Pulmonary vasodilator responses to vasoactive intestinal peptide in the cat

1985 ◽  
Vol 58 (5) ◽  
pp. 1723-1728 ◽  
Author(s):  
P. A. Nandiwada ◽  
P. J. Kadowitz ◽  
S. I. Said ◽  
M. Mojarad ◽  
A. L. Hyman
Keyword(s):  
Arterial Pressure ◽  
Vasoactive Intestinal Peptide ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Base Line ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Adrenergic Mechanism ◽  
Pulmonary Vascular Bed

We investigated the effects of vasoactive intestinal peptide (VIP) in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow when pulmonary vascular tone was at base-line levels and when vascular resistance was elevated. Under base-line conditions, VIP caused small but significant reductions in lobar arterial pressure without affecting left atrial pressure. Decreases in lobar arterial pressure in response to VIP were greater and were dose related when lobar vascular resistance was increased by intralobar infusion of U 46619, a stable prostaglandin endoperoxide analogue. Acetylcholine and isoproterenol also caused significant decreases in lobar arterial pressure under base-line conditions, and responses to these agents were enhanced when lobar vascular tone was elevated. Moreover, when doses of these agents are expressed in nanomoles, acetylcholine and isoproterenol were more potent than VIP in decreasing lobar arterial pressure. Responses to VIP were longer in duration with a slower onset than were responses to acetylcholine or isoproterenol. Pulmonary vasodilator responses to VIP were unchanged by indomethacin, atropine, or propranolol. The present data demonstrate that VIP has vasodilator activity in the pulmonary vascular bed and that responses are dependent on the existing level of vasoconstrictor tone. These studies indicate that this peptide is less potent than acetylcholine or isoproterenol in dilating the feline pulmonary vascular bed and that responses to VIP are not dependent on a muscarinic or beta-adrenergic mechanism or release of a dilator prostaglandin.

Methylene blue selectively inhibits pulmonary vasodilator responses in cats

1989 ◽  
Vol 66 (3) ◽  
pp. 1513-1517 ◽  
Author(s):  
A. L. Hyman ◽  
P. J. Kadowitz ◽  
H. L. Lippton
Keyword(s):  
Methylene Blue ◽  
Arterial Pressure ◽  
Left Atrial ◽  
Vascular Tone ◽  
Aortic Pressure ◽  
Base Line ◽  
Control Value ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pulmonary Vascular Bed

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3′,5′-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30–45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.

Pulmonary vasodilation to adrenomedullin: a novel peptide in humans

1995 ◽  
Vol 268 (6) ◽  
pp. H2211-H2215 ◽  
Author(s):  
J. Heaton ◽  
B. Lin ◽  
J. K. Chang ◽  
S. Steinberg ◽  
A. Hyman ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasodilation ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Cgrp Receptor Antagonist ◽  
Pulmonary Vascular Bed

The present study investigates the effects of human adrenomedullin (ADM) on the pulmonary vascular bed of isolated, blood-perfused rat lung. Because pulmonary blood flow and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. Under conditions of resting (low) pulmonary vasomotor tone, intra-arterial bolus injections of ADM-(1-52) and two truncated sequences of ADM-(1-52) [ADM-(1-12) and ADM-(13-52)] did not alter pulmonary arterial pressure. When pulmonary vasomotor tone was increased by U-46619, a thromboxane A2 mimic, intra-arterial bolus injections of ADM-(1-52) and ADM-(13-52) at similar doses produced similar, dose-dependent reductions in pulmonary arterial pressure. On a molar basis, ADM-(1-52) had greater pulmonary vasodilator activity than isoproterenol. In contrast, ADM-(1-12) had no activity. When pulmonary vasomotor tone was actively increased to the same level using KCl, the pulmonary vasodilator activity of ADM-(13-52) was decreased 10-fold. The present data demonstrate that ADM-(1-52) dilates the pulmonary vascular bed and suggest that the pulmonary vasodilator activity of ADM is greater on pulmonary blood vessels preconstricted through a receptor-dependent mechanism. Because meclofenamate, nitro-L-arginine methyl ester, methysergide, BW A-1433U83, U-37883A, and calcitonin gene-related peptide [CGRP-(8-37)], a CGRP-receptor antagonist, did not alter the pulmonary vasodilator response to ADM-(1-52), the present data suggest that ADM dilates the pulmonary vascular bed independently of cyclooxygenase products, endothelium-derived relaxation factor, serotoninergic receptors, adenosine1 purinoreceptors, ATP-dependent potassium channels, and CGRP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats

