THE ROLE OF NITRIC-OXIDE, ADRENERGIC ACTIVATION AND KININ-DEGRADATIONIN BLOOD-PRESSURE HOMEOSTASIS FOLLOWING AN ACUTE KININ-INDUCED HYPOTENSION

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 no t mediate the hypotensive response to bradykinin. In addition, the sig nificance of kininase II in terminating a kinin-induced hypotension an d the role of the adrenergic system in compensating for the acute fall in blood pressure (BP) was established.2 In normal rats, the NO-synth ase 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 alt ered by pretreatment with phentolamine (Delta BP = 50 +/- 6 mmHg, NS). L-MAME did not attenuate the acute fall in BP in response to bradykin in (3-30 mu g kg(-1)) or kallikrein (6-300 mu g kg(-1)). However, a si gnificant decrease was observed in the duration of the hypotensive res ponse (P<0.027). This shorter duration was not observed after pretreat ment with phentolamine in addition to L-NAME. Phentolamine alone prolo nged the hypotensive response to bradykinin (P<0.04). These experiment s confirm the role of NO-formation as a hypotensive component in BP ho meostasis but not the role of NO as a mediator in kinin-induced hypote nsion. It further shows that the continuous NO-release also impedes th e compensatory adrenergic hypertensive response following the acute fa ll in BP induced by bradykinin. 3 The hypertensive response to intrave nously administered phenylephrine was found to be unchanged by preadmi nistration of L-NAME (NS) thus showing that L-NAME did not change the sensitivity to the adrenergic response. In a separate protocol on L-NA ME-treated rats we found no difference in heart rate (NS) during the r ecovery period following bradykinin before as compared to after admini stration of phentolamine. It was therefore concluded that the observed alterations in the duration of the hypotensive response were most pro bably due to changes in peripheral vascular resistance. 4 To confirm f urther 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 inhib itor (CEI). To produce a hypotensive response purely dependent on kini n, the studies were performed after removal of the renin-angiotensin s ystem by nephrectomy (Nx). In this model, bradykinin (6 mu g kg(-1), i .v.) induced a prolonged hypotensive response. Pretreatment with L-NAM E did not alter the magnitude or the progression of the hypotensive re sponse to bradykinin, thus confirming that NO was not a mediator in BK -induced hypotension. 5 To study the mechanisms involved in terminatin g the hypotensive response to bradykinin, the results from the Nx CEI- treated rats were compared with Nx animals not treated with CEI. In th e 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). A fter kininase II-inhibition (and L-NAME), BP recovery was totally depe ndent on the adrenergic system, since phentolamine prevented a recover y in BP during the experimental period (P<0.01, compared to the CEI/L- NAME group). These results demonstrate the importance of kininase II a s the major agent in terminating a bradykinin-induced hypotension, whe reas the adrenergic system plays a small, although significant role in compensating for the fall in BP. The continuous release of NO therefo re not only lowers basal BP but also impedes the compensatory adrenerg ic response.