Diminished Natriuretic Response to Dopamine D₁Receptor Agonist, SKF‐38393 in Obese Zucker Rats

Abstract

Dopamine causes natriuresis and diuresis via activation of D1 receptors located on the renal proximal tubules and subsequent inhibition of the sodium transporters, Na-H exchanger and Na+/K+ ATPase. We have reported that dopamine fails to inhibit the activities of these two transporters in the obese Zucker rats (OZR). The present study was designed to examine the functional consequence of this phenomenon by determining the natriuretic and diuretic response to D1 receptor activation in lean Zucker rats (LZR) and OZR. In 11-12 week-old OZR and LZR, natriuretic and diuretic responses to intravenously administered D1 receptor agonist, SKF 38393 (3 microg/kg/min for 30 min) were measured under Inactin anesthesia. Plasma insulin and glucose levels were significantly higher in the obese rats as compared to the lean rats. Intravenous infusion of SKF 38393 caused significant increases in urine flow, urinary sodium excretion (U(Na)V), fractional excretion of sodium (FE(Na)), and glomerular filtration rate (GFR) in the lean rats. However, the natriuretic and diuretic response to SKF 38393 was markedly blunted in OZR. Infusion of SKF 38393 did not cause significant changes in the mean blood pressure and heart rate in either of the two groups. We suggest that the diminished natriuretic response to D1 receptor activation in OZR is the consequence of the previously reported defect in the D1 receptor-G-protein coupling and the failure of dopamine to inhibit the sodium transporters in these animals.

Angiotensin II Type 2 Receptor Agonist Directly Inhibits Proximal Tubule Sodium Pump Activity in Obese But Not in Lean Zucker Rats

“…6 In numerous studies, we have shown that dopamine D 1 receptor, which is known to increase tubular sodium excretion, is defective and unable to inhibit NKA activity in the PTs 18 and promote natriuresis in response to D 1 receptor agonist in obese rats. 33 Although D 1 receptor agonist was reported recently to promote AT 2 receptor translocation to the membrane and thereby enhance the AT 2 receptor function to promote natriuresis, 34 it is unlikely that defective D 1 receptor 18 contributed to the enhanced AT 2 receptor function as a compensatory mechanism in obese Zucker rats. 18 Similarly, an upregulation of the renal AT 2 receptor function on tubular sodium metabolism was found in streptozotocin-induced diabetic rats, 35 where dopamine D 1 receptors also are shown to be defective.…”

Renal Angiotensin II Type-2 Receptors Are Upregulated and Mediate the Candesartan-Induced Natriuresis/Diuresis in Obese Zucker Rats

“…12,13 Briefly, rats were anesthetized using Inactin (100 to 160 mg/kg IP). The left jugular vein and carotid artery were cannulated for saline/drug infusion and blood pressure measurement, respectively.…”

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D 1A Receptor in Obese Zucker Rats

“…Surgical procedures were carried out as described earlier. 17 Urine samples were collected throughout the 30-minute periods, and blood samples were collected at the end of each period. Renal function was evaluated as described previously.…”