Dopamine Receptor in the Pathogenesis of Genetic Hypertension

Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and receptor density, there is defective transduction of the D 1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport (Na 1 /H 1 exchanger [NHE] and Na 1 /K 1 ATPase activity) by dopamine. To determine if impaired D 1 receptor regulation of NHE in proximal tubules is related to hypertension, studies were performed in a F2 generation from female Wistar Kyoto (WKY) and male SHR crosses. A D 1 agonist, SKF 81297, inhibited (37.6 6 4.7%) NHE activity in brush border membranes of normotensive F2s (systolic blood pressure , 140 mm Hg, n 5 7) but not in hypertensive F2s ( n 5 21). Furthermore, a D 1 agonist, SKF 38393, when infused into the renal artery, dose dependently increased sodium excretion in normotensive F2s ( n 5 3) without altering renal blood flow but was inactive in hypertensive F2s ( n 5 21). Since the major D 1 receptor gene expressed in renal proximal tubules is the D 1A subtype, we determined the importance of this gene in the control of blood pressure in mice lacking functional D 1A receptors. Systolic blood pressure was greater in homozygous ( n 5 6) and heterozygous ( n 5 5) mice compared to normal sex matched litter mate controls ( n 5 12); moreover, the mice lacking one or both D 1A alleles developed diastolic hypertension. The cosegregation with hypertension of an impaired D 1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D 1A alleles suggest a causal relationship of the D 1A receptor gene with hypertension. ( J. Clin. Invest. 1996. 97:2283–2288.)