Generic names need stereochemical information. Signs of support.
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Molecular Conformation↗
Biomedical subjects
R R Ruffolo
Publications and source records attributed to R R Ruffolo.
The pharmacology of fenoldopam.
Fenoldopam is a selective dopamine1 (DA1) receptor agonist. Most of the DA1 receptor agonist activity of fenoldopam resides in the R-enantiomer, which also shows weaker alpha 2-adrenoceptor antagonist activity Fenoldopam produces vasodilation in vascular beds that are rich in vascular DA1 receptors, eg, renal and mesenteric receptors, and produces an increase in renal blood flow at doses that do not affect blood pressure. At higher doses, fenoldopam lowers blood pressure but still maintains renal perfusion. In addition to its renal vasodilator activity, fenoldopam is natriuretic, possibly resulting from a direct effect of DA1 receptors on the proximal convoluted tubule. In animals with spontaneous or drug-induced renal failure, fenoldopam improves renal function.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Effect of dopamine beta-hydroxylase inhibition on systemic hemodynamics in conscious, spontaneously hypertensive rats.
The acute and chronic effects of a potent and selective dopamine beta-hydroxylase inhibitor, SK&F 102698 [1-(3,5-difluorobenzyl)imidazole-2-thiol], on systemic hemodynamic variables were assessed in chronically instrumented spontaneously hypertensive and normotensive Wistar rats. The changes observed in the hypertensive rats were compared with those obtained by vehicle in a different group of rats. Following intragastric administration of SK&F 102698 (75 mg/kg), blood pressure and cardiac output decreased gradually in both strains of rats, while total peripheral vascular resistance remained unchanged. The antihypertensive effect of repeated daily administration of SK&F 102698 in the hypertensive rats was sustained for the duration of treatment. During the acute phase, the decrease in cardiac output was due to bradycardia. In addition, as a result of hemodynamic changes, SK&F 102698 significantly reduced the minute work output of the heart. The results indicate that SK&F 102698 lowers blood pressure primarily by decreasing cardiac output.
Animals↗
Effect of carvedilol on renal hemodynamics and renal excretory function in spontaneously hypertensive rats.
The effects of the novel antihypertensive agent, carvedilol, on renal hemodynamics and excretory function have been investigated and compared with the effects of labetalol in conscious, spontaneously hypertensive rats. Sustained intravenous infusion of carvedilol or labetalol at a rate of 10 micrograms/kg/min resulted in a significant decrease in blood pressure which was equivalent in magnitude for both drugs. Carvedilol had no effect on renal hemodynamic parameters; glomerular filtration rate, renal blood flow, and filtration fraction were unchanged. In contrast, labetalol decreased the glomerular filtration rate by 13% (p less than 0.01) and the filtration fraction was reduced from 28 to 24%. Inasmuch as renal blood flow was unchanged and perfusion pressure was reduced, both compounds decreased renal vascular resistance. Urine flow decreased and osmolality increased with both carvedilol and labetalol. However, excretion of electrolytes was affected differently with the two compounds. While sodium and potassium excretion were significantly decreased with labetalol, sodium and potassium excretion remained stable during carvedilol infusion, which represents an important beneficial effect for a potent systemic vasodilator. We conclude, therefore, that carvedilol does not compromise the renal autoregulatory integrity in hypertensive rats, and that the antihypertensive activity of the compound is associated with an apparent 'renal sparing' effect, in that the decrease in blood pressure does not compromise the urinary excretion of sodium.
Animals↗
Prevention and complete reversal of cyclosporine A-induced renal vasoconstriction and nephrotoxicity in the rat by fenoldopam.
The primary mechanism of cyclosporine A-induced nephrotoxicity involves renal vasoconstriction. In the present study, we have tested the effects of fenoldopam, a dopamine DA1, receptor agonist with renal vasodilator properties, on the changes in renal function induced by acute and subacute administration of cyclosporine A. In inactin-anesthetized rats, acute administration of cyclosporine A (100 mg/kg i.p.) significantly decreased paraaminohippuric acid (PAH) and inulin clearances. Fenoldopam, at a dose (10 micrograms/kg.min) which alone significantly increased PAH and inulin clearances, completely prevented the cyclosporine A-induced reductions in renal function. Similarly, subacute administration of cyclosporine A (20 mg/kg.day for 3 days) resulted in significant reductions in base-line PAH and inulin clearances which were normalized by administration of fenoldopam. These data indicate that administration of fenoldopam can both prevent and completely reverse cyclosporine A-induced renal vasoconstriction and nephrotoxicity.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Dobutamine vs dopamine: another look.
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Dobutamine↗
The interaction of the enantiomers of carvedilol with alpha 1- and beta 1-adrenoceptors.
