The role of Rho-kinase in the regulation of tone in the pulmonary vascular bed in the intact chest rat
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Description
Pulmonary arterial hypertension (PH) is a rare disorder that is progressive and often fatal within 3years. Recent advances in vascular research have identified the small GTP-binding protein RhoA and its downstream effector Rho-kinase as important regulators of a variety of physiologic functions, including vascular smooth muscle contraction. Rho-kinase is expressed in most cells and increases calcium sensitization by decreasing myosin phosphatase activity, leading to increased myosin light-chain phosphorylation and smooth muscle contraction. The present study was undertaken to clarify the role of the Rho-kinase pathway in regulating baseline tone and vasoconstrictor responses in the pulmonary vascular bed under physiologic and pathophysiologic conditions. These studies were carried out to determine the therapeutic potential of Rho-kinase inhibitors and how these agents can influence the pathophysiologic state of the pulmonary vascular bed. The effect of the Rho-kinase inhibitors, fasudil, Y-27632 and SB-772077-B on pulmonary and systemic arterial pressures, and cardiac output under baseline conditions was assessed. The intravenous injections of all three Rho-kinase inhibitors caused small decreases in pulmonary arterial pressure, larger dose dependent decreases in the systemic arterial pressure, increases in the cardiac output and decreases in pulmonary and systemic vascular resistance. The results show that Rho-kinase inhibitors decrease pulmonary and systemic arterial pressures and vascular resistances under baseline conditions suggesting that the Rho-kinase pathway has a constitutive role in regulating baseline tone in both the pulmonary and systemic vascular beds. In order to evaluate the role of the Rho-kinase pathway under elevated pulmonary arterial vascular tone conditions, responses were investigated when pulmonary vascular resistance was increased with the thromboxane agonist, U-46619, the nitric oxide inhibitor L-NAME or ventilation with a 10% O2-90% N2 gas mixture During infusion of U-46619, when tone in the pulmonary vascular bed was increased to a high steady level, intravenous injections of all three Rho-kinase inhibitors caused dose-dependent decreases in pulmonary and systemic arterial pressures, increases in cardiac output and decreases in pulmonary and systemic vascular resistances. Pulmonary vasodilator responses to these agents were enhanced when baseline tone was increased with U-46619 compared to controls. These results suggest that Rho-kinase-mediated Ca2+ sensitization plays a role in mediating the response to the thromboxane receptor agonist in the pulmonary vascular bed of the rat The effect of fasudil on pulmonary and systemic arterial pressure in animals treated with the nitric oxide synthase inhibitor L-NAME was studied and L-NAME caused a significant increase in systemic and pulmonary arterial pressure and a significant decrease in cardiac output. After administration of L-NAME, intravenous injections of fasudil, Y-27632 and SB-772077-B caused significant dose-dependent decreases in systemic and pulmonary arterial pressure and increases in cardiac output. When compared to control, pulmonary vasodilator responses to fasudil were enhanced in L-NAME treated animals. The present data suggest that Rho-kinase mediates the increase in vasoconstrictor tone when NO synthesis is inhibited in the rat The hypoxic pulmonary vasoconstrictor response is a n important mechanism that increases pulmonary arterial pressure and diverts mixed venous blood away from poorly ventilated areas of the lung. This physiologic response helps maintain alveolar ventilation and blood perfusion matching and improves gas exchange. Responses to the three Rho-kinase inhibitors were studied when animals breathed a 10% O2-90% N2 gas mixture. Ventilation with the hypoxic gas decreased arterial PO2 and increased pulmonary arterial pressure. The increase in pulmonary arterial pressure in response to ventilation with 10% O2 gas mixture was reversed by the intravenous injection of fasudil, Y-27632 and SB-772077-B and prevented by these agents. These results suggest that the Rho-kinase pathway is involved in mediating the hypoxic pulmonary vasoconstrictor resposne To determine the role of Rho-kinase in an experimental model of chronic PH responses to intravenous injections of the Rho-kinase inhibitor SB-772077-B were investigated in monocrotaline-treated rats. The intravenous injection of monocrotaline increases pulmonary arterial pressure in the rat, and the pulmonary hypertensive response develops over a period of weeks, with clinical manifestations and pathologic alterations similar to those observed in human with pulmonary disease In animals treated with monocrotaline, mean pulmonary arterial pressure averaged 46 +/- 4 mm Hg when the animals were catheterized, and right heart pressures were measured 28 days after administration of the plant alkaloid. When monocrotaline-treated animals were injected with 3 or 6 mg/kg i.p. SB-772077-B starting on days 15 through 35, pulmonary arterial pressure averaged 28 +/-2 mm Hg on day 36, when right heart pressures were measured. Systemic arterial pressure was not changed significantly compared in monocrotaline-treated and monocrotaline and SB-772077-B-treated animals on days 29 and 36 after intravenous injection of the plant alkaloid. In addition to attenuating monocrotaline-induced pulmonary hypertension, it has been suggested that Rho kinase inhibitors have a selective vasodilator effect in the pulmonary vascular bed. To determine whether SB-772077-B has a selective effect, decreases in pulmonary and systemic arterial pressure response to intravenous injections of the Rho kinase inhibitor were evaluated in monocrotaline-treated rats. The intravenous injection of SB-772077-B in monocrotaline-treated rats decreased pulmonary and systemic arterial pressures suggesting that chronic administration of SB-772077-B would be useful in pulmonary hypertensive disorders, although this agent does not have selective pulmonary vasodilator activity when administered acutely These findings suggest that Rho-kinase mediated calcium sensitization is a constitutively active process that plays a major role in the physiologic regulation of vasoconstrictor tone in the pulmonary and systemic vascular beds and in mediating pulmonary vasoconstrictor responses. The observation that Rho-kinase inhibitors promote vasodilation when tone is increased by diverse mechanisms including NOS inhibition may, in part, explain the beneficial effects of Rho-kinase inhibitors in cardiovascular diseases in which endothelial dysfunction is present and vasoconstrictor tone is increased by diverse mechanisms which increase intracellular Ca2+ concentrations