Renal vasodilators and hypertension

Ackerman, Dennis M.; Weinstock, Joseph; Wiebelhaus, Virgil D.; Berkowitz, Barry A.

doi:10.1002/ddr.430020308

Cited by 46 publications

(19 citation statements)

References 28 publications

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“…In this paper, we will present our current understanding ofthe pathogenesis ofarterial lesions caused in the rat by fenoldopam mesylate (FM), a selective post-junctional dopaminergic DA l agonist (10, 21-23, 26, 29, 32), and dopamine, an alpha-adrenergic, beta-adrenergic, and dopaminergic agonist (1,9,17,25,31). FM-induced arterial lesions originally reported by Morgan and Yuhas (19,35), were only observed in the rat, and only after continuous intravenous infusion for 24 hr at doses ranging from 1 to 100~g/kg/min.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of Arterial Lesions Induced by Dopaminergic Compounds in the Rat

Kerns¹,

Arena²,

Macia³

et al. 1989

Toxicol Pathol

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ABSTRACfFenoldopam mesylate (PM), a selective post-junctional dopaminergic (DA,) vasodilator, causes lesions of large caliber splanchnic arteries in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat, or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (< 100 Jlm) of the splanchnic, cerebral, coronary and renal vascular beds. Dopamine is an alpha-and beta-adrenoceptor and a dopaminergic receptor agonist. Because these arterial lesions are thought to result from the pharmacologic activity of these 2 compounds; we sought to ascertain the presence of DA, receptors in mesenteric arteries of the rat and to determine the role of these or other vascular receptor subtypes in lesion induction. We also studied the process of repair after arterial injury caused by FM or dopamine. The presence of DA 1 receptors was confirmed in isolated perfused mesenteric arteries by standard pharmacologic techniques; stimulation by PM resulted in vasodilation which was inhibited by the DA) receptor antagonist SK&F 83566-C. Likewise, SK&F 83566-C prevented the induction of hemorrhagic lesions of large caliber arteries in rats upon infusion of PM or dopamine. In rats co-exposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions oflarge caliber arteries were increased, but PBZ prevented the formation of dopamine-induced fibrinoid lesions in arteries ofsmall caliber. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and PM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA 1 receptors. Fibrinoid lesions of small arteries (alphaadrenoceptor-mediated) were repaired, as observed morphologically by 14 d after exposure to dopamine. Hemorrhagic lesions of large caliber arteries (DA) receptor-mediated) had undergone significant repair by 28 d after exposure to PM but these arteries possessed a thicker media surrounded by adventitial fibrosis. Thus, morphologically distinct receptor-mediated splanchnic arterial lesions induced by dopaminergic and alpha-adrenoceptor agonists follow a markedly different course of repair. Arterial lesions induced by FM or dopamine by activation ofpost-junctional dopaminergic DA, receptors may represent a model of polyarteritis nodosa.

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Section: Introductionmentioning

confidence: 99%

Pathogenesis of Arterial Lesions Induced by Dopaminergic Compounds in the Rat

Kerns¹,

Arena²,

Macia³

et al. 1989

Toxicol Pathol

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“…SKF 82526-J stimulates dopamine-sensitive adenylate cyclase in the rat caudate nucleus, an effect blocked by the dopamine antag- onists haloperidol, chlorpromazine, and bulbocapnine (13). SKF 82526-J has -3.5-fold the potency of dopamine in renal vasodilation in the dog, an effect also blocked by the dopamine antagonists, bulbocapnine and metoclopramide (13)(14)(15)(16). The compound is devoid of alpha-or beta-adrenergic receptor stimulating activity, is well absorbed orally, and does not cross the blood-brain barrier (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…SKF 82526-J has -3.5-fold the potency of dopamine in renal vasodilation in the dog, an effect also blocked by the dopamine antagonists, bulbocapnine and metoclopramide (13)(14)(15)(16). The compound is devoid of alpha-or beta-adrenergic receptor stimulating activity, is well absorbed orally, and does not cross the blood-brain barrier (13)(14)(15)(16). SKF 82526-J does not inhibit nerve-evoked norepinephrine release (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.

