LOSARTAN AND CAPTOPRIL FOLLOW DIFFERENT MECHANISMS TO DECREASE PRESSOR-RESPONSES IN THE PITHED RAT

1. We investigated the effects of losartan and captopril on noradrenal ine (NA) release and vascular reactivity to NA in the pithed rat, 2, T he presser responses to sympathetic nerve stimulation (SNS) before and after i,v, administration of captopril (1 mg/kg), losartan (1 and 10 mg/kg), sodium nitroprusside (SNP; 5 mu g/kg per min), losartan (1mg/k g) + captopril (1mg/kg), captopril (1mg/kg) + losartan (1mg/kg) or the bradykinin B-2 receptor antagonist HOE140 (1mg/kg) + captopril (1mg/k g) were measured, Plasma NA concentrations were measured during 60 s S NS before and after losartan (1mg/kg), captopril (1mg/kg), SNP (5 mu g /kg per min) or HOE140 (1mg/kg) + captopril (1mg/kg), Presser response s to exogenous NA were measured before and after administration of los artan (1 mg/kg), captopril (1 mg/kg), HOE 140 (1 mg/kg) + captopril (1 mg/kg) or the nitric oxide synthase (NO) inhibitor, NG-nitro-L-arginin e methyl ester (L-NAME; 10 mg/kg) + captopril (1 mg/kg). 3, Captopril, losartan and SNP decreased frequency-response curves to a similar ext ent, The captopril-induced decrease in presser responses to SNS was re stored by pretreatment with HOE 140, Adding captopril to losartan decr eased the curve more than did adding losartan to captopril, Both losar tan, captopril and HOE 140 + captopril significantly decreased the pla sma NA concentration after SNS (34.1+/-5.0, 27.4+/-2.6 and 41.4+/-8.1% , respectively), Sodium nitroprusside did not change the plasma NA con centration after SNS (3.8+/-28.2%), The dose-response curves to i,v, N A were not affected by losartan, but were significantly decreased by c aptopril, However, responses to NA that were reduced by captopril were restored to control values by pretreatment with HOE 140 or L-NAME.4, We suggest that both losartan and captopril decrease presser responses to SNS by inhibiting NA release from sympathetic nerve endings; howev er, captopril also decreases 'vascular reactivity' to NA, which is med iated by nitric oxide produced by activation of the bradykinin B-2 rec eptors.