Renal vascular dopamine receptor

Figure 1. Topographical model of the renal vascular dopamine receptor (12).

Erhardt, P. W. (1983). Renal vascular dopamine receptor topography—Structure-activity relationships that suggest the presence of a ceiling. In C. Kaiser, J. W. Kebabian (Eds.), ACS Symposium Series, 224, Dopamine Receptors (pp. 275—280). Washington, DC ACS. 

A topographical model has been proposed to explain why (E)-2-(3,4-dihydroxyphenyl)cyclopropylamine, 1, and alpha-methyldopamine (AMDA) are inactive in the renal vascular dopamine (DA) receptor system. In this model a steric protrusion (S2) resides approximately lX above the generalized plane of the receptor and acts to impede interaction with molecules such as 1 and AMDA which possess additional bulk in this region. Recent developments in DA structure-activity relationships offer further support for the existence of the S2 site. 

Vasopressin causes vasoconstrictive effects that, unlike adrenergic receptor agonists, are preserved during hypoxia and severe acidosis. It also causes vasodilation in the pulmonary, coronary, and selected renal vascular beds that may reduce pulmonary artery pressure and preserve cardiac and renal function. However, based on available evidence, vasopressin is not recommended as a replacement for norepinephrine or dopamine in patients with septic shock but may be considered in patients who are refractory to catecholamine vasopressors despite adequate fluid resuscitation. If used, the dose should not exceed 0.01 to 0.04 units/min. 

Dopamine is an intermediate product in the biosynthesis of noradrenaline. Furthermore it is an active transmitter by itself in basal ganglia (caudate nucleus), the nucleus accumbens, the olfactory tubercle, the central nucleus of the amygdala, the median eminence and some areas in the frontal cortex. It is functionally important, for example in the extra-pyramidal system and the central regulation of emesis. In the periphery specific dopamine receptors (Di-receptors) can be found in the upper gastrointestinal tract, in which a reduction of motility is mediated, and on vascular smooth muscle cells of splanchnic and renal arteries. Beside its effect on specific D-receptors, dopamine activates, at higher concentrations, a- and -adrenoceptors as well. Since its clinical profile is different from adrenaline and noradrenaline there are particular indications for dopamine, like situations of circulatory shock with a reduced kidney perfusion. Dopamine can dose-dependently induce nausea, vomiting, tachyarrhythmia and peripheral vasoconstriction. Dopamine can worsen cardiac ischaemia. 

The cardiovascular response to dopamine in humans depends on the concentration infused. Low rates of dopamine infusion can produce vasodilation in the renal, mesenteric, coronary, and intercerebral vascular beds with little effect on other blood vessels or on the heart. The vasodilation produced by dopamine is not antagonized by the p-adrenoceptor blocking agent propranolol but is antagonized by haloperidol and other dopamine receptor-blocking agents. 

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of Di receptors. Activation of the Di receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates Bj receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a. receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. 

The required properties of such an agent Included (1) selectivity for peripheral vascular dopaminergic receptors versus < -and 6-adrenerglc receptors which could mediate pressor and cardiac effects, (2) absence of central dopaminergic and emetic effects, and (3) potent oral renal vasodilator effects. Dopamine has been associated with diuresis and natriuresls. Possible mechanisms include a direct tubular effect on sodium transport, indirect effects produced by changes in total or regional renal blood flow, or effects resulting from a dopamine Induced decrease in aldosterone release from the adrenal (9). Since diuretics play a key role in antihypertensive therapy, the addition of a natriuretic/diuretic component to the renal vasodilator profile would be valuable and appeared to be feasible. 

The cardiovascular effects of dopamine are mediated by several distinct types of receptors that vary in their affinity to dopamine. At low concentrations, the primary interaction of dopamine is with vascular Dj receptors, especially in the renal, mesenteric, and coronary beds. By activating adeny-lyl cyclase and raising intracellular concentrations of... 

Peripheral dopaminergic receptor agents are useful in the treatment of congestive heart failure (CHF). Two distinct subtypes of dopamine receptors have been identified. The dopamine (DAi) receptors, which are located on vascular smooth muscles, cause vasodilation in the renal, mesentery, cerebral, and coronary vascular beds (see Figure 49). Thus, the pharmacologic response to activation of the DA2- and DAj-receptor receptors is hypotension, bradycardia, diuresis, and natriuresis. Fenoldopam is an orally active DA -receptor agonist. It is more potent than dopamine in causing... 

Dopamine is an endogenous catecholamine and an immediate precursor of adrenaline and noradrenaline. At low doses it stimulates vascular DAI dopaminergic receptors, especially those in renal, mesenteric and coronary vessels. As the dose increases it progressively stimulates 31 and al adrenoceptors. Thus, depending on the dose it may act as a renal vasodilator, a myocardial inotrope, or a peripheral vasoconstrictor. Dopamine also causes release of noradrenaline from autonomic nerve endings (DA2 receptors). 

Vascular smooth muscle tone is regulated by adrenoceptors consequently, catecholamines are important in controlling peripheral vascular resistance and venous capacitance. Alpha receptors increase arterial resistance, whereas 2 receptors promote smooth muscle relaxation. There are major differences in receptor types in the various vascular beds (Table 9-4). The skin vessels have predominantly receptors and constrict in the presence of epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether ffor 13 receptors are activated. Consequently, the overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at and 8receptors and the anatomic sites of the vessels affected. In addition, Di receptors promote vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels. Activation of the Di receptors in the renal vasculature may play a major role in the natriuresis induced by pharmacologic administration of dopamine. 

Age-dependent, receptor-mediated drug effects have been observed with dopamine. The effect of dopamine on blood flow (estimated by measuring the pulsatility index by ultrasonography) was assessed in the right renal, superior mesenteric, and middle cerebral arteries in sick premature infants (52). Renal blood flow increased during the dopamine infusion, but mesenteric and cerebral blood flow were not altered. In adults, dopamine does increase blood flow to the intestine, indicating that the lack of response in preterm neonates is related to the immaturity of the mesenteric vascular bed. 

Dopamine (DA) activates Dj receptors, causing vasodilation in renal and mesenteric vascular beds. 

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