EFFECTS OF CALCIUM-CHANNEL BLOCKADE ON THE AORTIC INTIMA IN SPONTANEOUSLY HYPERTENSIVE RATS

Hypertension is associated with an intimal dysfunction characterized by endothelium-dependent constriction to serotonin, decreased endothelium-dependent relaxation to acetylcholine, and a subendothelial infiltration of monocyte-macrophages. The goal of our study was to evaluate the effect of long-term calcium channel blockade with Ro 40-5967, a new long-acting calcium channel blocker, on these alterations in aortas of spontaneously hypertensive rats (SHR). Arterial blood pressure was decreased by Ro 40-5967. In aortas from Ro 40-5967-treated SHR, the serotonin ratio (maximal contraction to serotonin on rings with endothelium over maxima[ contraction on paired rings without endothelium) was reduced (1.14+/-0.10) compared with control SHR (1.72+/-0.12, P<.01) because of inhibition of maximal contraction in rings with endothelium. This effect of Ro 40-5967 was partially reversed by an inhibitor of nitric oxide (NO) synthase, N(G)-nitro-L-arginine-methyl ester, and partially inhibited in the presence of the thromboxane/prostaglandin H-2 receptor antagonist AH 23848. Maximal relaxation to acetylcholine in rings with endothelium was increased by Ro 40-5967. In rings without endothelium, Ro 40-5967 treatment enhanced the sensitivity to sodium nitroprusside-induced relaxation. Cyclic GMP content, an indicator of NO release, was not increased in aortas from Ro 40-5967-treated SHR. Thus, improvement of endothelial function was probably achieved by facilitating the action of NO at the level of the smooth muscle cells and by reducing prostaglandin H-2-induced constriction. Finally, the number of monocyte-macrophages in the subendothelium was decreased by Ro 40-5967. We conclude that long-term treatment with Ro 40-5967 reverses both the functional and morphological changes of the aortic intima in hypertension.