Renal dopamine receptor signaling mechanisms in spontaneously hypertensiveand fischer 344 old rats

Dopamine plays an important role in the regulation of renal sodium excretio n. The activation of D-1-like receptors located on the proximal tubules cau ses inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D-1-like receptors are linked via G proteins to the multiple cellular signaling systems namely adenylyl cyclase and phos pholipase C (PLC). A defective renal dopamine receptor function exists in s pontaneously hypertensive rats (SHR). In the proximal tubules of SHR, the s timulation of adenylyl cyclase and PLC caused by dopamine was significantly reduced in comparison with Wistar-Kyoto (WKY) rats. Also unlike the effect s seen in WKY, D-1-like receptor activation did not inhibit Na,K-ATPase and Na,H-exchanger activities in SHR. In addition, reduced quantity of Gq/11 a lpha proteins was detected in the basolateral membranes of SHR compared to WKY rats. Studies revealed that there may be a primary defect in D-1-like r eceptors leading to an altered signaling system in the proximal tubules and reduced dopamine-mediated effect on renal sodium excretion in SHR. Recentl y, it has been shown that the disruption of D-1A receptors at the gene leve l causes hypertension in mice. Similar to SHR, dopamine and D-1-like recept or agonist failed to inhibit Na,K-ATPase activity in the proximal tubules o f old Fischer 344 rats. Unlike the observations in SHR where D-1-like recep tors were equal to WKY rats, there is a 50% decrease in D-1-like receptor n umber in basolateral membranes of the old rats compared to the adult rats. Dopamine was unable to stimulate G proteins in the basolateral membranes of old rats compared to the adult rats. It is suggested that a defective dopa mine receptors/signaling system may contribute to the development and maint enance of hypertension. Also, the inability of dopamine to inhibit Na,K-ATP ase may lead to a reduced renal sodium excretion in response to dopamine in old rats.