Effects of angiotensin II and angiotensin converting enzyme inhibitors on contractile and growth responses in isolated carotid arteries of the rat.
We evaluated effects of inhibitors of angiotensin converting enzyme (ACE) on growth responses in isolated rat carotid arteries (CA) during continuous exposure to exogenous growth factors in vitro. In freshly isolated CA of adult Wistar-Kyoto rats (WKY) that had been denuded of endothelium, angiotensin-I (AT-I) and angiotensin-II (AT-II) induced concentration dependent contractions (1 nM to 1 microM). Captopril (100 microM) and lisinopril (10 microM) did not affect responses to AT-II, but increased the ED50 for AT-I 50-fold. To study the effects of ACE inhibition on arterial growth responses in vitro, we measured nuclear incorporation of the thymidine analogue, 5-bromo-2'-deoxyuridine (BrdUrd), during organoid culture of isolated CA segments in continuous presence of 20% calf serum. During 4 days of organoid culture 7-10% of the medial smooth muscle nuclei incorporated BrdUrd. During long-term culture (15 days) a new layer of cells developed at the adventitial border of the arterial segments. Continuous presence of captopril (10 microM to 100 microM) or lisinopril (1 microM to 10 microM) did not affect the extent of DNA synthesis in the media or in the newly formed cell layer. Unlike endothelin-1 (ET-1), exogenous AT-II did not stimulate DNA synthesis in isolated renal artery segments. These observations indicate the presence of ACE accessible to exogenous AT-I in arterial compartments other than the endothelium. Interference with this enzyme did not alter growth responses of the isolated arterial wall to serum. Since, in addition, exogenous AT-II did not stimulate intra-arterial DNA synthesis, effects of ACE-inhibitors on arterial growth responses in vivo are most likely due to an indirect effect.
Schiffers
P M
PM
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Struyker-Boudier
H A
HA
De Mey
J G
JG
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D017706:Lisinopril; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D004656:Enalapril; D004247:DNA; D000803:Angiotensin I; D002216:Captopril; D017706:Lisinopril