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),Oic(8)]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140-treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet. Controls were given 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 versus 213+/-3 g, respectively, P<.01), whereas urinary creatinine excretion 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 direct intra-arterial measurement) persisted after 20 days of dietary sodium loading, whereas it was nullified by sodium restriction. In additional experiments, the offspring of untreated rats received Hoe 140 or vehicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140-treated rats compared with controls, and heart rate was similar. In addition, Hoe 140-treated rats showed higher sodium levels in serum and erythrocytes and a greater ratio of heart weight to body weight compared with controls; 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 antagonist is given since the early phases of life. Our data suggest that endogenous kinins may play a role in the regulation of cardiovascular function by influencing renal function and the activity of the sympathetic nervous system during development.