POSSIBLE ROLE OF T-TYPE CA2-NNA VASOCONSTRICTION OF HYPERTENSIVE RAT LUNGS( CHANNELS IN L)

Acute inhibition of endothelium-derived nitric oxide (NO) synthesis by L-arginine analogs such as N-omega-nitro-L-arginine (L-NNA) has littl e effect on basal vascular tone in normal rat lungs but elicits marked vasoconstriction in hypertensive lungs. The NO-suppressible vasoconst riction is dependent on extracellular Ca2+ but is not mediated by L-ty pe Ca2+ channels. This study tested whether the response was mediated by Ca2+ influx through receptor-operated channels, reverse Na+/Ca2+ ex change, or low-threshold voltage-gated (T-type) Ca2+ channels. We firs t examined whether SKF-96365, a blocker of receptor-operated Ca2+ chan nels, inhibited L-NNA-induced vasoconstriction in salt solution-perfus ed hypertensive lungs isolated from chronically hypoxic male rats (exp osed to hypobaria of 410 mmHg for 3-5 wk). Whereas 50 mu M SKF-96365 i nhibited presser responses to angiotensin II and acute hypoxia, it did not reduce vasoconstriction in response to 100 mu M L-NNA. We next ex amined effects of pretreatment with Na+/Ca2+ exchange blockers and obs erved that L-NNA vasoconstriction was reduced by both 100 mu M amilori de and 50 mu M ethylisopropyl amiloride (EIPA). The third experiment s howed that each of two different blockers of T-type Ca2+ channels, 10 mu M Ro-40-5967 and 300 mu M nordihydroguariaretic acid, inhibited L-N NA vasoconstriction and that the combination of EIPA and Ro-40-5967 di d not cause more inhibition than did Ro-40-5967 alone. These results s uggest that, whereas receptor-operated Ca2+ channels are not significa ntly involved in the mechanism of NO-suppressible vasoconstriction in hypertensive rat lungs, Ca2+ influx through reverse Na+/Ca2+ exchange and/or T-type Ca2+ channels may play a role. Because both amiloride an d EIPA also inhibit T-type Ca2+ channels, we speculate that Ca2+ influ x through these channels rather than through reverse Na+/Ca2+ exchange is an important mediator of the vasoconstriction.