Functional study of the [Ca2+]i signaling pathway in aortas of L-NAME-hypertensive rats.

A variety of mechanisms has been proposed to suggest that nitric oxide participates in the regulation of smooth muscle free [Ca(2+)](c) (the primary determinant of contractile tone), including inhibition of Ca(2+) influx across the plasma membrane and inhibition of intracellular Ca(2+) release. In view of such considerations, the aim of this study was to investigate the possible alterations in contractile responses induced by drugs that mobilize Ca(2+) from different sources in aortae from N(G)-nitro-L-arginine methyl ester (L-NAME) hypertensive rats (LHR). Treatment with L-NAME did not alter the contractile response induced by phenylephrine; however, indomethacin increased the contraction to phenylephrine only in LHR aortae (1.36 +/- 0.08 g, n = 6, vs. 1.97 +/- 0.09 g, n = 7). Both phenylephrine and caffeine evoked rapid and phasic contractions in intact or denuded aortic rings in Ca(2+)-free solution containing EGTA. Phenylephrine-elicited phasic contractions were lower in normotensive rats (NR; 0.41 +/- 0.05 g, n = 9) than in LHR (0.57 +/- 0.06 g, n = 6) and were increased by endothelium removal only in the NR group (0.64 +/- 0.05 g, n = 6). Conversely, neither with treatment with L-NAME nor endothelium removal altered the phasic contractile responses induced by caffeine. The Ca(2+) influx stimulated with phenylephrine was greater in NR (1.95 +/- 0.08 g; pD(2) 6.06 +/- 0.69; n = 8) than in the LHR denuded aorta (1.63 +/- 0.11 g; pD(2) 3.52 +/- 0.06; n = 6). Similarly, contractions stimulated with phorbol ester in denuded arteries were greater in NR (1.76 +/- 0.08 g, n = 7) than in LHR (1.11 +/- 0.11 g, n = 7). In the same manner, indomethacin failed to alter the contraction stimulated with phorbol ester in NR arteries (2.01 +/- 0.21 g, n = 7), although it completely blocked the inhibitory effect of chronic treatment with L-NAME on this contractile response (1.94 +/- 0.24 g; n = 9). Indomethacin did not change the contractile responses stimulated by increasing concentrations of extracellular Ca(2+) in either NR aortas (1.44 +/- 0.26 g; pD(2) 4.74 +/- 0.79; n = 6) or LHR aorta (1.99 +/- 0.19 g; pD(2) 4.10 +/- 0.47; n = 8). However, in the presence of indomethacin, the Ca(2+) influx was similar in NR and LHR aortae. Taken together, these results suggest that, in this model of hypertension, the increase in agonist-induced release of Ca(2+) from intracellular stores may be partly compensated by inhibition of Ca(2+) influx and that this effect is due to the increased production of the relaxant prostanoid in vascular smooth muscle cells.