Dopamine regulation of renal Na+,K(+)-ATPase activity is lacking in Dahl salt-sensitive rats.

Abstract

Dopamine is a natriuretic hormone that acts by inhibiting tubular Na + JC + -ATPase activity by activation of the dopamine-1 receptor (the thick ascending limb [TAL] of Henle) or by a synergistic effect of dopamine-1 and dopamine-2 receptors (the proximal tubule). The dopamine-1 receptor is coupled to adenylate cyclase. In this article we show that prehypertensive Dahl salt-sensitive (DS) rats have a blunted natriuretic response to dopamine determined during euvolemk conditions compared with Dahl salt-resistant (DR) rats. Furthermore, we have examined the renal tubular effects of dopamine in DS and DR rats. Basal Na 5 Activation of the DA-1 receptor is in both cases associated with adenylate cyclase activation.Several lines of evidence suggest that an aberrant renal dopaminergic system may be a factor in the pathogenesis of salt-sensitive hypertension.6 " 8 This has prompted us to examine the renal effects of dopamine in the Dahl salt-sensitive (DS) rat. The DS rat is extremely sensitive to the blood pressure elevation effect of a high salt diet 9 and exhibits impaired intrinsic natriuretic capacity.1011 Its control strain is the Dahl salt-resistant (DR) rat, which remains normotensive even during long periods of high salt intake.We show that Na + ,K + -ATPase activity in the PT and TAL segments from DS rats are, in contrast to DR rats, Received March 18, 1992; accepted in revised form January 13, 1993. not responsive to dopamine and the DA-1 agonist fenoldopam. We also show that DS rats have an attenuated natriuretic response to dopamine. In addition, our studies on the effects of dopamine on renal cyclic adenosine monophosphate (cAMP) levels and the effects of cAMP on tubular Na + ,K + -ATPase activity add evidence to the hypothesis, originally suggested by Felder et al,[12][13] that the coupling of the DA-1 receptor to adenylate cyclase may be defective in genetic hypertension. Methods AnimalsStudies were performed on male prehypertensive DS (SS/Jr) and DR (SR/Jr) rats aged 7-8 weeks and weighing 160-240 g. These rats were purchased from M0llegaards Breeding Center, Ejby, Denmark. The rats receiving a normal salt diet were fed a standard rat chow (R3, Ewos, Sodertalje, Sweden) that contains 0.7% NaCl and received tap water ad libitum.Rats were anesthetized with Inactin-Byk (Byk-Gulden, Konstanz, FRG) (80 mg/kg body wt i.p.). Mean arterial pressure was recorded via one carotid artery. Inactin-Byk anesthesia does not influence mean arterial pressure, as shown previously.14 Mean arterial pressure values were similar in DS and DR rats on a normal salt diet (116±3 versus 110±2 mmHg). Preparation of TubulesKidney perfusion and tubule microdissection were performed as described.15 After a midline incision, the left kidney was exposed and perfused with the following modified Hanks' solution (mM): N a d 137, KQ 5, MgSO<

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

“…5B). These results are in agreement with previous studies showing that the desensitization of the D 1 receptor in genetic hypertension is renal specific (3,7,8,16). The renal vasodilatory effect of D 1 -like agonists may be preserved in genetic hypertension (3).…”

“…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).…”

“…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). Also, the coding region of the D 1 receptor is unchanged in hypertensive subjects (16), as well as in rodents with genetic hypertension (unpublished studies).In renal proximal tubules from humans with essential hypertension and from rodents with genetic hypertension, the D 1 -like receptor is uncoupled from its G protein͞effector enzyme complex (3,(7)(8)(9)(10)16). 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).…”

“…In renal proximal tubules from humans with essential hypertension and from rodents with genetic hypertension, the D 1 -like receptor is uncoupled from its G protein͞effector enzyme complex (3,(7)(8)(9)(10)16). 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).…”

“…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.…”