Renal alpha 1-adrenergic receptor response coupling in spontaneously hypertensive rats.
Renal sympathetic antidiuretic, antinatriuretic, and vasoconstrictor responses are mediated by alpha 1-adrenergic receptors in the normal rat. Since the renal nerve has been implicated in the pathogenesis of rat genetic hypertension, we investigated renal alpha 1-adrenergic receptor coupling to phosphoinositide turnover in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In cortical slices from adult (13-week-old) SHR and WKY, stimulation with norepinephrine (10(-7)-10(-3) M) caused a concentration-dependent increase in accumulation of [3H]inositol phosphates. However, dose-response curves for SHR characteristically displayed a depression of the maximum response as compared with those for WKY. Baseline accumulation of [3H]inositol phosphates was not different between strains (39.4 +/- 2.2 cpm/mg tissue/hr for WKY and 34.4 +/- 2.1 cpm/mg tissue/hr for SHR slices; n = 5 rats/group, determined in triplicate). Antagonist competition studies revealed that norepinephrine-stimulated (10(-4) M) [3H]inositol phosphate accumulation was mediated by alpha 1-adrenergic receptors (IC50) for prazosin: 65 +/- 11 nM for SHR and 64 +/- 5 nM for WKY). The reduction in norepinephrine-stimulated [3H]inositol phosphate accumulation in SHR cortex was not the result of the hypertension, since it was also present in cortical slices from young (4-week-old) SHR in which the blood pressure was not yet significantly different from that in WKY and since [3H]inositol phosphate accumulation was unchanged from control values in rats made hypertensive by treatment with deoxycorticosterone acetate. Scatchard analysis of [3H]prazosin binding in renal cortical membranes of young and adult SHR and WKY revealed no significant differences in alpha 1-adrenergic receptor density or affinity between strains at either age. Our results suggest that renal alpha 1-adrenergic receptor coupling to phospholipase C is less efficient in SHR than in WKY. This impaired response is not the result of hypertension or changes in receptor density; this defect may play a role in increased renal sympathetic nerve activity and in the development or maintenance of hypertension in SHR.
Jeffries
W B
WB
University of Texas Health Science Center, Department of Pharmacology, Dallas 75235.
Yang
E
E
Pettinger
W A
WA
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007295:Inositol Phosphates / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D000804:Angiotensin II; D015016:Yohimbine; D012701:Serotonin; D002217:Carbachol; D010738:Type C Phospholipases; D009638:Norepinephrine; D011224:Prazosin