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1 Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
* To whom correspondence should be addressed. E-mail: tresta{at}salud.unm.edu.
Myogenic tone in the pulmonary vasculature of normoxic adult animals is minimal or nonexistent. Whereas chronic hypoxia (CH) increases basal tone in pulmonary arteries, it is unclear if a portion of this elevated tone is due to development of myogenicity. Since basal arterial RhoA activity and Rho kinase (ROK) expression are augmented in CH, we hypothesized that CH elicits myogenic reactivity in pulmonary arteries through ROK-dependent vascular smooth muscle (VSM) Ca2+ sensitization. To test this hypothesis, we assessed the contribution of ROK to basal tone and pressure-induced vasoconstriction in endothelium-denuded pulmonary arteries [50-300μm inner diameter (i.d.)] from control and CH (4wk at 0.5atm) rats. Arteries were loaded with fura-2 AM to continuously monitor VSM [Ca2+]i. Basal VSM [Ca2+]i was not different between groups. The ROK inhibitor, HA-1077 (100nM-30µM), caused a concentration-dependent reduction of basal tone in CH arteries, but had no effect in control vessels. In contrast, protein kinase C inhibition with GF109203X (1µM) did not alter basal tone. Furthermore, significant vasoconstriction in response to step-wise increases in intraluminal pressure (5-45mmHg) was observed at 12, 15, 25 and 35mmHg in arteries (50-200µm i.d.) from CH rats. This myogenic reactivity was abolished by HA-1077 (10µM) but not by GF109203X. VSM [Ca2+]i was not altered by HA-1077, GF109203X or by increases in pressure in either group. Myogenicity was not observed in larger vessels (200-300µm i.d.). We conclude that CH induces myogenic tone in small pulmonary arteries through ROK-dependent myofilament Ca2+ sensitization.
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