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 collar around the common carotid arteries of normocholesterolaemic rabbits. Vessel segments taken from the mid-region of the collared and control region of the same artery were studied 7 days after surgery. Placebo rabbits were provided ab libitum with regular tap water, and treated animals were supplied with water containing perindopril (0.3 mg/kg/day) for 14 days. Perindopril treatment reduced plasma angiotensin converting enzyme (ACE) activity by 88%, but did not significantly alter arterial blood pressure or heart rate. In control rings from placebo rabbits perindoprilat in vitro (0.1-1.0 microM) reduced the sensitivity to angiotension I up to 20-fold but did not affect that of angiotensin II. In placebo rabbits, the collared arterial segments were approximately five-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. Development of the lesion in placebo or perindopril-treated rabbits did not 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, whereas the maximum endothelium-dependent vasorelaxant response to acetylcholine was reduced from 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 restored in collared vessels and was no longer significantly different from the control sections. In contrast, perindoprilat in vitro (1.0 microM) did not alter the vasorelaxant response to acetylcholine in control or collared rings in a separate series of placebo rabbits. Morphologically, vessel segments taken from the centre of the collared artery of all placebo rabbits showed a thickened intima filled with cells that had the appearance of synthetic-state smooth muscle. The intimal/medial cross-sectional area ratio was reduced from 0.11 +/- 0.02 (n = 10) in placebo rabbits to 0.05 +/- 0.01 (n = 9) in perindopril-treated rabbits, whereas cross-sectional area of media of the collared vessels was similar in the two groups. Thus ACE may have important roles in the initiation and progression of atheroma-like lesions. Inhibition of ACE with perindopril reduces intimal thickening and restores the defective vasodilatation induced by the endothelial-dependent vasodilator, acetylcholine.
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
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Hickey
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Makdissi
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Hyland
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Wilks
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Dusting
D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020913:Perindopril; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000804:Angiotensin II; C053500:perindoprilat; D009569:Nitric Oxide; D012701:Serotonin; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril