Dopamine (DA) receptor agonists of DA-1 and DA-2 subtypes are reported to lower blood pressure and cause natriuresis. It is also suggested that endogenous DA formed within the kidney may play a role in promoting sodium excretion. The overall objectives of the proposed study are to determine the influence of long term treatment with selective DA-1 (fenoldopam) and DA-2 receptor (quinpirole) agonists on the development of hypertension and urinary sodium excretion in genetic hypertensive rats on different levels of dietary sodium intake. Furthermore, urinary excretion of sodium and DA will be measured beginning with prehypertensive stage to the established phase of hypertension in rats on different levels of sodium intake. Spontaneously hypertensive rats and Wistar-Kyoto rats will be obtained when they are 4 weeks old and placed on either normal or high sodium diet. Their blood pressure, body weights will be measured and 24- hour urine collections will be made twice a week for four weeks. Some of the rats will be sacrificed and their blood samples collected. The remaining rats will be followed for an additional 4-week period and then sacrificed. The urine samples will be assayed for NE, DA, E, sodium, potassium and creatinine whereas plasma will be assayed for aldosterone, PRA, NE, DA, E and creatinine. GFR will be calculated from the clearance of creatinine. Separate groups of SHR and WKY on different diets will be implanted with minipumps containing either fenoldopam or quinpirole when they are 5 weeks old and the influence of this treatment on the parameters menitioned above for control series will be determined during 8 weeks of chronic drug treatment. Dahl salt-sensitive and salt-resistant rats will be obtained when they are 3 weeks old and placed on low sodium diet for one week. Beginning with week 5, they will be placed on either low or high sodium diet. Similar measurements to those mentioned for SHR and WKY will be made over an 8 week period under control conditions and during treatment with DA receptor agonists. Groups of SHR, WKY, DS and DR rats on different sodium intake will also be implanted with minipumps containing SCH 23390 (DA- 1 antagonist), domperidone (DA-2 antagonist) or metoclopramide (DA-1/DA-2 antagonist) and the influence of selective and mixed blockade of DA receptor subtypes on BP, urinary sodium excretion, DA and other hormones will be examined over the 8- week period as described for agonist studies. These experiments should allow us to identify the potential beneficial effect of DA- ergic stimulation in genetic hypertension as well as the potential involvement of renal DA-ergic mechanism in the urinary excretion of sodium and thereby the maintenance of fluid volume and blood pressure in genetic hypertensive rats on different levels of sodium intake.
