Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat - PubMed (original) (raw)

Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat

T P Robertson et al. Br J Pharmacol. 2000 Sep.

Abstract

We have examined the effects of Y-27632, a specific inhibitor of Rho-activated kinases (ROCK I and ROCK II) upon sustained hypoxic pulmonary vasoconstriction (HPV) in both rat isolated small intrapulmonary arteries (IPA) and perfused rat lungs in situ. Y-27632 (100 nM - 3 microM) was found to cause a concentration-dependent inhibition of acute sustained HPV in rat IPA. Application of Y-27632 (10-600 nM) in perfused rat lungs caused no change in basal perfusion pressure, but was found to inhibit HPV in a concentration-dependent manner, resulting in complete ablation of the pressor response to hypoxia at a concentration of 600 nM. Furthermore, addition of Y-27632 at any point during hypoxia caused a reversal of HPV in perfused rat lungs. These results suggest that activation of Rho-associated kinase may be a pivotal step in the generation of sustained HPV.

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Figures

Figure 1

Figure 1

Effect of Y-27632 (1, 3 and 10 μ

M

) pre-incubation upon KPSS (A) and PGF2α (B) induced vasoconstriction in isolated rat IPA. Each point is the mean of 4–6 experiments.

Figure 2

Figure 2

Effect of Y-27632 upon HPV in rat isolated IPA. Each point is the mean of 7–25 experiments.

Figure 3

Figure 3

Effect of Y-27632 upon HPV in perfused rat lung in situ. (A) Two hypoxic challenges, 1 h apart. (B) Effect of pre-incubation with 60 n

M

Y-27632. (C) Effect of 600 n

M

Y-27632. (D) Effect of addition of Y-27632 (60 and 600 n

M

) after the establishment of the pressor response to hypoxia. Data are presented as perfusion pressure in mmHg.

Figure 4

Figure 4

Effect of pre-incubation with Y-27632 upon the maximum responses to hypoxia in the perfused lung in situ, phase 2 and phase 1 of HPV in isolated rat IPA, 100 μ

M

PGF2a and 70 m

M

KPSS in isolated rat IPA. Data are presented as per cent inhibition of the control response, and each point is the mean of 4–9 experiments. Concentration-response curves were fitted using non-linear least-squares regression (SigmaPlot, Jandel Scientific, U.S.A.).

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