Analysis of responses to substance P in the pulmonary vascular bed of the cat

1993 ◽  
Vol 264 (2) ◽  
pp. H394-H402 ◽  
Author(s):  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Substance P ◽  
Guanylate Cyclase ◽  
Left Atrial ◽  
Soluble Guanylate Cyclase ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Synthesis Inhibitor ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pulmonary Vascular Bed

Responses to substance P were investigated in the pulmonary vascular bed of the cat with controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, intralobar injections of substance P caused small, inconsistent reductions in lobar arterial pressure (AP) and significant reductions in mean systemic AP without affecting left atrial pressure. Decreases in lobar AP were significant and dose related when lobar vascular resistance was increased with U-46619, a thromboxane A2 mimetic. When compared with other vasodilator agents, the order of potency was substance P approximately bradykinin > pituitary adenylate cyclase activating polypeptide (PACAP) > acetylcholine (in nmol). Pulmonary vasodilator responses to substance P were unchanged by administration of atropine, glibenclamide, or sodium meclofenamate or when airflow to the left lower lung lobe was interrupted by bronchial occlusion. The NO synthesis inhibitor, N omega-nitro-L-argininemethyl ester (L-NAME), and the soluble guanylate cyclase inhibitor, methylene blue (MB), selectively inhibited pulmonary vasodilator responses to substance P and to acetylcholine. MB or L-NAME had no significant effect on pulmonary vasodilator responses to albuterol, lemakalim, or PACAP, whereas MB inhibited and L-NAME enhanced vasodilator responses to NO and sodium nitroprusside. The present investigation demonstrates that, when tone is increased experimentally, substance P has potent pulmonary vasodilator activity, and responses are not dependent on changes in bronchomotor tone, on the activation of muscarinic receptors or ATP-sensitive K+ channels, or on the release of a dilator prostaglandin but do involve, at least in part, endothelium-derived NO release and soluble guanylate cyclase activation.

Methylene blue inhibits neurogenic cholinergic vasodilator responses in the pulmonary vascular bed of the cat

1992 ◽  
Vol 263 (5) ◽  
pp. L575-L584 ◽  
Author(s):  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Methylene Blue ◽  
Arterial Pressure ◽  
Guanylate Cyclase ◽  
Left Atrial ◽  
Vagal Stimulation ◽  
Stimulus Frequency ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

The effects of methylene blue, an inhibitor of soluble guanylate cyclase, on pulmonary vasodilator responses to efferent vagal stimulation were investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. In animals pretreated with reserpine or phenoxybenzamine, under elevated tone conditions, efferent vagal stimulation at frequencies of 2-16 Hz caused stimulus-frequency-dependent decreases in lobar arterial pressure and pulmonary lobar vascular resistance. The vasodilator response to vagal stimulation was reproducible, blocked by atropine, and reduced by methylene blue. Intralobar infusion of methylene blue increased lobar arterial pressure without significantly altering systemic arterial or left atrial pressure. Methylene blue had no significant effect on vasodilator responses to isoproterenol, albuterol, atriopeptin III, lemakalim, adenosine, ATP, and pituitary adenylate cyclase-activating polypeptide-27 but significantly decreased vasodilator responses to acetylcholine, nitric oxide (NO), sodium nitroprusside, and the S-nitrosothiol, S-nitroso-N-acetyl-penicillamine. The effects of methylene blue on responses to vagal stimulation were reversible and were similar with the addition of a NO synthase inhibitor. The present data suggest that vasodilator responses to cholinergic nerve stimulation involve an increase in the production of guanosine 3',5'-cyclic monophosphate in the pulmonary vascular bed. These results provide additional evidence to support the hypothesis that neurogenically released acetylcholine induces endothelium-dependent, muscarinic, guanylate cyclase-mediated vasodilation.

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)

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.

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.

