Differential Human Renal Tubular Responses to Dopamine Type 1 Receptor Stimulation Are Determined by Blood Pressure Status

Abstract

We performed the present studies to determine whether a proximal renal tubular dopamine D1-like receptor defect exists in human essential hypertension. Twenty-four subjects were studied (13 normotensive and 11 hypertensive) in a randomized, double-blind, vehicle-controlled study using fenoldopam, a selective D1-like receptor agonist. Subjects were studied in sodium metabolic balance at 300 mEq/d, after which the salt sensitivity of their blood pressure was determined. Fenoldopam at peak doses of 0.1 to 0.2 microgram/kg per minute decreased mean arterial pressure in hypertensive subjects but did not change mean pressure in normotensive subjects. Fenoldopam increased renal plasma flow to a greater extent in hypertensive than normotensive subjects. Fenoldopam increased both urinary and fractional sodium excretions in the hypertensive and normotensive groups. In normotensive but not hypertensive subjects, fenoldopam increased the fractional excretion of lithium and distal sodium delivery. In contrast, both distal fractional sodium reabsorption and sodium-potassium exchange fell significantly in hypertensive subjects. We conclude that human essential hypertension is associated with a reduction in the proximal tubular response to D1-like receptor stimulation compared with normotensive subjects. Hypertensive subjects appear to have a compensatory upregulation of renal vascular and distal tubular D1-like receptor function that offsets the proximal tubular defect, resulting in an enhanced natriuretic response to D1-like receptor stimulation.

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

“…Thus, the ability of fenoldopam to decrease renal vascular resistance is maintained in the spontaneously hypertensive rat (SHR) (41). Fenoldopam increases effective renal plasma flow to a greater extent in salt-sensitive hypertensive than in normotensive subjects (15). The ability of dopamine to relax renal artery strips is also increased in stroke-prone SHRs (42).…”

“…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).…”

Dopamine, hypertension and obesity

“…23 It has been shown that the absence of DA codifying alleles is related to increases in systolic and diastolic pressure, thus suggesting a causal relation between the gene for the D 1A receptor and AHT. 24,25 Also, defects of coupling or activation of second messengers by this receptor (without affecting their distribution or quantity) are also related to the AHT appearance. 21 In this regard, the presence of polymorphic forms of the D 1 codifying gene has been described in patients with essential AHT.…”