Renal vasodilation

Kidney Function. Prostanoids influence a variety of kidney functions including renal blood flow, secretion of renin, glomerular filtration rate, and salt and water excretion. They do not have a critical role in modulating normal kidney function but play an important role when the kidney is under stress. Eor example, PGE2 and -I2 are renal vasodilators (70,71) and both are released as a result of various vasoconstrictor stimuli. They thus counterbalance the vasoconstrictor effects of the stimulus and prevent renal ischemia. The renal side effects of NSAIDS are primarily observed when normal kidney function is compromised. 

Fenoldopam (76) is an antihypertensive renal vasodilator apparently operating through the dopamine system. It is conceptually similar to trepipam. Fenoldopam is superior to dopamine itself because of its oral activity and selectivity for dopamine D-1 receptors (D-2 receptors are as.sociated with emesis). It is synthesized by reduction of 3,4-dimethoxyphenylacetonitrile (70) to dimethoxyphenethylamine (71). Attack of diis last on 4-methoxystyrene oxide (72) leads to the product of attack on the epoxide on the less hindered side (73). Ring closure with strong acid leads to substituted benzazepine 74. O-Dealkylation is accomplished with boron tribromide and the catechol moiety is oxidized to the ortho-quinone 75. Treatment with 9NHC1 results in conjugate (1,6) chloride addition and the formation of fenoldopam (76) [20,21]. 

There is significant controversy over the role of loop diuretics in the treatment of ARE Theoretical benefits in hastening recovery of renal function include decreased metabolic oxygen requirements of the kidney, increased resistance to ischemia, increased urine flow rates that reduce intraluminal obstruction and filtrate backleak, and renal vasodilation.6 Theoretically, these effects could lead to increased urine output, decreased need for dialysis, improved renal recovery, and ultimately, increased survival. However, there are conflicting... 

D Brooks, PD Depalma, MJ Cyronak, MA Bryant, K Karpinski, B Mico, D Gaita-nopoulos, PA Chambers, KF Erhard, J Weinstock. The identification of fenoldopam prodrugs with prolonged renal vasodilator. J Pharmacol Exper Ther 254(3) 1084— 1089, 1990. 

Dopamine can exert pronounced cardiovascular and renal effects through the activation of both Dj- and Dz-receptor subtypes. Stimulation of the Dj-receptor, which is present on blood vessels and certain other peripheral sites, will result in vasodilation, natriuresis, and diuresis. Dz-receptors are found on ganglia, on sympathetic nerve terminals, on the adrenal cortex, and within the cardiovascular centers of the CNS their activation produces hypotension, bradycardia, and regional vasodilation (e.g., renal vasodilation). The kidney appears to be a particularly rich source for endogenous dopamine in the periphery. 

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). 

Ibopamine, which is active orally, is capable of eliciting peripheral and renal vasodilation, positive vasodilation, and a positive inotropic action. Ibopamine is converted to epinine, which is the active drug. 

Fenoldopam is an orally active DA,-receptor agonist. It is more potent than dopamine in causing renal vasodilation without having adrenergic, cholinergic, or histaminergic properties. 

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. 

SK F 38393 is about ten times less potent than dopamine as a renal vasodilator in anesthetized dogs, and shows only about half the maximal renal vasodilator effect. However, while at high doses dopamine increased mean arterial pressure and heart rate, high doses of SK F 38393 increased only blood pressure. 

In contrast, SK F 82526 is about ten times as potent as dopamine, and has about 1.6 times the maximal effect of dopamine as a renal vasodilator in anesthetized dogs. It causes a slight tachycardia, and at higher doses moderately decreases blood pressure. SK F 87516 is about three times as potent as, and shows about 80% of the maximal effect of dopamine as a renal vasodilator. However, it produces negligible blood pressure effects and exhibits a potent and profound bradycardiac effect suggesting that it may have presynaptic dopamine agonist activ-... 

Fluorine substitution in place of chlorine (compare SK F 87516 to SK F 82526) seems even more trivial than the changes discussed above, but it apparently enhances diuretic activity and introduces substantial peripheral presynaptic (D-2) activity. Since the renal vasodilator potency is essentially unchanged, this suggests that diuretic activity is determined by receptors with different properties than the renal vasodilator... 

The N-allyl group of SK F 85174 is another group with a large influence on dopaminergic profile. It allows renal vasodilator activity and stimulation of adenylate cyclase, while most N-alkyl groups cause inhibition of renal vasodilator activity and adenylate cyclase (24). It induces potent D-2 activity in contrast to the selective D-l profile of SK F 82526. 

Only the unexpected result with (R)- and (S)-III is remarkable. The fact that (R)-III is 30 times more potent than (R,S)-III in vivo as a renal vasodilator is not reflected in vitro in the other models. A possible change in mechanism of action was mentioned. The effects of (R)— and (S)-III on a-adrenergic receptors, for example, are unreported but could be relevant. The data may not rule out receptor blockade by ( 3)-III (e.g., what is the effect of ( 3)-III on the activities of other agonists such as DA or (R)-II ), though the binding data offer no hint of that. This intriguing observation merits further study. 

Most NSAIDs attenuate the antihypertensive effect of p-blockers (but not perhaps of atenolol), presumably due to inhibition of formation of renal vasodilator prostaglandins, leading to sodium retention. 

The overriding aim of therapy is to increase renal blood flow. This can be achieved either indirectly through splanchnic vasoconstriction or directly by encouraging renal vasodilation. Hereby, certain problems arise concerning substances which spill over into the splanchnic circulation causing splanchnic vasoconstriction and at the same time exacerbating the renal vasoconstriction already present. (5-7, 10, 12, 19, 33, 43, 58, 60, 63)... 

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