IMPAIRED ABILITY OF PROSTAGLANDINS TO BUFFER RENAL VASOCONSTRICTION IN GENETICALLY HYPERTENSIVE RATS

The purpose of this study was to gain insight into the mechanism(s) responsible for the exaggerated angiotensin II (ANG II)-induced renal vasoconstriction during the development of hypertension. In previous studies we observed that ANG II produces a twofold larger decrease in renal blood flow (RBF) in spontaneously hypertensive (SHR) compared with Wistar-Kyoto (WKY) rats before but not after cyclooxygenase inhibition. We suggested that this strain difference could be attributed to differences in renal prostaglandin (PG) levels and/or action. To evaluate these possibilities, measurements of RBF were made in 6-wk-old, anesthetized SHR and WKY pretreated with indomethacin. ANG II was injected intrarenally before and during continuous intrarenal infusion of a low dose of PGE2, viprostol (PGE2 analogue), PGI2, iloprost (PGI2 analogue), and bradykinin. In the control period ANG II reduced RBF by 50% in both strains. Infusion of PGs reduced the vasoconstrictor effect of ANG II in WKY, but had no effect in SHR. In contrast, infusion of bradykinin blunted the ANG II-induced vasoconstriction to a similar degree in both WKY and SHR. To investigate whether this lack of protection in SHR is due to strain differences in the number and/or affinity of renal receptors of PGs, radiolabeled ligand binding studies for PGE2 and PGI2 receptors were undertaken in glomeruli isolated from young WKY and SHR. Scatchard analysis revealed a single, high-affinity receptor site for PGE2 that was similar in both strains of rats. Both strains also exhibited a single, high-affinity PGI2 receptor site. No differences were observed in the PGE2 or PGI2 receptor number between WKY and SHR. These findings suggest that the exaggerated renal vascular reactivity to ANG II in young SHR is a functional defect, related to a vascular mechanism rather than the local concentration of vasodilator PGs per se.