Analysis of responses to sarafotoxin 6a and sarafotoxin 6c in the pulmonary vascular bed of the cat

1991 ◽  
Vol 71 (5) ◽  
pp. 2019-2025 ◽  
Author(s):  
T. J. McMahon ◽  
J. S. Hood ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Left Atrial ◽  
Lower Lobe ◽  
Thromboxane A2 ◽  
Aortic Pressure ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Lung Lobe ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

Pulmonary vascular responses to sarafotoxins 6a and 6c (S6a and S6c) were investigated in the intact-chest cat under constant flow conditions. Injections of S6a and S6c into the perfused lobar artery caused dose-related increases in lobar arterial pressure, increased left atrial pressure, and produced biphasic changes in systemic arterial (aortic) pressure. When left atrial pressure was maintained constant, injections of S6a, S6c, and endothelin 1 (ET-1) caused dose-related increases in lobar arterial pressure. The increases in lobar arterial pressure in response to S6a and S6c were not altered by treatment with a cyclooxygenase inhibitor or a thromboxane receptor blocking agent. Increases in lobar arterial pressure in response to S6a and S6c were not altered when airflow to the left lower lung lobe was interrupted by bronchial occlusion, and pressor responses were not diminished when the left lower lobe was perfused with low-molecular-weight dextran. Under conditions of controlled blood flow and constant left atrial pressure, S6a, S6b, S6c, and ET-1 had similar pressor activity, whereas the thromboxane A2 mimic, U-46619, had far greater activity when compared on a nanomolar basis. The present studies demonstrate that S6a and S6c have significant vasoconstrictor activity in the feline pulmonary vascular bed. These data suggest that pulmonary vasoconstrictor responses to the endothelin peptides are not dependent on release of cyclooxygenase products and the activation of thromboxane A2 receptors, alterations in bronchomotor tone, or interaction with formed elements in blood.

Comparative effects of L-NNA and alkyl esters of L-NNA on pulmonary vasodilator responses to ACh, BK, and SP

1994 ◽  
Vol 266 (6) ◽  
pp. H2416-H2422 ◽  
Author(s):  
D. Y. Cheng ◽  
B. J. DeWitt ◽  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Substance P ◽  
Vagal Stimulation ◽  
Benzyl Ester ◽  
No Synthase ◽  
Flow Conditions ◽  
Inhibitory Effects ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Benzyl Esters ◽  
Pulmonary Vascular Bed

The comparative effects of the nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine (L-NNA), N omega-nitro-L-arginine methyl ester (L-NAME), and N omega-nitro-L-arginine benzyl ester (L-NABE) on baseline tone and on vasodilator responses to acetylcholine (ACh), bradykinin (BK), and substance P (SP) were compared in the pulmonary vascular bed of the cat under constant flow conditions. After administration of the NO synthase inhibitors in intravenous doses of 100 mg/kg, the increase in lobar arterial pressure and the attenuation of vasodilator responses to ACh, BK, and SP were similar, whereas responses to adenosine and felodipine, endothelium-independent vasodilator agents, were not altered. In addition to inhibiting responses to ACh, BK, and substance P, the NO synthase inhibitors enhanced vasodilator responses to S-nitroso-N-acetylpenicillamine and NO. Moreover, atropine inhibited pulmonary vasodilator responses to ACh but not to SP or BK, and L-NAME or L-NABE had no effect on the decrease in heart rate in response to efferent vagal stimulation, a muscarinic receptor-mediated response that is independent of NO release. The similar inhibitory effects of L-NNA, L-NAME, and L-NABE on vasodilator responses to ACh, BK, and SP suggest that the L-arginine analogue, L-NNA, as well as the methyl and benzyl esters of L-NNA are useful probes for studying NO-mediated endothelium-dependent responses in the pulmonary vascular bed of the intact-chest cat.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of responses to adrenomedullin-(13—52) in the pulmonary vascular bed of rats

1998 ◽  
Vol 274 (4) ◽  
pp. H1255-H1263 ◽  
Author(s):  
Bulent Gumusel ◽  
Quingzhong Hao ◽  
Albert L. Hyman ◽  
Philip J. Kadowitz ◽  
Hunter C. Champion ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Left Atrial ◽  
Channel Activation ◽  
Nitric Oxide Release ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Calcitonin Gene ◽  
Voltage Dependent ◽  
Endothelial Nitric Oxide ◽  
Pulmonary Vascular Bed

