAY 41-8543 were investigated under baseline and elevated tone conditions and when NO synthase (NOS) was inhibited with N(ω)-nitro-L-arginine methyl ester (L-NAME). Under baseline conditions, intravenous injections of BAY 41-8543 caused small decreases in pulmonary arterial pressure, larger decreases in systemic arterial pressure, and increases in cardiac output. When pulmonary arterial pressure was increased to ∼30 mmHg with an intravenous infusion of U-46619, intravenous injections of BAY 41-8543 produced larger dose-dependent decreases in pulmonary arterial pressure, and the relative decreases in pulmonary and systemic arterial pressure in response to the sGC stimulator were similar. Treatment with L-NAME markedly decreased responses to BAY 41-8543 when pulmonary arterial pressure was increased to similar values (∼30 mmHg) in U-46619-infused and in U-46619-infused plus L-NAME-treated animals. The intravenous injection of a small dose of sodium nitroprusside (SNP) when combined with BAY 41-8543 enhanced pulmonary and systemic vasodilator responses to the sGC stimulator in L-NAME-treated animals. The present results indicate that BAY 41-8543 has similar vasodilator activity in the systemic and pulmonary vascular beds when pulmonary vasoconstrictor tone is increased with U-46619. These results demonstrate that pulmonary and systemic vasodilator responses to BAY 41-8543 are significantly attenuated when NOS is inhibited by L-NAME and show that vasodilator responses to BAY 41-8543 are enhanced when combined with a small dose of SNP in L-NAME-treated animals. The present results are consistent with the concept that pulmonary and systemic vasodilator responses to the sGC stimulator are NO-independent; however, the vasodilator activity of the compound is greatly diminished when endogenous NO production is inhibited with L-NAME. These data show that BAY 41-8543 has similar vasodilator activity in the pulmonary and systemic vascular beds in the rat.

Hemopressin, a hemoglobin fragment, dilates the rat systemic vascular bed through release of nitric oxide

The present study was undertaken to investigate the effects of intravenous (i.v.) administration of rat hemopressin (rHP), 30–1000 μg/kg, on systemic arterial pressure (SAP), cardiac output (CO) and systemic vascular resistance (SVR) in the anesthetized rat. Bolus i.v. injections of rHP produced mild decreases in SAP that were dose-dependent. Since CO was not altered, the decreases in SAP reflect reductions in SVR. The systemic vasodilator response to rHP was not subject to tachyphylaxis. The systemic vasodilator response to rHP was abolished by l-nitro-arginine methylester ( l-NAME) but was not altered by meclofenamate. In addition, rHP lacked direct contractile and relaxant activity on isolated rat aortic rings (AA) and pulmonary arterial rings (PA). The present data suggest rHP dilates the rat systemic vascular bed through the endogenous release of nitric oxide (NO) independent of the formation of cyclooxygenase products including prostacyclin. It is possible rHP acts as an endogenous vasodilator substance to regulate local blood flow during clinical states of altered red cell turnover, microvascular disease and hemolysis.

Gender difference in vascular and platelet reactivity to thromboxane A 2-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA 2, which is thrombogenic. Testosterone up-regulates platelet TXA 2 receptors and the aggregation response to thromboxane mimetics. Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits platelet aggregation. Hemodynamic studies were undertaken with the determination of dose–response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME). Platelet aggregation response was evaluated using whole blood impedance aggregometry. There were significant gender differences in the systemic blood pressure and RCF response to TXA 2-mimetic U46619 and angiotensin-II ( P<0.02, ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a paradoxical hypotensive response to U46619 (−18±11 mmHg) compared with a peak pressor response of +6±1 mmHg in female rats ( P<0.01, ANOVA). The male rats exhibited an attenuated systemic vasodilator response ( P<0.001, ANOVA) to acetylcholine (fall in MAP in male diabetic rats being −24±8 mmHg, compared with a fall of −50±8 mmHg in females), but a greater rise in the renal cortical resistance in response to NO inhibition by L-NAME ( P<0.03) compared with the female rats. Both the slope (46±2) and the peak magnitude of the U46619-induced whole blood platelet aggregation (13±1) ohms were significantly higher ( P<0.01, ANOVA) in male ( n=10) compared with female diabetic rats ( n=8) (29±0.8 slope, 10.0±0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an impaired response to vasoconstrictors (U46619 and angiotensin-II) and to endothelial (NO)-mediated vasodilation. The male gender may therefore be associated with the greater prothrombotic activity and a worse impairment of endothelial reactivity in the type-2 diabetic state.

Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction.

Left ventricular (LV) dysfunction caused by myocardial infarction (MI) is accompanied by endothelial dysfunction, most notably a loss of nitric oxide (NO) availability. We tested the hypothesis that endothelial dysfunction contributes to impaired tissue perfusion during increased metabolic demands as produced by exercise, and we determined the contribution of NO to regulation of regional systemic, pulmonary, and coronary vasomotor tone in exercising swine with LV dysfunction produced by a 2- to 3-wk-old MI. LV dysfunction resulted in blunted systemic and coronary vasodilator responses to ATP, whereas the responses to nitroprusside were maintained. Exercise resulted in blunted systemic and pulmonary vasodilator responses in MI that resembled the vasodilator responses in normal (N) swine following blockade of NO synthase with N(omega)-nitro-L-arginine (L-NNA, 20 mg/kg iv). However, L-NNA resulted in similar decreases in systemic (43 +/- 3% in N swine and 49 +/- 4% in MI swine), pulmonary (45 +/- 5% in N swine and 49 +/- 4% in MI swine), and coronary (28 +/- 4% in N and 35 +/- 3% in MI) vascular conductances in N and MI swine under resting conditions; similar effects were observed during treadmill exercise. Selective inhibition of inducible NO synthase with aminoguanidine (20 mg/kg iv) had no effect on vascular tone in MI. These findings indicate that while agonist-induced vasodilation is already blunted early after myocardial infarction, the contribution of endothelial NO synthase-derived NO to regulation of vascular tone under basal conditions and during exercise is maintained.

Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats.

The type-2 (AT(2)) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT(1)) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT(2) receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT(1) receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112+/-3 to 168+/-7 mm Hg (P<0.001) and LOS (30 mg/kg) alone decreased BP to 89+/-7 mm Hg (P<0.0001 from control). Ang II administered together with LOS decreased BP further to 71+/-4 mm Hg (P<0.00001 from control and LOS alone). AT(2) receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (P=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98+/-5 to 86+/-3 mm Hg (P<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69+/-3 mm Hg (P<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 microg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119+/-3 mm Hg during the control period, decreased to 86+/-6 mm Hg during 3 days of VAL alone, (P<0.00001) and decreased further to 65+/-7 mm Hg (P<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT(2) receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT(1) receptor.

The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin.

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs. A 1 h infusion of Z13752A (128 microgram kg(-1) min(-1) intravenously) decreased arterial blood pressure (by 11+/-3%; P<0. 05) and increased coronary blood flow (by 12+/-4%, P<0.05). There were no other significant haemodynamic changes. Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated. When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2+/-0.1 c.p. 10.7+/-3.3; P<0. 05). Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia-reperfusion insult 67% c.p. 0% in controls; P<0.05). Z13752A reduced two other indices of ischaemia severity; epicardial ST-segment elevation and inhomogeneity of electrical activation. These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls. We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin. British Journal of Pharmacology (2000) 129, 671 - 680

Blunting of pulmonary but not systemic vasodilator responses to dobutamine in newborn lambs.

