title: Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension.
abstract: The development of hypertension in the spontaneously hypertensive rat (SHR) is associated with renal dysfunction and vasoconstriction. The kidneys of young SHRs exhibit exaggerated reactivity to angiotensin II (Ang-II) and attenuated responses to vasodilators that normally activate the cAMP signal to buffer hormone-induced vasoconstriction. The present study investigates the mechanism(s) responsible for this abnormality in activation of the cAMP second-messenger pathway in hypertensive animals. Renal vascular reactivity was assessed in 7-week-old anesthetized SHRs and normotensive Wistar-Kyoto rats. The animals were pretreated with indomethacin to block prostanoid production throughout an experiment. Ang-II was injected into the renal artery either alone or mixed with the vasodilator fenoldopam, a dopamine-receptor agonist. These two opposing vasoactive agents were administered before and during intrarenal infusion of NaF or cholera toxin, two activators of G proteins that stimulate cAMP production. The results show that Ang-II reduced renal blood flow by 45% in both strains. In Wistar-Kyoto rats, fenoldopam reduced the Ang-II-induced decrease in renal blood flow from -45% to -30%. This protective effect of fenoldopam was increased further during infusion of NaF or cholera toxin (-18% or -19% decrease in renal blood flow). In SHRs, fenoldopam failed to attenuate Ang II-mediated vasoconstriction (-45% vs. -44%). In contrast, fenoldopam effectively blunted the Ang-II-induced vasoconstriction when it was given concurrently with NaF or cholera toxin (-27 or -31% decrease in renal blood flow). These findings provide evidence for defective interaction between receptor coupling and activation of guanine nucleotide stimulatory factor proteins in the renal microcirculation of 7-week-old SHRs. Such a deficiency could play an important role in renal dysfunction associated with the development of genetic hypertension.
authors.affiliation: Department of Physiology, University of North Carolina, Chapel Hill 27599-7545, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chatziantoniou
authors.forename: X
authors.initials: X
authors.lastname: Ruan
authors.forename: W J
authors.initials: WJ
authors.lastname: Arendshorst
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D018818:Fenoldopam / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006400:Hematocrit; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects; D015398:Signal Transduction; D012969:Sodium Fluoride / Q000494:pharmacology; D013045:Species Specificity; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000804:Angiotensin II; D012969:Sodium Fluoride; D002772:Cholera Toxin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D018818:Fenoldopam