The effects of human adrenomedullin-(13—52) [hADM-(13—52)] were investigated in the rat pulmonary vascular bed and in isolated rings from the rat pulmonary artery (PA). Under conditions of controlled blood flow and constant left atrial pressure when tone was increased with U-46619, injections of hADM-(13—52) produced dose-related decreases in lobar arterial pressure. Pulmonary vasodilator responses in the intact rat and vasorelaxant responses to hADM-(13—52) in rat PA rings were inhibited by N G-nitro-l-arginine methyl ester (l-NAME) andl- N 5-(1-iminoethyl)ornithine hydrochloride (l-NIO). Vasorelaxant responses to hADM-(13—52) were also inhibited by methylene blue, endothelium removal, hADM-(26—52), and iberiotoxin, whereas meclofenamate, calcitonin gene-related peptide-(8—37) [CGRP-(8—37)], glibenclamide, and apamin were without effect. Because vasorelaxant responses to NS-1619, a large-conductance Ca2+-activated K+ channel agonist, were not altered by l-NAME and vasorelaxant responses to acetylcholine and CGRP were not altered by hADM-(26—52), the present data suggest that ADM-(13—52) acts on a receptor in the pulmonary vascular bed that is coupled to endothelial nitric oxide release. These data suggest that this nitric oxide release may lead to guanosine 3′,5′-cyclic monophosphate-dependent K+ channel activation, which produces a pulmonary vasorelaxant response through hyperpolarization of vascular smooth muscle cells. The present data suggest that ADM-(13—52) modulates receptor-mediated, but not voltage-dependent, pulmonary vascular contraction by influencing Ca2+influx. These results suggest that the ADM fragment, hADM-(13—52), acts as an endothelium-dependent vasodilator agent in the pulmonary vascular bed of the rat.

Influence of inhibitors of prostaglandin synthesis on the canine pulmonary vascular bed

1975 ◽  
Vol 229 (4) ◽  
pp. 941-946 ◽  
Author(s):  
PJ Kadowitz ◽  
BM Chapnick ◽  
PD Joiner ◽  
AL Hyman
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Vascular Resistance ◽  
Airway Pressure ◽  
Left Atrial ◽  
Prostaglandin Synthesis ◽  
Left Atrial Pressure ◽  
Small Arteries ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

The effects of two chemically dissimilar inhibitors of prostaglandin (PG) synthesis on vascular resistance and responses to pressor and depressor hormones were evaluated in the canine pulmonary vascular bed. Indomethacin or meclofenamate, 2.5-5 mg/kg iv, increased lobar arterial pressure. Since lobar blood flow was held constant and left atrial pressure did not change, the rise in pressure reflects an increase in vascular resistance. The rise in lobar pressure after indomethacin occurred in the absence of a change in lobar venous or translobar airway pressure. This agent enhanced the response to angiotensin but not to norepinephrine. Meclofenamate decreased responses to both agents. Indomethacin enhanced the dilator response to PGE1 and both indomethacin and meclofenamate increased the response to PGF2alpha. These data indicate that the rise in resistance after indomethacin or meclofenamate was the result of vasoconstriction in vessels upstream to the small veins, presumed to be small arteries. These data are consistent with the hypothesis that under resting conditions synthesis of a dilator prostaglandin may be important for the maintenance of the pulmonary vascular bed in a dilated state. However, results of the present study are not consistent with the postulate that prostaglandins modulate responses to norepinephrine but suggest that indomethacin and meclofenamate interfere with the inactivation of PGF2alpha and PGE1 in the lung.

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.

Analysis of responses to bradykinin in the pulmonary vascular bed of the cat

1994 ◽  
Vol 266 (6) ◽  
pp. H2256-H2267 ◽  
Author(s):  
B. J. DeWitt ◽  
D. Y. Cheng ◽  
T. J. McMahon ◽  
B. D. Nossaman ◽  
P. J. Kadowitz
Keyword(s):  
Methylene Blue ◽  
Arterial Pressure ◽  
Left Atrial ◽  
Soluble Guanylate Cyclase ◽  
Phosphodiesterase Inhibitor ◽  
Benzyl Ester ◽  
No Synthase ◽  
Vascular Bed ◽  
Steady Level ◽  
Pulmonary Vascular Bed

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

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