EARLY BLOCKADE OF BRADYKININ B-2-RECEPTORS ALTERS THE ADULT CARDIOVASCULAR PHENOTYPE IN RATS

We evaluated whether long-term inhibition of bradykinin B-2-receptors by the long-acting antagonist Hoe 140 (D-Arg,[Hyp(3),Thi(5),D-Tic(7),O ic(8)]-bradykinin) affects the blood pressure of normotensive rats. Ne ither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systo lic pressure of adult rats on a normal or high sodium intake. In furth er experiments, pairs of Hoe 140-treated rats were mated and their off spring maintained on Hoe 140 and a normal sodium diet. Controls were g iven vehicle instead of Hoe 140. At 9 weeks of age, rats given Hoe 140 during prenatal and postnatal phases of life showed greater systolic pressures, heart rates, and body weights than controls (122+/-1 versus 113+/-1 mm Hg, 444+/-6 versus 395+/-8 beats per minute, 258+/-7 versu s 213+/-3 g, respectively, P<.01), whereas urinary creatinine excretio n was reduced (1.13+/-0.05 versus 1.36+/-0.04 mu mol/100 g body wt in controls, P<.05). The difference in blood pressure (confirmed by direc t intra-arterial measurement) persisted after 20 days of dietary sodiu m loading, whereas it was nullified by sodium restriction. In addition al experiments, the offspring of untreated rats received Hoe 140 or ve hicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140-treated rats co mpared with controls, and heart rate was similar. In addition, Hoe 140 -treated rats showed higher sodium levels in serum and erythrocytes an d a greater ratio of heart weight to body weight compared with control s; hematocrit and the ratio of kidney weight to body weight were lower . In conclusion, long-term blockade of bradykinin receptors by Hoe 140 alters the adult cardiovascular phenotype, provided that the antagoni st is given since the early phases of life. Our data suggest that endo genous kinins may play a role in the regulation of cardiovascular func tion by influencing renal function and the activity of the sympathetic nervous system during development.