CHRONIC HYPOXIA SELECTIVELY AUGMENTS ENDOTHELIUM-DEPENDENT PULMONARY ARTERIAL VASODILATION

We have previously demonstrated that chronic hypoxia (CH) augments pul monary arterial dilation to the endothelium-derived nitric oxide (EDNO )-dependent pulmonary vasodilator arginine vasopressin (ATP). The pres ent study examined 1) whether this enhanced vasoreactivity is observed with other agents that act by stimulating constitutive NO synthase (c NOS), 2) whether CH increases arterial vascular smooth muscle sensitiv ity to NO, and 3) whether endogenous endothelin (ET) or an endothelium -derived hyperpolarizing factor (EDHF) contributes to this altered art erial reactivity following CH. We examined responses to the receptor-m ediated EDNO-dependent dilators histamine and ET-1, the nonreceptor-me diated EDNO-dependent dilator ionomycin, and the NO donors 1,3-propane diamine, 4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino] butyl} (sp ermine NONOate) and S-nitroso-N-acetylpenicillamine (SNAP:, in U-46619 -constricted, isolated perfused lungs from control and CH rats. Additi onal experiments examined responses to ATP in the presence of the ET-r eceptor antagonist PD-145065 or the K+ channel blockers glibenclamide or tetraethylammonium (TEA) in lungs from each group. Microvascular pr essure was assessed by double occlusion, allowing calculation of segme ntal resistances. Total and arterial vasodilatory responses to histami ne, ET-1, and ionomycin were augmented in lungs from CH vs, control an imals. However, CH did not alter the vasodilation to spermine NONOate or SNAP. PD-145065, glibenclamide, and TEA had no effect on responses to AVP in either group. We conclude that increased activity of arteria l cNOS may be responsible for the augmented pulmonary arterial dilatio n to EDNO-dependent vasodilators following CH.