Little is known about the changes in systemic and pulmonary vascular responses to dobutamine that occur during postnatal development. To address this question, vascular pressures and cardiac output were measured in anesthetized 1- to 2-d-old (n = 6), 7- to 10-d-old (n = 7), and 6- to 8-wk-old lambs (n = 6) while dobutamine was infused incrementally in the dose range of 0.5-40 microg x kg(-1) x min(-1). Dobutamine reduced pulmonary vascular resistance in the three age groups (all p<0.005). However, although this reduction reached a plateau over the infusion range of 15-40 microg x kg(-1) x min(-1) at all ages, its magnitude was less (p<0.02) in 1- to 2-d-old lambs (24+/-2%) than in 7- to 10-d-old (41+/-7%) or 6- to 8-wk-old lambs (42+/-6%). Over the same infusion range, dobutamine produced a fall in systemic vascular resistance (all p<0.005) that was proportionally similar in 1- to 2-d-old (51+/-3%), 7- to 10-d-old (48+/-3%), and 6- to 8-wk-old lambs (42+/-6%). In separate subgroups of 1- to 2-d-old lambs, pulmonary and systemic responses to dobutamine were not affected by pretreatment with selective alpha1-, beta1-, or beta2-adrenoceptor antagonists. Taken together, these findings suggest that the pulmonary but not systemic vasodilator response to dobutamine in lambs is blunted in the initial days after birth, and that this pulmonary effect is not directly related to the adrenoceptor-stimulating properties of dobutamine.

Impaired renal vascular response to a D1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats.

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D1-like receptor agonist fenoldopam (2 microg/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p < 0.01), whereas this response was absent in SHRs (+7 +/- 3%; NS). Mean arterial pressure (MAP) was significantly reduced in SHRs (-11 +/- 2%; p < 0.001), demonstrating a systemic vasodilator response to fenoldopam in SHRs. The reduction in renal vascular resistance (RVR) was more pronounced in WKY rats (-24 +/- 2%) than in SHRs (-13 +/- 4%; p < 0.05). Captopril significantly increased ERPF in SHRs (+16 +/- 3%; p < 0.001), demonstrating a preserved renal vasodilatory capacity in SHRs. The blunting of the renal vasodilatory response to fenoldopam in SHRs is present during a high as well as a low sodium intake. In conscious SHRs, the renal vasodilatory response to a D1-like receptor agonist is impaired, whereas the blood pressure response is more pronounced. The preserved renal vasodilatory response to captopril indicates that the defective vasodilatory response in SHRs is functional rather than due to altered structural properties of the renal vascular bed.

Role of endothelin-B receptors in the pulmonary circulation

Endothelin-1 (ET-1) is a potent vasoactive peptide and is thought to play an important role in the regulation of vascular tone. ET-1 can both constrict blood vessels, via endothelin-A (ET-A) receptors in vascular smooth muscle cells, and dilate then via endothelin-B (ET-B) receptors in endothelial cells in the systemic circulation. To determine the role of ET-B receptors in the pulmonary circulation, we examined the hemodynamic effects of a selective ET-B receptor agonist (IRL 1620) in rats. In rat lungs perfused with a salt solution, IRL 1620 caused pulmonary vasoconstriction in a dose-dependent manner. In lungs perfused with a hypoxic half-blood solution (10% O2), doses of IRL 1620 less than 10 nM caused pulmonary vasodilation, but higher doses caused pulmonary vasoconstriction. IRL 1620 caused transient vasodilation of the systemic circulation at every dose used (0.1, 1, and 5 nmol/kg) in anesthetized rats. In contrast, the effects of IRL 1620 on the pulmonary circulation varied with the dose. Small doses (0.1 or 1 nmol/kg) caused pulmonary vasodilation, but a higher dose (5 nmol/kg) caused pulmonary vasoconstriction. These results show tachyphylaxis in the pulmonary vasodilator response to IRL 1620, but not in the systemic vasodilator response. The present data show the dual action (vasoconstriction and vasodilation) of ET-B receptors.

