We studied the role of nitric oxide and adrenergic activation in the blood pressure (BP) response to exogenous bradykinin in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rats (WKY). Rats were pretreated with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the alpha-adrenergic receptor antagonist phentolamine together with L-NAME, or phentolamine alone. Sham-injected rats were used as controls. All rats subsequently received bradykinin (3, 6, and 30 micrograms/kg i.v.). Bradykinin induced a concentration-dependent fall in BP in both WKY and SHR (P < .0005). The change in BP was greater in SHR than WKY (P < .0001). BP before bradykinin administration was elevated in the L-NAME group in both strains. In WKY, L-NAME or L-NAME plus phentolamine did not alter the delta BP concentration-response curve to bradykinin (P = NS), whereas in SHR, the delta BP concentration-response curve was attenuated (P < .0048). The attenuation was observed for the two lower bradykinin doses (P < .0005) but not the highest. In SHR, phentolamine alone reduced BP before bradykinin to the same level as in WKY controls, and its delta BP concentration-response curve was not different from that of the normotensive controls or L-NAME and L-NAME plus phentolamine SHR groups. No difference was observed in the duration of the hypotensive response in SHR compared with WKY. The present results confirm that in normotensive rats, the hypotensive effect of bradykinin was mediated by an unknown mechanism other than through the release of nitric oxide. However, in SHR, this mechanism was amplified by additional activation of nitric oxide synthesis. This bradykinin-activated nitric oxide production may be a pressure-induced mechanism to counteract the hypertensive condition.

1 The role of endogenous bradykinin in mean arterial blood pressure (BP) homeostasis was studied in spontaneously hypertensive (SHR) and normotensive (WKY) rats by the use of a bradykinin B2-receptor antagonist (BKant; Hoe 140, 11.6 pg kg-') and converting enzyme (kininase II) inhibitor (captopril, 10 mg). To obtain a response to captopril that was induced through inhibition of kinin-degradation only and not through inhibition of angiotensin II-formation, the studies were performed on binephrectomized male rats to eliminate the renin-angiotensin system. 2 The role of the nitric oxide (NO) and the adrenergic systems were evaluated by the use of NOsynthase inhibitor (L-NAME, 0.3 g kg-') and phentolamine (2 mg kg-'), respectively. 3 The rats were anaesthetized and pretreated with two injections of vehicle (PBS) or drugs spaced 5 min apart: PBS + PBS; BKant + PBS; PBS + L-NAME; BKant + L-NAME; or phentolamine + L-NAME. All rats were given captopril 15 min later. Time-control groups were treated with L-NAME but not captopril. 4 In WKY rats, captopril did not significantly alter BP in any of the groups. In the SHR-PBS + PBS group, on the other hand, captopril induced an immediate fall in BP (ABP = -23 + 4 mmHg, P< 0.0017) which was completely blocked by BKant (ABP=2+2 mmHg) (P<0.0011). L-NAME did not significantly alter the immediate hypotensive response to captopril but disclosed a later hypertensive reaction. In L-NAME + BKant-treated rats, both the hypotensive response and the late hypertension was abolished. In rats treated with phentolamine + L-NAME, the immediate fall in BP was not different from the controls whereas the late hypertension was absent. 5 BKant itself had no effect on basal BP in either WKY or SHR even when a 10 times higher dose was tested in a separate set of experiments. This was true also for conscious, nonnephrectomized SHR rats. 6 It was concluded that endogenous production of bradykinin was demonstrable through kininase IIinhibition in hypertensive but not in normotensive rats. However, this endogenous bradykinin did not play a role in basal BP homeostasis. The captopril-induced hypotension depended on kinin but, under the present conditions, not on NO as a mediator. The fall in BP induced a compensatory adrenergic hypertensive response which was revealed when the continuous NO-synthesis was blocked by L-NAME.

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1 We have, in the present work, studied the importance of the kidneys and the renal hypotensive agent, medullipin, in modulating the blood pressure (BP) response to bradykinin, as well as their ability to influence the balance between the NO-and the adrenergic systems superimposed on a bradykinininduced hypotension.2 The rats were pretreated with the NO-synthase inhibitor, Nw-nitro-L-arginine methyl esther (L-NAME) (0.3 g kg-1), proadifen (50 mg kg-1), an inhibitor of the medullipin-system, and nephrectomy (24 h) (Nx) alone, and L-NAME in combination with proadifen, Nx or phentolamine (2 mg kg-1).Subsequent injections of bradykinin (3, 6, 15, 30 jug kg-1) induced an acute hypotensive response. The fall in BP was dose-dependent in all groups (P<0.01), except in the Nx/L-NAME group. No differences in the fall in BP were observed between the groups. 3 The duration of the hypotensive response was abbreviated after L-NAME-treatment (P<0.05). Proadifen-treatment and Nx had no significant effect on the duration of the hypotension in control rats or in L-NAME-treated rats. Pretreatment with phentolamine prevented the L-NAME-induced rapid restoration of BP (P<0.001). 4 In L-NAME-treated rats a transient hypertension followed the bradykinin-induced hypotensive response. This hypertensive response was not observed after Nx or proadifen-treatment alone, and addition of Nx or proadifen to L-NAME treatment did not alter the hypertensive response as compared to L-NAME alone. Phentolamine, however, abolished the L-NAME-induced hypertension (P<0.05). 5 In conclusion, the present results do not support the involvement of the medullipin-system or other hypotensive systems localized in the kidneys, in modulating and counteracting the compensatory adrenergic response following an acute bradykinin-induced hypotension. A hampering modulating effect of the NO-system on this compensatory adrenergic response was confirmed, indicating a close relationship between these two systems in BP homeostasis.