Carey¹,

Stote²,

Dubb³

et al. 1984

J. Clin. Invest.

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Abstract. SKF 82526-J, or fenoldopam, a benzazepine derivative, is a selective dopamine-1 (DA-1) agonist devoid of activity at dopamine-2, alpha-or beta-adrenergic receptors. We studied SKF 82526-J in 10 patients with essential hypertension and five normal control subjects on constant 150-meq sodium, 60 meq potassium intake. In the hypertensive patients, during a 6-d placebo period supine blood pressure and heart rate were stable at 156±6/105±4 mmHg and 76±5 beats/ min, respectively. In response to a single oral dose of 100 mg of SKF 82526-J, supine blood pressure decreased to a nadir of 141±5/89±8 mmHg (P < 0.0001) at 90 min and remained decreased at 145±6/99±3 mmHg (P < 0.0001) at 4 h. Heart rate increased to 91±5 beats/ min (P < 0.002), but returned to control levels (82±5 beats/min) at 4 h. Renal blood flow increased from 371±57 to a peak of 659±104 ml/min and renal vascular resistance fell from 34±5 to 19±2 dyn sec cm-5 X 103 (P < 0.01). Urine volume, sodium and fractional sodium excretion, and plasma renin activity were increased as a result of SKF 82526-J administration. During the ensuing 3 wk of SKF 82526-J, blood pressure remained decreased and returned to control levels after placebo administration. In These results suggest that reduced dopaminergic activity expressed at the peripheral DA-1 receptor may contribute to the pathophysiology and/or maintenance of increased blood pressure in essential hypertension. In addition, the results suggest that peripheral DA-1 receptor stimulation with SKF 82526-J may be efficacious in the treatment of human essential hypertension.

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“…Preliminary studies in animals9 10 and patients"1 have indicated that it acts through stimulation of specific postsynaptic dopamine receptors in the renal vascular bed. However, unlike dopamine, higher doses of fenoldopam do not seem to increase either blood pressure or heart rate.9 This study was designed to determine the systemic and regional hemodynamic, cardiac, reflexive, and biochemical effects of a single oral dose of fenoldopam in patients with essential hypertension.…”

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confidence: 99%

Immediate hemodynamic effects of a dopamine-receptor agonist (fenoldopam) in patients with essential hypertension.

Ventura¹,

Messerli²,

Fröhlich³

et al. 1984

Circulation

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Systemic, splanchnic, and renal hemodynamics, intravascular volume, and reflexive and endocrine changes were measured before and after a single dose of fenoldopam, a novel antihypertensive agent that acts through stimulation of specific dopamine receptors. A 13% reduction in mean arterial pressure was mediated by a fall in total peripheral resistance associated with an increase in cardiac index, heart rate, stroke volume, left ventricular ejection rate, and circumferential fiber shortening. Renal blood flow increased, thereby reducing the renal vascular resistance by more than 40%. In contrast, splanchnic hemodynamics failed to change. Likewise, there were no changes in intravascular volume, plasma renin activity, or norepinephrine, serum aldosterone, or prolactin levels. Circulation 69, No. 6, 1142No. 6, -1145No. 6, , 1984 THE KIDNEY has been said to be the primary site that both initiates the hypertensive process1 2 and is affected by hypertensive vascular disease. Thus arterial pressure may become elevated by an altered renal excretory "set point" that requires a higher perfusion pressure to excrete its sodium load, perhaps because of afferent glomerular arteriolar constriction.2 3 In contrast, as a result of the systemic arteriolar constriction, blood flow to the kidney may be diminished.`' Therefore a vasodilating agent, preferably with greater effects on the kidney, should be particularly useful in the treatment of patients with essential hypertension.Fenoldopam, a benzazepine derivative, is a novel antihypertensive agent with selective renal vasodilating properties. Preliminary studies in animals9 10 and patients"1 have indicated that it acts through stimulation of specific postsynaptic dopamine receptors in the renal vascular bed. However, unlike dopamine, higher doses of fenoldopam do not seem to increase either blood pressure or heart rate.9 This study was designed to determine the systemic and regional hemodynamic, cardiac, reflexive, and biochemical effects of a single Materials and methodsFourteen patients (10 men and four women) with mild established essential hypertension were included in this study. All had either never received antihypertensive therapy or had therapy discontinued at least 4 weeks before entering the study. Detailed clinical evaluation did not reveal any secondary cause for the hypertension or any concomitant disorders. 12 Each subject provided informed consent to a protocol previously approved by our institution's review committee.All patients had a supine diastolic pressure (phase V of Korotkoff sounds) consistently above 90 mm Hg but not exceeding 120 mm Hg. Systemic and regional hemodynamics together with M mode echocardiograms, electrocardiograms, and blood samples for measurement of plasma renin activity and norepinephrine, serum aldosterone, and prolactin levels were obtained before (after placebo) and 1 hr after the oral administration of fenoldopam (50 [n = 5] or 100 mg [n = 9]). Systemic and regional hemodynamics were determined by methods previously report...

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Renal vasodilators and hypertension

Cited by 46 publications

References 28 publications

Pathogenesis of Arterial Lesions Induced by Dopaminergic Compounds in the Rat

Pathogenesis of Arterial Lesions Induced by Dopaminergic Compounds in the Rat

Selective peripheral dopamine-1 receptor stimulation with fenoldopam in human essential hypertension.

Immediate hemodynamic effects of a dopamine-receptor agonist (fenoldopam) in patients with essential hypertension.

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