Role of nitric oxide in systemic hemodynamic responses to dobutamine, epinephrine, and amrinone

This study was designed to investigate the extent to which the systemic vasodilator effects of dobutamine, epinephrine, and amrinone are modulated by the endothelium-derived relaxing factor, nitric oxide (NO). This was a prospective study of low and high doses of the agonists before and after inhibition of NO synthesis. Experiments were performed in the basic research laboratories of the Center for Anesthesiology Research. Pentobarbital-anesthetized, intact Sprague-Dawley rats were studied in seven separate groups of eight rats each. The systemic vasodilator responses to the agonists were assessed before and after the administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester. Decreases in systemic vascular resistance in response to dobutamine and epinephrine were not observed after inhibition of NO synthesis, whereas the decrease in systemic vascular resistance in response to amrinone was still apparent. The results suggest that dobutamine and epinephrine produce systemic vasodilation through the release of NO, whereas amrinone produces vasodilation independent of NO release.

Mechanism of systemic vasodilation during normovolemic hemodilution.

In the nonfailing heart, normovolemic hemodilution increases cardiac output and decreases total peripheral resistance (TPR). Putative mechanisms mediating the decrease in TPR include reflex vasodilation and changes in the local regulation of blood flow. Our objectives were to determine whether ablation of reflex neural mechanisms or the inhibition of nitric oxide (NO) synthase, the enzyme responsible for the synthesis of the endothelium-derived relaxing factor (EDRF-NO), modulates the systemic vasodilator response to normovolemic hemodilution. Three groups of male Sprague-Dawley rats were subjected to acute normovolemic hemodilution, which was achieved by exchanging a volume of blood equivalent to 3.8% of body weight with hydroxyethyl starch. Hemodilution increased cardiac output and decreased TPR. Subsequent administration of the NO synthase inhibitor, L-nitroarginine (LNA), returned both cardiac output and TPR to control values. Pretreatment with LNA prior to hemodilution increased TPR, an effect that was partially reversed by the NO donor, sodium nitroprusside. In this setting, hemodilution failed to decrease TPR. After spinal cord destruction by "pithing," hemodilution decreased TPR to the same extent as that observed in intact rats. This hemodilution-induced decrease in TPR was abolished by the subsequent administration of LNA. These results indicate that neural reflexes do not modulate the systemic vascular response to hemodilution. Moreover, the systemic vasodilator response to hemodilution is abolished after inhibition of endogenous NO synthesis.

Role of G proteins in the vasodilator response to endothelin isopeptides in vivo

The purpose of the present study was to determine the influence of pertussis toxin (PTX) on the pulmonary and systemic vasodilator responses to endothelin (ET) isopeptides in the intact cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by an intralobar arterial infusion of U-46619, intralobar arterial bolus injections of ET-1, ET-2, and ET-3 decreased lobar arterial pressure and systemic vascular resistance in a dose-related manner. The vasodilator responses to ET-1 and ET-2 in the cat lung were abolished by PTX pretreatment, whereas PTX pretreatment did not alter the pulmonary vasodilator response to ET-3 and cromakalim, a specific ATP-sensitive potassium (KATP) channel activator, and the systemic vasodilator responses to all ET isopeptides studied. Glipizide, an inhibitor of KATP channels, inhibited the pulmonary vasodilator responses to ET-1, ET-2, and ET-3, whereas the systemic vasodilator responses to these isopeptides were not changed. The present data are the first to provide a functional correlate in vivo suggesting the existence of different signal transduction mechanisms for two pulmonary vascular ET receptor subtypes, ETA-like that is PTX sensitive and has greater sensitivity to ET-1 and ET-2 (than to ET-3) and ETc-like that is PTX insensitive and has sensitivity to ET-3 (than to ET-1 and ET-2). However, both ET-receptor subtypes promote vasodilation in the adult pulmonary vascular bed by activating KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of noradrenergic constriction of large coronary arteries by inhibition of nitric oxide synthesis in anaesthetized dogs.

