Rhokinase Activity Mediates Increased Basal Vascular Tone in Hypertensive Rat Lungs

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To investigate if Rho/Rho-kinase signaling plays a role in increased vascular tone in HPH, we measured acute effects of intravenous Y-27632 (10 mg/kg) on pulmonary and systemic arterial blood pressures and cardiac output in normoxic control and chronically hypoxic rats breathing 21% 02 (47). Normoxic control rats were kept at Denver's barometric pressure of -630 mmHg (inspired Po2 ~ The chronically hypoxic rats were exposed to hypobaric hypoxia (barometric pressure ~ 410 mmHg, inspired Po2 ~ 76 mmHg) for 3 to 4 weeks before being returned to normoxia for 2 days for catheterization and hemodynamic measurements. Although these rats were no longer undergoing hypoxic vasoconstriction, they maintained high pulmonary artery pressures, i.e., "residual pulmonary hypertension". While the Rho-kinase inhibitor had little effect on pulmonary artery pressure and pulmonary vascular resistance in control rats, it almost normalized the residual pulmonary hypertension in chronically hypoxic rats (Fig. 3). Y-27632 also reduced the pulmonary pressor response to acute hypoxia (10 min of 10% 02) from 10±2 to 2±0.4 mmHg in control rats and from 8±1 to 1±0.5 mmHg in chronically hypoxic rats. The vasodilation by intravenous Y-27632 was not selective for the hypertensive lung, and there was marked systemic vasodilation in both the control and chronically hypoxic rats. Interestingly, in a preliminary experiment in chronically hypoxic rats, an oral dose of Y-27632 (30 mg/kg) initially caused both pulmonary and systemic vasodilation, but whereas systemic pressure gradually returned to pretreatment level, the fall in pulmonary pressure was sustained for up to 24 hrs. We do not know why oral Y-27632 caused selective sustained pulmonary vasodilation, but it appears that chronic administration via subcutaneous osmotic minipump acts similarly (see Section 11).

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Figure 3. A: Acute intravenous administration of the Rho-kinase inhibitor Y-27632 (10 mg/kg) almost completely reverses the residual pulmonary hypertension (pulmonary artery pressure, PAP, left) and high total pulmonary resistance (TPR, right) in chronically hypoxic rats (•) after 2 days of re-exposure to normoxia. Y-27632 has minimal effects on pressure and resistance in normoxic control rats (o) (* P<0.05 vs. before value; n=5/group). B: Y-27632 (10 jxM) but not nifedipine (10 pM) markedly reduces perfusion pressure in chronically hypoxic hypertensive rat lungs (•) perfused with blood at constant flow (* P<0.05 vs. respective before value; n=3/group). Y-27632 also causes a smaller reduction in PAP in normoxic normotensive control lungs (o). These findings in both catheterized rats and perfused lungs indicate that most of the increased TPR after 3-4 weeks of chronic hypoxia is attributable to Rho-kinase-mediated vasoconstriction rather than simply to vascular remodeling.

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Y-27632 Y-27632 Nifedipine Y-27632

Figure 3. A: Acute intravenous administration of the Rho-kinase inhibitor Y-27632 (10 mg/kg) almost completely reverses the residual pulmonary hypertension (pulmonary artery pressure, PAP, left) and high total pulmonary resistance (TPR, right) in chronically hypoxic rats (•) after 2 days of re-exposure to normoxia. Y-27632 has minimal effects on pressure and resistance in normoxic control rats (o) (* P<0.05 vs. before value; n=5/group). B: Y-27632 (10 jxM) but not nifedipine (10 pM) markedly reduces perfusion pressure in chronically hypoxic hypertensive rat lungs (•) perfused with blood at constant flow (* P<0.05 vs. respective before value; n=3/group). Y-27632 also causes a smaller reduction in PAP in normoxic normotensive control lungs (o). These findings in both catheterized rats and perfused lungs indicate that most of the increased TPR after 3-4 weeks of chronic hypoxia is attributable to Rho-kinase-mediated vasoconstriction rather than simply to vascular remodeling.

In contrast to the ability of Y-27632 to both inhibit acute HPV and reverse residual pulmonary hypertension in chronically hypoxic rats after return to normoxia, we have previously observed that the L-type channel blocker nifedipine inhibits HPV but does not reduce the residual pulmonary hypertension(46, 48). We have also observed that whereas inhaled NO (80 ppm) acutely reduces the residual pulmonary hypertension by 15±2% (46), it appears to be less effective than the intravenous Rho-kinase inhibitor that reduces the pressure by 36±2% (Fig. 3A).

We have also compared the acute effects of Y-27632 and nifedipine on baseline perfusion pressure in lungs isolated from control and chronically hypoxic rats and perfused with blood at constant flow (37). Normotensive lungs were ventilated with 21% 02 and hypertensive lungs with 8% 02 to more closely mimic in vivo conditions. The Rho-kinase inhibitor, but not nifedipine, caused slight vasodilation in normotensive lungs and marked vasodilation in hypertensive lungs (the high perfusion pressure in hypertensive lungs was nearly normalized) (Fig. 3B). Although pulmonary vascular remodeling, i.e., medial thickening of pulmonary arteries and muscularization of pulmonary arterioles, is present in rats after 3-4 weeks of hypoxia (28), the ability of Y-27632 to nearly normalize the increased pulmonary vascular resistance in both catheterized rats and isolated lungs suggests that Rho-kinase-mediated vasoconstriction is a major component of the elevated resistance at this stage of HPH. It is also apparent that this Rho-kinase-mediated vasoconstriction is partially reversed by inhaled NO, but not by short-term normoxia.

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