Effects of Kinin Blockade on the Blood Pressure of Salt-Loaded Pregnant Rats

Abstract

Abstract We evaluated whether chronic inhibition of bradykinin B 2 receptors by the long-acting antagonist d -Arg,[Hyp 3 ,Thi 5 , d -Tic 7 ,Oic 8 ]-bradykinin (Hoe 140) affects blood pressure of salt-loaded pregnant rats. Pairs of rats fed a high sodium diet (0.84 mmol sodium per gram chow) were mated at 14 weeks of age. Infusion of vehicle or Hoe 140 (300 nmol/d per kilogram body weight) was performed throughout each dam’s pregnancy by use of an Alzet osmotic pump implanted in the abdominal cavity. In both groups, no significant change in systolic pressure (tail-cuff plethysmography) or renal blood flow (Doppler flowmeter) was observed from that in the unmated state to that at midterm pregnancy. In the control group, systolic pressure decreased at the 21st day of pregnancy (from 126±2 to 97±2 mm Hg, P <.01), and renal blood flow increased (from 6.1±0.1 to 7.5±0.2 kHz, P <.01). These changes were nullified by the administration of Hoe 140 (systolic pressure changing from 124±2 to 118±4 mm Hg, P =NS; renal blood flow changing from 6.3±0.2 to 6.2±0.1 kHz, P =NS). In the group given Hoe 140, placental weight was greater (0.50±0.01 versus 0.43±0.01 g in controls, P <.01) and the fetal/placental weight ratio was reduced (4.53±0.09 versus 5.31±0.17 in controls, P <.01). A separate set of experiments was performed in the progeny of vehicle- and antagonist-treated dams to evaluate the effect of early postnatal administration of Hoe 140 combined with high sodium intake on survival rate. In the offspring of vehicle-treated rats, survival rate was reduced by chronic postnatal administration of Hoe 140 (at 70 days, 34% versus 62% in controls given vehicle). An earlier and more pronounced fall in survival rate was observed in the offspring of Hoe 140–treated rats maintained on antagonist or vehicle treatment during the postnatal period (0% and 18%, respectively, at 70 days). These results indicate that the kallikrein-kinin system plays a role in the regulation of blood pressure in pregnant rats exposed to a high sodium diet. The mechanism responsible for the increased early mortality in the progeny of Hoe 140–treated rats remains unknown. The possibility that it is related to blockade of kinin receptors may suggest a protective effect of endogenous kinins against the deleterious consequences of a dietary excess of sodium.