1. Coronary vascular responses to bilateral carotid occlusion (BCO) and the intravenous infusion of tyramine (Tyr, 20 micrograms kg-1 min-1) and noradrenaline (NA, 0.5 microgram kg-1 min-1) were examined after bilateral vagotomy and antagonism of beta-adrenoceptors. BCO, Tyr and NA decreased large coronary artery diameter and increased mean coronary resistance and systemic arterial pressure without affecting heart rate. 2. Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA, 5 and 15 mg kg-1) significantly increased mean arterial pressure and decreased heart rate and large coronary artery diameter. Mean coronary resistance was unaffected by either dose of L-NNA. L-NNA significantly reduced depressor and coronary vasodilator responses to the endothelium-dependent vasodilator acetylcholine (ACh, 10 micrograms kg-1, i.v.). Systemic and coronary vasodilator responses to sodium nitroprusside (SNP, 5 micrograms kg-1) were unaffected by L-NNA with the exception that the dilatation of the large coronary artery was significantly enhanced by the higher dose. 3. L-NNA significantly enhanced constriction of the large coronary arteries caused by BCO, Tyr and NA but did not affect the increases in mean coronary resistance or systemic arterial pressure. 4. Inhibition of NO synthesis enhances adrenergic constriction of large coronary arteries caused by both neuronally released and exogenous noradrenaline. In contrast, L-NNA did not affect adrenergic constriction of coronary or systemic resistance vessels. Endothelium-derived NO may play an important role in the modulation of noradrenergic vasoconstriction in coronary conductance arteries.

An adrenomedullin (ADM) fragment retains the systematic vasodilator activity of human ADM

The present study was undertaken to investigate the effects of human ADM, a newly discovered peptide present in normal human plasma, as well as a fragment of human ADM, human ADM 13–52, on systemic hemodynamics in the anesthetized cat. Intravenous (i.v.) bolus injections of human ADM and human ADM 13–52 decreased systemic arterial pressure (SAP) in a dose-dependent manner. Since neither peptide altered cardiac output, the decreases in SAP reflect reductions in systemic vascular resistance. The systemic vasodilator responses to the same doses of human ADM and human ADM 13–52 in the cat were similar. The present study demonstrates the systemic vasodilator activity of ADM is conserved across species. The present data suggest that human ADM 13–52 or a peptide structurally similar to it may mediate the hemodynamic properties of ADM in vivo in man. Since cardiac output and heart rate were not altered during the marked systemic vasodepressor response to ADM, activation of the ADM vasodilator mechanism may represent a therapeutic alternative in the clinical management of hypertensive diseases.

Functional evidence for different endothelin receptors in the lung

The present study was undertaken to compare and contrast the characteristics of the pulmonary and systemic vascular responses to endothelin (ET) isoforms in the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone (PVT) was actively increased by intralobar infusion of U-46619, intralobar arterial bolus injections of 1 microgram ET-1, 1 microgram ET-2, or 3 micrograms ET-3 markedly decreased lobar arterial pressure, systemic arterial pressure, and systemic vascular resistance. After seven repeated injections of ET-1 or ET-2 to separate groups of cats, pulmonary and systemic responses were largely reversed from vasodilation to vasoconstriction. In contrast, the pulmonary vasodilator response to ET-3 remained intact after multiple ET-3 injections, whereas its systemic vasodilator response was lost. Repeated intralobar arterial bolus injections of ET-1, ET-2, or ET-3 also caused the loss of pulmonary vasodilation to subsequent doses of ET-1, ET-2, or sarafotoxin 6b but not to ET-3. The present data suggest that the pulmonary and systemic vasodilator responses to ET-1 and ET-2 undergo tachyphylaxis and cross-tachyphylaxis. In contrast, the pulmonary vasodilator response to ET-3, unlike its systemic vasodilator response, is resistant to tachyphylaxis and cross-tachyphylaxis. The present data provide a functional correlate for the existence of at least two ET receptor subtypes, ETA-like and ETC-like receptors, in the adult pulmonary vascular bed.

Pulmonary vasodilation to endothelin isopeptides in vivo is mediated by potassium channel activation

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1 microgram), ET-2 (1 microgram), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg iv). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms) and cromakalim (10 and 30 micrograms), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 microgram), prostaglandin I2 (0.1 and 0.3 microgram), and isoproterenol (0.03 and 0.1 microgram) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)