1996 ◽  
Vol 270 (5) ◽  
pp. L782-L789 ◽  
Author(s):  
B. D. Nossaman ◽  
C. J. Feng ◽  
A. D. Kaye ◽  
B. DeWitt ◽  
D. H. Coy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Vascular Resistance ◽  
Rat Lung ◽  
Related Peptide ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Carboxy Terminal ◽  
Pulmonary Vascular Bed

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Tone-dependent responses to acetylcholine in the feline pulmonary vascular bed

1988 ◽  
Vol 64 (5) ◽  
pp. 2002-2009 ◽  
Author(s):  
A. L. Hyman ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Base Line ◽  
High Tone ◽  
Vascular Responses ◽  
Vascular Bed ◽  
Vasoconstrictor Response ◽  
Steady Level ◽  
Low Tone ◽  
Type Receptor ◽  
Pulmonary Vascular Bed

The effects of an increase in base-line tone on pulmonary vascular responses to acetylcholine were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, intralobar injections of acetylcholine under low-tone base-line conditions increased lobar arterial pressure in a dose-related manner. When tone was increased moderately by alveolar hypoxia, acetylcholine elicited dose-dependent decreases in lobar arterial pressure, and at the highest dose studied, acetylcholine produced a biphasic response. When tone was raised to a high steady level with the prostaglandin analogue, U46619, acetylcholine elicited marked dose-related decreases in lobar arterial pressure. Atropine blocked both vasoconstrictor responses at low tone and vasodilator responses at high tone, whereas meclofenamate and BW 755C had no effect on responses to acetylcholine at low or high tone. The vasoconstrictor response at low tone was blocked by pirenzepine (20 and 50 micrograms/kg iv) but not gallamine (10 mg/kg iv). The vasodilator response at high tone was not blocked by pirenzepine (50 micrograms/kg iv) or gallamine or pancuronium (10 mg/kg iv). The present data support the concept that pulmonary vascular responses to acetylcholine are tone dependent and suggest that the vasoconstrictor response under low-tone conditions is mediated by a high-affinity muscarinic (M1)-type receptor. These data also suggest that vasodilator responses under high-tone conditions are mediated by muscarinic receptors that are neither M1 nor M2 low-affinity muscarinic-type receptor and that responses to acetylcholine are not dependent on the release of cyclooxygenase or lipoxygenase products.

Differential effects of L-N5-(1-iminoethyl)-ornithine on tone and endothelium-dependent vasodilator responses

1997 ◽  
Vol 273 (3) ◽  
pp. L588-L594 ◽  
Author(s):  
B. J. DeWitt ◽  
H. C. Champion ◽  
J. R. Marrone ◽  
D. B. McNamara ◽  
T. D. Giles ◽  
...  
Keyword(s):  
Methyl Ester ◽  
Substance P ◽  
Arterial Pressure ◽  
Inhibitory Effect ◽  
Benzyl Ester ◽  
Inhibitory Effects ◽  
Synthesis Inhibitor ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pulmonary Vascular Bed

The effects of the nitric oxide (NO) synthesis inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO) on baseline tone and on responses to the endothelium-dependent vasodilator agents were investigated in the pulmonary vascular bed of the cat under constant-flow conditions. When administered in doses of 1 and 5 mg/kg i.v., L-NIO inhibited pulmonary vasodilator responses to acetylcholine, bradykinin, and substance P but did not alter vasodilator responses to adenosine, pinacidil, or adrenomedullin. L-NIO in doses of 1-10 mg/kg i.v. did not significantly affect baseline lobar arterial pressure, and when administered in doses of 10-30 mg/kg i.v. the inhibitory effect on responses to bradykinin and substance P was not greater than that observed when the lower doses of L-NIO were administered. L-NIO in doses of 5-30 mg/kg i.v. reduced plasma reactive nitrogen intermediate levels. The inhibitory effects of L-NIO were similar to the inhibitory effects of N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, and N omega-nitro-L-arginine benzyl ester. The highest dose of L-NIO studied (30 mg/kg i.v.) caused a significant increased in lobar arterial pressure, and the administration of N omega-nitro-L-arginine methyl ester (100 mg/kg i.v.) caused a significant increase in lobar arterial pressure in animals previously treated with L-NIO (1 mg/kg i.v.). The results of the present study show that the effects of L-NIO on endothelium-dependent vasodilator responses and on baseline tone can be separated and may be interpreted to suggest that basal release of NO does not play an important role in the maintenance of baseline tone in the pulmonary vascular bed of the cat.

Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed

1993 ◽  
Vol 74 (4) ◽  
pp. 1704-1711 ◽  
Author(s):  
T. J. McMahon ◽  
L. J. Ignarro ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Left Atrial ◽  
Vascular Tone ◽  
Vagal Stimulation ◽  
Phosphodiesterase Inhibitor ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Synthesis Inhibitor ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

The influence of Zaprinast (M&B 22948), a guanosine 3′,5′-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, was investigated in the pulmonary vascular bed of the cat under conditions of controlled blood flow and constant left atrial pressure. Under baseline conditions, injections of Zaprinast into the perfused lobar artery produced small decreases in lobar arterial pressure without altering systemic arterial or left atrial pressure. When tone was increased with U-46619, Zaprinast caused larger dose-dependent decreases in lobar arterial pressure without altering left atrial pressure. The decreases in lobar arterial pressure were reduced significantly by treatment with the nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the guanylate cyclase inhibitor methylene blue. Under elevated tone conditions, efferent vagal stimulation and intralobar injections of acetylcholine, substance P, NO solution, and the S-nitrosothiols [S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-L-cysteine (CysNO)] decreased lobar arterial pressure in a frequency-dependent and dose-related manner. After treatment with Zaprinast, the decreases in lobar arterial pressure in response to efferent vagal stimulation, the endothelium-dependent vasodilators, and the nitrovasodilators were not changed, whereas the duration of the vasodilator responses as measured by the half times was increased significantly. Vasodilator responses to adenosine, albuterol, and pinacidil were not altered by Zaprinast. These data suggest that cGMP hydrolysis in the lung is rapid and that endothelium-derived NO is important in stimulating basal cGMP production and in regulating vascular tone.(ABSTRACT TRUNCATED AT 250 WORDS)

L-NAME enhances pulmonary vasoconstriction without inhibiting EDRF-dependent vasodilation

1992 ◽  
Vol 73 (6) ◽  
pp. 2432-2439 ◽  
Author(s):  
H. L. Lippton ◽  
Q. Hao ◽  
A. Hyman
Keyword(s):  
Arterial Pressure ◽  
Receptor Agonist ◽  
Bolus Administration ◽  
Vasodilator Response ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasoconstrictor Response ◽  
Serotonin2 Receptor ◽  
Pulmonary Vascular Bed

The purpose of the present study was to determine the influence of NG-nitro-L-arginine methyl ester (L-NAME) on pulmonary vascular responses to endothelium-dependent relaxing factor- (EDRF) dependent and EDRF-independent substances in the pulmonary vascular bed of the anesthetized cat. Because pulmonary blood flow and left atrial pressure were kept constant, changes in lobar arterial pressure directly reflect changes in pulmonary vascular resistance. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of acetylcholine, bradykinin, serotonin, and 5-carboxyamidotryptamine (a serotonin1A receptor agonist) decreased lobar arterial pressure in a dose-related manner. The pulmonary vasodilator response to serotonin, but not to 5-carboxyamidotryptamine, acetylcholine, and bradykinin, was significantly decreased by L-NAME (100 mg/kg i.v.). Administration of ritanserin (0.5 mg/kg i.v.), but not L-arginine (1 g/kg i.v. with 60 mg.kg-1 x min-1 i.v. infusion), reversed the inhibitory effects of L-NAME on the pulmonary vasodilator response to serotonin and abolished the enhanced pulmonary vasoconstrictor response to (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoproprane hydrochloride (a serotonin2 receptor agonist) after L-NAME administration. In conclusion, the present experiments suggest that L-NAME inhibits the pulmonary vasodilator response to serotonin by increasing the sensitivity of serotonin2 receptor-mediated vasoconstriction and not by inhibiting EDRF formation. Because the pulmonary vasodilator responses to bolus administration of acetylcholine and bradykinin were not inhibited by L-NAME, these data suggest that L-NAME does not appear to be an adequate probe to study the role of endogenous EDRF in the adult feline pulmonary vascular bed in vivo.

