CARDIOVASCULAR EFFECTS OF BRAIN KININ RECEPTOR BLOCKADE IN SPONTANEOUSLY HYPERTENSIVE RATS

We studied the role of brain kinins in the regulation of cardiovascula r function. Intracerebroventricular injection of 380 pmol bradykinin i ncreased mean blood pressure by 20+/-2 mm Hg (P<.01) in normotensive W istar-Kyoto (WKY) rats. Complete inhibition of this effect was achieve d with intracerebroventricular administration of the newly synthesized , long-acting B-2 receptor antagonist D-Arg,[Hyp(3),Thi(5),D-Tic(7),Oi c(8)]-bradykinin (Hoe 140). On a molar basis, Hoe 140 was two orders o f magnitude more potent than antagonists of the first generation. Baro receptor sensitivity, estimated as the heart rate response to blood pr essure changes induced by intravenous injection of phenylephrine or so dium nitroprusside, was not altered by Hoe 140 in WKY rats. In spontan eously hypertensive rats (SHR), baroreceptor reflex sensitivity to inc rements in mean blood pressure was reduced by Hoe 140 (mean slope valu e: -0.47+/-0.07 Versus -0.92+/-0.13 beats per minute per millimeter of mercury in controls, P<.05). Hoe 140 did not affect the tachycardic c omponent of the baroreceptor reflex. Two-week intracerebroventricular infusion of Hoe 140 did not alter systolic blood pressure or heart rat e in WKY rats. In SHR, systolic blood pressure increased (P<.10) simil arly during the infusion of Hoe 140 or vehicle (from 174+/-6 to 220+/- 5 mm Hg and 178+/-4 to 210+/-4 mm Hg at 2 weeks, respectively), wherea s heart rate did not change. Failure of long-term blockade of B-2 rece ptors to affect normal blood pressure of WKY rats and to blunt the pro gression of hypertension in SHR does not favor the hypothesis that bra in kinins are involved in the regulation of blood pressure. On the oth er hand, the present study suggests modulation of barorereceptor refle x sensitivity by brain kinins in genetic hypertension.