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 maximal 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, NG-nitro-L-arginine-methyl ester, and partially inhibited in the presence of the thromboxane/prostaglandin H2 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 H2-induced constriction. Finally, the number of monocyte-macrophages in the subendothelium was decreased by Ro 40-5967. 40-5967.(ABSTRACT TRUNCATED AT 250 WORDS)
Gray
G A
GA
Preclinical Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Clozel
M
M
Clozel
J P
JP
Baumgartner
H R
HR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D008297:Male; D020748:Mibefradil; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D013931:Thromboxanes; D009599:Nitroprusside; D020748:Mibefradil; D009569:Nitric Oxide; D012701:Serotonin; C046926:AH 23848; D001120:Arginine; D006152:Cyclic GMP; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester