Diminished phospholipase C activation by dopamine in spontaneously hypertensive rats.

Abstract

It is reported that a defect in dopamine-1 (DA-1) receptor adenylate cyclase coupling in the proximal convoluted tubule in the spontaneously hypertensive rat may contribute to the diminished natriuretic response to DA-1 receptor agonists. Since the tubular DA-1 receptor is also coupled to phospholipase C, and both of these cellular signaling processes are involved in DA-1 receptor-mediated diuresis and natriuresis, it is important to know whether a similar defect is also present in DA-1 receptor-coupled phospholipase C pathway. The present study was therefore designed to determine the functional status of DA-1 receptor-phospholipase C coupling system of adult spontaneously hypertensive rats using a renal cortical slice preparation. In addition, the renal response to exogenously administered dopamine (1 /ig/kg/min i.v.) was also determined. We found that basal phospholipase C activity was significantly higher in hypertensive rats than in age-matched Wistar-Kyoto rats (7J6±0J2% versus 5.61±0.27%, p<0.05). However, compared with the normotensive controls, dopamine-induced increases in phospholipase C activity were significantly attenuated in the preparations of hypertensive rats in a concentration-dependent manner (13±6% versus 38±6% for 1 mM dopamine, p<0.05; 49±6% versus 71±9% for 3 mM dopamine, p<0.05; 50±16% versus 106±22%, p<0.05 for 10 mM dopamine). The diminished dopamine-induced phospholipase C activation was due to a deficiency in dopamine receptor-phospholipase coupling since the DA-1 receptor antagonist SCH 23390 (30 /iM), which blocked 50% of dopamine-induced inositol phosphate production in the Wistar-Kyoto rats, did not exert such an effect in the spontaneously hypertensive rats. The in vivo functional study showed that the diuretic and natriuretic responses to intravenous administration of dopamine were significantly diminished in spontaneously hypertensive rats compared with Wistar-Kyoto rats (urine output, 34± 1 versus 63±10 fil/30 min,p<0.05; urinary sodium excretion, 1.8±0.1 versus 3.2±0.2 ^teq/30 min,/x0.05). These results suggest that there is a defect in the tubular DA-1 receptor-phospholipase C coupling process in spontaneously hypertensive rats that may contribute to a diminished natiiuretic response to DA-1 receptor activation. (Hypertension 1992;19:102-108) I t is generally accepted that an abnormality in renal handling of sodium is one of the factors in the pathogenesis and/or maintenance of high blood pressure in genetic hypertension. Central to this assumption are the observations that spontaneously hypertensive rats (SHR), as opposed to their normotensive Wistar-Kyoto (WKY) counterparts, retain sodium avidly before the development of hypertension 1 and that urinary sodium excretion (U Na V) in SHR is normal or subnormal despite the presence of elevated blood pressure.2 Furthermore, dietary sodium restriction retards the development of hypertension in SHR.

Role of the D1A dopamine receptor in the pathogenesis of genetic hypertension.

“…In conscious, as well as in anesthetized animals, up to 60% of sodium excretion during an acute volume load is mediated by D 1 receptors (7); this is due both to an increase in renal dopamine production and to an increased sensitivity of sodium transporters to dopaminergic inhibition (7,12). In the spontaneously hypertensive rat (SHR), 1 the ability of exogenous and endogenous renal dopamine to engender a natriuresis is impaired (13)(14)(15). Since renal dopamine levels in genetic models of hypertension are not lower than those found in their normotensive controls (16,17), the impaired intrarenal paracrine effect of dopamine in these animal models of hypertension appears to be receptor or postreceptor-mediated.…”

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

“…In addition, disruption of the D 1 receptor in mice produces hypertension (12, 13). The pivotal role of dopamine in the excretion of sodium after increased sodium intake has led to the hypothesis that an aberrant renal dopaminergic system is important in the pathogenesis of some forms of genetic hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several mechanisms potentially responsible for the failure of endogenous renal dopamine to engender a natriuretic effect in genetic hypertension have been investigated and ruled out, including decreased renal dopamine production and receptor expression, aberrant nephron segment distribution of dopamine receptors, defective effector enzymes (adenylyl cyclase or phospholipase C), and abnormal renal sodium transporters (3,8,13,17).…”

“…The paracrine͞ autocrine dopaminergic regulation of sodium excretion is mediated by tubular but not by hemodynamic mechanisms (6). The ability of dopamine and D 1 -like agonists to decrease renal proximal tubular sodium reabsorption is impaired in genetic rodent hypertension and human essential hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15). Indeed, the aberrant D 1 -like receptor function in the kidney precedes and cosegregates with high blood pressure in spontaneously hypertensive rats.…”

“…This uncoupling is thought to be the mechanism for the failure of dopamine to engender a natriuresis in genetic hypertension (3,5,(11)(12)(13)(14)(15). This mechanism is similar to but distinct from homologous desensitization (18,19) because the uncoupling in hypertension is independent of renal dopamine levels (3,16,20).…”

Renal Dopamine System

“…62 Subsequently, studies from many laboratories have confirmed and extended these observations. [63][64][65][66][67][68][69] This defect is present in human proximal tubule cells and is confined to the proximal tubule. 53 Studies now are beginning to point toward a possible defect in D 1 receptor-G protein complex recycling and recruitment of receptors to the cell membrane.…”