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin

1991 ◽  
Vol 71 (5) ◽  
pp. 2026-2031 ◽  
Author(s):  
T. J. McMahon ◽  
J. S. Hood ◽  
J. A. Bellan ◽  
P. J. Kadowitz
Keyword(s):  
Methyl Ester ◽  
Left Atrial ◽  
Vascular Tone ◽  
Control Period ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pressor Responses ◽  
Pulmonary Vascular Bed

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3′,5′-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.

Pulmonary vasodilator responses to atrial natriuretic factor and sodium nitroprusside

1989 ◽  
Vol 67 (6) ◽  
pp. 2269-2275 ◽  
Author(s):  
I. Cigarini ◽  
S. Adnot ◽  
P. E. Chabrier ◽  
I. Viossat ◽  
P. Braquet ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Atrial Natriuretic Factor ◽  
Vascular Tone ◽  
Venous Pressure ◽  
Lung Lobe ◽  
Vascular Bed ◽  
Natriuretic Factor ◽  
Pulmonary Vasodilator ◽  
Atrial Natriuretic ◽  
Pulmonary Vascular Bed

The objective of this study was to determine the direct actions of atrial natriuretic factor (ANF) on the pulmonary vascular bed and to compare these actions with those of sodium nitroprusside (SNP). The responses to incremental infusion rates of 1, 5, 10, and 50 ng.kg-1.min-1 synthetic human ANF and to 1-2 micrograms.kg-1.min-1 SNP were examined in the in situ autoperfused lung lobe of open-chest anesthetized pigs under conditions of normal and elevated pulmonary vascular tone. During basal conditions, ANF and SNP caused small but significant reductions in pulmonary artery pressure (Ppa) and pulmonary venous pressure (Ppv) with no change in lobar vascular resistance (LVR). When pulmonary vascular tone was increased by prostaglandin F2 alpha (20 micrograms/min), ANF infusion at doses greater than 1 ng.kg-1.min-1 decreased Ppa and LVR in a dose-related fashion. Infusion of 50 ng.kg-1.min-1 ANF and of 2 micrograms.kg-1.min-1 SNP maximally decreased Ppa, from 33 +/- 3 to 20 +/- 2 mmHg (P less than 0.001) and from 31 +/- 4 to 18 +/- 1 mmHg (P less than 0.001), respectively. At these doses, ANF reduced systemic arterial pressure by only 11.5 +/- 3% compared with 34 +/- 4% decreased with SNP (P less than 0.001). The results indicate that ANF, similarly to SNP, exerts a direct potent vasodilator activity in the porcine pulmonary vascular bed, which is dependent on the existing level of vasoconstrictor tone.

Nisoldipine inhibits vasoconstrictor responses in the cat pulmonary vascular bed

1989 ◽  
Vol 66 (6) ◽  
pp. 2885-2890 ◽  
Author(s):  
P. J. Kadowitz ◽  
H. L. Lippton ◽  
J. A. Bellan ◽  
A. L. Hyman
Keyword(s):  
Arterial Pressure ◽  
Vascular Resistance ◽  
Blocking Agent ◽  
Systemic Arterial Pressure ◽  
Calcium Entry ◽  
Bay K 8644 ◽  
Vascular Bed ◽  
Adrenoceptor Agonists ◽  
Thromboxane Receptors ◽  
Pulmonary Vascular Bed

The influence of nisoldipine, a dihydropyridine calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the feline pulmonary vascular bed under conditions of controlled blood flow. The calcium channel blocking agent caused a small reduction in lobar vascular resistance and blocked pulmonary vasoconstrictor responses to BAY K 8644, an agent which promotes calcium entry. The calcium entry blocking agent also reduced pulmonary vasoconstrictor responses to methoxamine and to BHT 933, alpha 1- and alpha 2-adrenoceptor agonists, and to U 46619, an agent which mimics the actions of thromboxane A2. Although there was a marked difference in vasoconstrictor potency in the pulmonary vascular bed, responses to the thromboxane mimic and to the alpha 1- and alpha 2-adrenoceptor agonists were reduced by approximately the same extent. The increases in systemic arterial pressure in response to BAY K 8644, methoxamine, and BHT 933 were also reduced by nisoldipine, and the calcium entry antagonist reduced systemic arterial pressure and systemic vascular resistance. The results of the present study suggest that an extracellular source of calcium is required for the maintenance of vascular tone and for the expression of vasoconstrictor responses, resulting from activation of alpha 1- and postjunctional alpha 2-adrenoceptors and thromboxane receptors in the feline pulmonary vascular bed.

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