Possible role of T-type Ca2+ channels in L-NNA vasoconstriction of hypertensive rat lungs

Abstract

Acute inhibition of endothelium-derived nitric oxide (NO) synthesis by L-arginine analogs such as N omega-nitro-L-arginine (L-NNA) has little effect on basal vascular tone in normal rat lungs but elicits marked vasoconstriction in hypertensive lungs. The NO-suppressible vasoconstriction is dependent on extracellular Ca2+ but is not mediated by L-type Ca2+ channels. This study tested whether the response was mediated by Ca2+ influx through receptor-operated channels, reverse Na+/Ca2+ exchange, or low-threshold voltage-gated (T-type) Ca2+ channels. We first examined whether SKF-96365, a blocker of receptor-operated Ca2+ channels, inhibited L-NNA-induced vasoconstriction in salt solution-perfused hypertensive lungs isolated from chronically hypoxic male rats (exposed to hypobaria of 410 mmHg for 3-5 wk). Whereas 50 microM SKF-96365 inhibited pressor responses to angiotensin II and acute hypoxia, it did not reduce vasoconstriction in response to 100 microM L-NNA. We next examined effects of pretreatment with Na+/Ca2+ exchange blockers and observed that L-NNA vasoconstriction was reduced by both 100 microM amiloride and 50 microM ethylisopropyl amiloride (EIPA). The third experiment showed that each of two different blockers of T-type Ca2+ channels, 10 microM Ro-40-5967 and 300 microM nordihydroguariaretic acid, inhibited L-NNA vasoconstriction and that the combination of EIPA and Ro-40-5967 did not cause more inhibition than did Ro-40-5967 alone. These results suggest that, whereas receptor-operated Ca2+ channels are not significantly 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 and EIPA also inhibit T-type Ca2+ channels, we speculate that Ca2+ influx through these channels rather than through reverse Na+/Ca2+ exchange is an important mediator of the vasoconstriction.