Amlodipine, but not verapamil or nifedipine, dilates rabbit femoral artery largely through a nitric oxide- and kinin-dependent mechanism

1 We investigated the nitric oxide (NO) dependence of vasorelaxation in response to different calcium channel blockers (CCB), in rabbit femoral artery in vivo. 2 Anaesthetized rabbits underwent femoral artery ligation, and blood from the proximal artery was returned distal to the ligature through a constant infusion pump. The effects of local injection of CCB on perfusion pressure and plasma nitrite+ nitrate (NOx, which reflects local NO biosynthesis) concentration in this system were determined. 3 Intra-arterial verapamil, nifedipine or amlodipine 10 mumol kg(-1) each reduced perfusion pressure. Pre-treatment with intra-arterial N-G-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) 1 mumol kg(-1) did not affect responses to verapamil or nifedipine, but attenuated the reduction in perfusion pressure to amlodipine, from 33.2 +/- 2.1% to 22.5 +/- 1.6% (P = 0.002). 4 Intra-arterial amlodipine - unlike verapamil or nifedipine - increased femoral venous NOx, from 9.1 +/- 0.4 muM to 14.1 +/- 0.5 muM (P = 0.005). 5 The bradykinin B-2 receptor antagonist HOE 140, 30 mg kg(-1), attenuated the reduction in perfusion pressure and abolished the rise in venous NOx concentration, following intra-arterial amlodipine. 6 Amlodipine potently inhibited serum angiotensin converting-enzyme (ACE) activity in vitro, as effectively as enalapril at similar concentrations. 7 These, results suggest that the vasorelaxant effects of nifedipine and verapamil are NO-independent, whereas those of amlodipine are partly NO-dependent, in rabbit femoral artery in vivo. This effect of amlodipine occurs through B-2 receptor activation, and may be related to an increase in local bradykinin through inhibition of ACE.