PERINDOPRIL TREATMENT PREVENTS THE LOSS OF ENDOTHELIAL NITRIC-OXIDE FUNCTION AND DEVELOPMENT OF NEO INTIMA IN RABBITS

An atheroma-like neo-intima was produced by positioning a flexible col lar around the common carotid arteries of normocholesterolaemic rabbit s. Vessel segments taken from the mid-region of the collared and contr ol region of the same artery were studied 7 days after surgery. Placeb o rabbits were provided ab libitum with regular tap water, and treated animals were supplied with water containing perindopril (0.3 mg/kg/da y) for 14 days. Perindopril treatment reduced plasma angiotensin conve rting enzyme (ACE) activity by 88%, but did not significantly alter ar terial blood pressure or heart rate, In control rings from placebo rab bits, perindoprilat in vitro (0.1-1.0 mu M) reduced the sensitivity to angiotension I up to 20-fold but did not affect that of angiotensin I I, In placebo rabbits, the collared arterial segments were approximate ly Eve-fold more sensitive to the vasoconstrictor action of 5-HT (P<0. 05) than the corresponding control segments. Perindopril treatment did not prevent the supersensitivity of the collared vessels to 5-HT. Dev elopment of the lesion in placebo or perindopril-treated rabbits did n ot alter the vascular sensitivity to either angiotensin I (10(-9)-10(- 5) M) or angiotensin II (10(-10)-10(-6) M). The vasorelaxant action of sodium nitroprusside was similar in collared and control rings, where as the maximum endothelium-dependent vasorelaxant response to acetylch oline was reduced horn 68+/-5% in control rings, to 44 +/- 8% (mean+/- S.E.M., n=9, P<0.05) in collared rings of placebo-treated rabbits, In the perindopril-treated animals, this impairment of relaxation was res tored in collared vessels and was no longer significantly different fr om the control sections,In contrast, perindoprilat in vitro (1.0 mu M) did not alter the vasorelaxant response to acetylcholine in control o r collared rings in a separate series of placebo rabbits. Morphologica lly vessel segments taken from the centre of the collared artery of al l placebo rabbits showed a thickened intima filled with cells that had the appearance of synthetic-state smooth muscle. The intimal/medial c ross-sectional area ratio was reduced from 0.11+/-0.02 (n=10) in place bo rabbits to 0.05+/-0.01 (n=9) in perindopril-treated rabbits, wherea s cross-sectional area of media of the collared vessels was similar in the two groups, Thus ACE may have important roles in the initiation a nd progression of atheroma-like lesions. Inhibition of ACE with perind opril reduces intimal thickening and restores the defective vasodilata tion induced by the endothelial-dependent vasodilator, acetylcholine. (C) 1996 Academic Press Limited