Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat.
Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% O(2)-90% N(2) gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in l-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase.
Casey
David B
DB
Department of Pharmacology, Health Sciences Center, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112, USA.
Badejo
Adeleke M
AM
Dhaliwal
Jasdeep S
JS
Sikora
James L
JL
Fokin
Alex
A
Golwala
Neel H
NH
Greco
Anthony J
AJ
Murthy
Subramanyam N
SN
Nossaman
Bobby D
BD
Hyman
Albert L
AL
Kadowitz
Philip J
PJ
D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D016686:Monocrotaline; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D000959:Antihypertensive Agents; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C108830:Y 27632; D009569:Nitric Oxide; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D054460:rho-Associated Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase