DEFECTIVE G-PROTEIN ACTIVATION OF THE CAMP PATHWAY IN RAT-KIDNEY DURING GENETIC-HYPERTENSION

The development of hypertension in the spontaneously hypertensive rat (SHR) is associated,vith renal dysfunction and vasoconstriction. The k idneys of young SHRs exhibit exaggerated reactivity to angiotensin II (Ang-II) and attenuated responses to vasodilators that normally activa te the cAMP signal to buffer hormone-induced vasoconstriction. The pre sent study investigates the mechanism(s) responsible for this abnormal ity in activation of the cAMP second-messenger pathway in hypertensive animals. Renal vascular reactivity was assessed in 7-week-old anesthe tized SHRs and normotensive Wistar-Kyoto rats. The animals were pretre ated with indomethacin to block prostanoid production throughout an ex periment. Ang-II was injected into the renal artery either alone or mi xed with the vasodilator fenoldopam, a dopamine-receptor agonist. Thes e two opposing vasoactive agents were administered before and during i ntrarenal infusion of NaF or cholera toxin, two activators of G protei ns that stimulate cAMP production. The results show that ring-II reduc ed renal blood flow by 45% in both strains. In Wistar-Kyoto rats, feno ldopam reduced the Ang-II-induced decrease in renal blood flow from -4 5% to -30%. This protective effect of fenoldopam was increased further during infusion of NaF or cholera toxin (-18% or -19% decrease in ren al blood flow). In SHRs, fenoldopam failed to attenuate Ang II-mediate d vasoconstriction (-45 vs. -44%). In contrast, fenoldopam effectively blunted the Ang-II-induced vasoconstriction when it was given concurr ently with NaF or cholera toxin (-27 or -31% decrease in renal blood f low). These findings provide evidence for defective interaction betwee n receptor coupling and activation of guanine nucleotide stimulatory f actor proteins in the renal microcirculation of 7-week-old SHRs. Such a deficiency could play an important role in renal dysfunction associa ted with the development of genetic hypertension.