The role of nitric oxide, adrenergic activation and kinin‐degradation in blood pressure homeostasis following an acute kinin‐induced hypotension

Abstract

1. Nitric oxide (NO) has been suggested as the mediator of the vascular response to bradykinin. In the present study, we found that NO did not mediate the hypotensive response to bradykinin. In addition, the significance of kininase II in terminating a kinin-induced hypotension and the role of the adrenergic system in compensating for the acute fall in blood pressure (BP) was established. 2. In normal rats, the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) induced a rise in basal BP (delta BP = 40 +/- 6 mmHg, P < 0.0014) which was not altered by pretreatment with phentolamine (delta BP = 50 +/- 6 mmHg, NS). L-NAME did not attenuate the acute fall in BP in response to bradykinin (3-30 micrograms kg-1) or kallikrein (6-300 micrograms kg-1). However, a significant decrease was observed in the duration of the hypotensive response (P < 0.027). This shorter duration was not observed after pretreatment with phenotolamine in addition to L-NAME. Phentolamine alone prolonged the hypotensive response to bradykinin (P < 0.04). These experiments confirm the role of NO-formation as a hypotensive component in BP homeostasis but not the role of NO as a mediator in kinin-induced hypotension. It further shows that the continuous NO-release also impedes the compensatory adrenergic hypertensive response following the acute fall in BP induced by bradykinin. 3. The hypertensive response to intravenously administered phenylephrine was found to be unchanged by preadministration of L-NAME (NS) thus showing that L-NAME did not change the sensitivity to the adrenergic response. In a separate protocol on L-NAME-treated rats we found no difference in heart rate (NS) during the recovery period following bradykinin before as compared to after administration of phentolamine. It was therefore concluded that the observed alterations in the duration of the hypotensive response were most probably due to changes in peripheral vascular resistance.4. To confirm further that NO is not a mediator in kinin-induced hypotension, we used an experimental model where the response to bradykinin was prolonged by preventing kinin degradation by kininase II-converting enzyme inhibitor (CEI). To produce a hypotensive response purely dependent on kinin, the studies were performed after removal of the renin-angiotensin system by nephrectomy (Nx). In this model, bradykinin (6 microg kg-1, i.v.) induced a prolonged hypotensive response. Pretreatment with LNAME did not alter the magnitude or the progression of the hypotensive response to bradykinin, thus confirming that NO was not a mediator in BK-induced hypotension.5. To study the mechanisms involved in terminating the hypotensive response to bradykinin, the results from the Nx CEI-treated rats were compared with Nx animals not treated with CEL. In the latter group,bradykinin induced a short hypotensive response, i.e. 0.5 +/- 0.1 min as compared to the 17 +/- 1 min after CEI (P<0.003). After kininase II-inhibition (and L-NAME), BP recovery was totally dependent on the adrenergic system, since phentolamine prevented a recovery in BP during the experimental period(P<0.01, compared to the CEI/L-NAME group). These results demonstrate the importance of kininase II as the major agent in terminating a bradykinin-induced hypotension, whereas the adrenergic system plays a small, although significant role in compensating for the fall in BP. The continuous release of NO therefore not only lowers basal BP but also impedes the compensatory adrenergic response.