Defective renal dopamine D1 receptor function contributes to hyperinsulinemia-mediated hypertension.
Hyperinsulinemia is reported to play a role in hypertension, as abnormalities in blood pressure regulation and sodium handling exist in diabetes mellitus. Kidney dopamine promotes sodium excretion via the activation of renal D1 receptors. Because there is a close relationship between renal D1 receptor function and sodium excretion, it is hypothesized that a defect in this mechanism may contribute to decreased sodium excretion and hypertension during hyperinsulinemia. Renal D1 receptor function was studied in insulin-induced hypertension in male Sprague Dawley rats. Insulin pellets were implanted subcutaneously for controlled insulin release for three weeks; sham rats served as a control. Compared to control rats, insulin pellets increased plasma insulin levels by eight fold and decreased blood glucose by 40%. Insulin also caused a 22 mmHg increase in mean arterial blood pressure compared to control animals. The intravenous infusion of SKF-38393, a D1 receptor agonist, increased sodium excretion in control rats, but SKF-38393 failed to produce natriuresis in hyperinsulinemic animals. Renal proximal tubules from hyperinsulinemic rats had a reduced D1 receptor number, defective receptor-G protein coupling, and blunted SKF-38393 induced Na, K-ATPase inhibition. Insulin seems to reduce D1 receptor expression and coupling to the G-protein, leading to a reduced D1 receptor-mediated Na, K-ATPase inhibition, and a diminished natriuretic response to SKF-38393. These phenomena could account for sodium retention and hypertension associated with hyperinsulinemia.
Ahmad Banday
Anees
A
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas 77204, USA.
Lokhandwala
Mustafa F
MF
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006946:Hyperinsulinism / Q000150:complications* / Q000378:metabolism*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism
D001786:Blood Glucose; D018491:Dopamine Agonists; D007328:Insulin; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D012964:Sodium; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase