Kinin B2 receptor is not involved in enalapril-induced apoptosis and regression of hypertrophy in spontaneously hypertensive rat aorta: possible role of B1 receptor.
1. Treatment with enalapril induces smooth muscle cell apoptosis and regression of aortic hypertrophy in spontaneously hypertensive rats (SHRs), whereas combined blockade of angiotensin II AT(1) and AT(2) receptors does not. We postulated that vascular apoptosis with enalapril involves enhanced half-life of bradykinin (BK) and kinin B(2) receptor stimulation. 2. SHR, 11-weeks old, were treated for 4 weeks with enalapril (30 mg kg(-1) day(-1)), Hoe 140 (500 microg kg(-1) day(-1); B(2) receptor antagonist), alone or in combination. Controls received vehicle. 3. The half-life of hypotensive responses to intra-arterial bolus injections of BK were significantly increased in SHR anesthetized after 4 weeks of enalapril, an effect prevented by Hoe 140. The magnitude of BK-induced hypotension was significantly attenuated in all rats treated with Hoe 140. 4. As compared to placebo, enalapril treatment significantly reduced blood pressure (-34+/-2%), aortic hypertrophy (-20+/-3%), hyperplasia (-37+/-5%) and DNA synthesis (-61+/-8%), while it increased aortic DNA fragmentation by two-fold. Hoe 140 given alone or in combination with enalapril affected none of these parameters. 5. As a possible alternative mechanism, aortae isolated during the second week of enalapril treatment showed a transient upregulation of contractile responses to des-Arg(9)BK (EC(50)<1 nM), which were significantly reduced by [Leu(8)]des-Arg(9)BK (10 microM). Moreover, in vitro receptor autoradiography revealed an increase in expression of B(1) and B(2) receptor binding sites by 8-11 days of enalapril treatment. 6. Aortic apoptosis induction and hypertrophy regression with enalapril do not involve kinin B(2) receptors in SHR. Kinins acting via B(1) receptors remains a candidate mechanism.
Duguay
David
D
Department of Pharmacology, Université de Montreal Hospital (CHUM) Research Center 3840, St-Urbain St., Room 7-132B, Montréal, PQ, Canada, H2W 1T8.
Der Sarkissian
Shant
S
Kouz
Rémi
R
Ongali
Brice
B
Couture
Réjean
R
deBlois
Denis
D
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D001345:Autoradiography; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology*; D004247:DNA / Q000378:metabolism; D004656:Enalapril / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D006965:Hyperplasia / Q000473:pathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D043783:Receptor, Bradykinin B1 / Q000187:drug effects / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling
D000806:Angiotensin-Converting Enzyme Inhibitors; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D004656:Enalapril; C065679:icatibant; D004247:DNA; D001920:Bradykinin