The stereoselectivity of carvedilol, a novel beta-adrenoceptor antagonist and vasodilator with one asymmetric carbon atom, was examined at alpha 1- and beta 1-adrenoceptors in vitro and in vivo. (-)-(S)-Carvedilol is a potent, competitive antagonist of the beta 1-adrenoceptor-mediated positive chronotropic response to isoproterenol in guinea pig atrium, with a dissociation constant (KB) of 0.4 nM. (+)-(R)-Carvedilol was more than 100-fold less potent than the (-)-S-enantiomer as an antagonist of beta 1-andrenoceptors, having a KB of approximately 45 nM. Consistent with these findings (-)-(S)-carvedilol (0.1 mg/kg, i.v.) produced a 25-fold rightward shift in the beta 1-adrenoceptor-mediated positive chronotropic response to isoproterenol in pithed rats, whereas the (+)-R-enantiomer had no beta 1-adrenoceptor blocking activity in vivo at this dose. In contrast to the marked degree of stereoselectivity observed at beta 1-adrenoceptors, both (-)-(S)- and (+)-(R)-carvedilol produced equal antagonism of the alpha 1-adrenoceptor-mediated vasoconstrictor response to norepinephrine in rabbit aorta, with KB values of 14 and 16 nM, respectively. Furthermore, in the pithed rat, the alpha 1-adrenoceptor-mediated pressor dose-response curve to cirazoline was shifted approximately 6-fold to the right by both the (+)-R- and (-)-S-enantiomers of carvedilol at a dose of 1 mg/kg, i.v. In anesthetized spontaneously hypertensive rats, (-)-(S)-carvedilol was 6-fold more potent as an antihypertensive than (+)-(R)-carvedilol.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Dobutamine: ten years later.
Dobutamine is a commonly used positive inotrope for the short-term management of heart failure. It is commercially available as a 50:50 mixture of two isomers with unique effects on alpha- and beta adrenergic receptors. In dosages of 2-15 micrograms/kg/minute, dobutamine has been shown to increase cardiac output (mainly through stroke volume), reduce systemic vascular resistance, lower central venous and pulmonary artery wedge pressures, improve renal blood flow, and relieve signs and symptoms of congestive heart failure. At higher dosages it can increase heart rate and induce arrhythmias. Recent evidence indicates that effects of dobutamine last long after the drug has been eliminated from the plasma, and some work has been done on ambulatory use of this agent. Dobutamine has been used successfully in several circumstances, such as after cardiac surgery, in patients with myocardial infarction, and in various shock states. An understanding of the pathophysiology of the underlying disorder is important in deciding which catecholamine to use. With this in mind, monotherapy or combination therapy with inodilators such as dobutamine, or inopressors like dopamine will follow logically.
Cardiac Output, Low↗
In vitro pharmacologic profile of the novel beta-adrenoceptor antagonist and vasodilator, carvedilol.
The pharmacologic profile of the novel beta-adrenoceptor antagonist/vasodilator, carvedilol, has been investigated in vitro. Carvedilol produced competitive antagonism of the beta 1-adrenoceptor mediated positive chronotropic response to isoproterenol in guinea pig atria, and the beta 2-adrenoceptor mediated relaxation to isoproterenol in carbachol (1 mumol/l) precontracted guinea pig trachea, with a dissociation constant (KB) for beta 1-adrenoceptors of 0.8 nmol/l and beta 2-adrenoceptors of 1.3 nmol/l. At slightly higher concentrations, carvedilol produced competitive inhibition of the alpha 1-adrenoceptor mediated contractile response to norepinephrine in rabbit aorta with a KB of 11 nmol/l. Carvedilol had no significant effect on the contractile response to angiotensin II in rabbit aorta at concentrations up to 10 mumol/l, thus demonstrating the lack of nonspecific vasodilator actions in arteries. In canine saphenous vein, carvedilol produced noncompetitive blockade of alpha 2-adrenoceptor mediated vasoconstriction, indicative of some additional activity. In estrogen-primed rat uterus precontracted by depolarization with KCl (70 mmol/l), carvedilol produced concentration-dependent relaxation (IC50 of 7.6 mumol/l), consistent with the notion that carvedilol may be a calcium channel antagonist. Support for this hypothesis was obtained in KCl (70 mmol/l) depolarized rabbit aorta where carvediol (10 mumol/l) produced a 10-fold parallel rightward shift in the concentration-response curve to calcium chloride. These studies demonstrate that carvedilol is a potent beta 1-, beta 2- and alpha 1-adrenoceptor antagonist, and a moderately potent calcium channel antagonist. These multiple activities of carvedilol may contribute to the antihypertensive activity of the compound.
Adrenergic alpha-Antagonists↗
Effect of pertussis toxin treatment on postjunctional alpha-1 and alpha-2 adrenoceptor function in the cardiovascular system of the pithed rat.
The role of pertussis toxin sensitive guanine nucleotide regulatory proteins (G-proteins) in the signal transduction processes involved in postjunctional vascular alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction has been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 micrograms/kg i.v., 3 days before experimentation) produced a marked inhibition of the alpha-2 adrenoceptor-mediated pressor response to B-HT 933. In contrast, pertussis toxin treatment had only a small effect on the alpha-1 adrenoceptor-mediated pressor response to cirazoline. However, after elimination of the alpha-1 adrenoceptor reserve for cirazoline with phenoxybenzamine (0.1 mg/kg i.v.), the pressor response to this agonist became highly sensitive to inhibition by pertussis toxin treatment. This pattern of inhibition of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by pertussis toxin is identical to that produced by inhibition of extracellular calcium influx by a high dose of the calcium channel antagonist, nifedipine (1.5 mg/kg i.a.), suggesting that those components of the alpha-1 and alpha-2 adrenoceptor-mediated vasoconstrictor processes that are dependent upon the translocation of extracellular calcium may involve a pertussis toxin sensitive G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Localization and characterization of alpha-2 adrenoceptors in the isolated canine pulmonary vein.
Alpha-1 and alpha-2 adrenoceptor-mediated contractile responses were studied in isolated canine pulmonary veins. Norepinephrine elicited concentration-dependent contractile responses which were antagonized in a competitive manner by the selective alpha-2 adrenergic antagonist, rauwolscine, with a dissociation constant of 15.7 nM, whereas the selective alpha-1 adrenoceptor antagonist, prazosin, produced nonparallel rightward shifts in the norepinephrine concentration-response curve with a marked depression in the maximal response, indicating noncompetitive antagonism. B-HT 933, a selective alpha-2 adrenoceptor agonist, also produced a concentration-dependent contraction in canine pulmonary vein, with the maximal contraction elicited by B-HT 933 being approximately 45% of that produced by norepinephrine. The response mediated by B-HT 933 was antagonized in a competitive manner by rauwolscine with a dissociation constant of 4.4 nM, whereas prazosin again behaved in a noncompetitive manner producing nonparallel rightward shifts in the B-HT 933 concentration-response curve with a marked depression in the maximal response. However, another alpha-1 adrenoceptor antagonist, corynanthine, weakly blocked the response produced by B-HT 933 with a dissociation constant of 1400 nM, and this low affinity for corynanthine is consistent with interaction at alpha-2 adrenoceptors. Cirazoline, a selective alpha-1 adrenoceptor agonist, also produced a concentration-dependent vasoconstrictor response in canine pulmonary veins which was antagonized competitively by both alpha-1 adrenoceptor antagonists, corynanthine and prazosin, with dissociation constants of 180 and 1.4 nM, respectively, indicative of an interaction with alpha-1 adrenoceptors. Rauwolscine (10 nM) did not significantly affect the response produced by cirazoline.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Canine pulmonary artery contains a homogeneous population of alpha-1 adrenoceptors.
We have investigated systemically the hypothesis that there exist subtypes of the alpha-1 adrenoceptor in the canine pulmonary artery. The affinity of the alpha-1 adrenoceptor antagonist, prazosin, was assessed by Schild Regression Analysis against the agonists, phenylephrine, norepinephrine and methoxamine, in rings prepared from canine pulmonary artery using the classical technique in which control and treatment concentration-response curves are obtained in every tissue. This technique allows for appropriate corrections to be made in tissue-dependent differences in agonist potency, time-dependent changes in agonist sensitivity and differences in maximum responses that result from nonspecific effects of agonists occurring at higher concentrations, as was found to be the case for methoxamine. Two cumulative concentration-response curves were constructed for each agonist at 2-hr intervals, with the first (control) concentration-response curve being constructed before the addition of prazosin, and the second concentration-response curve obtained 1 hr after exposure to prazosin. Prazosin had similar pA2 values against phenylephrine (9.56), norepinephrine (9.32) and methoxamine (9.35), with slopes of the Schild Regressions not differing significantly from the theoretical value of unity, suggesting that blockade was competitive in all cases. The results provide no evidence for heterogeneity in alpha-1 adrenoceptors in canine pulmonary artery when assessed using the classical method involving two concentration-response curves in a single tissue and allowing for appropriate corrections in tissue-dependent differences and time-dependent changes in agonist response.
Animals↗
Effect of aromatic fluorine substitution on the alpha and beta adrenoceptor-mediated effects of 3,4-dihydroxytolazoline in the pithed rat.
The alpha and beta adrenoceptor-mediated effects of the catecholimidazoline, 3,4-dihydroxytolazoline, and its 2-, 5- and 6-aromatic fluorine-substituted derivatives have been studied in the cardiovascular system of the pithed rat. All four compounds produced vasopressor responses in beta adrenoceptor blocked (propranolol, 3 mg/kg i.v.) animals. The pressor responses produced by all four compounds were antagonized by the selective alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and were relatively unaffected by the selective alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.), indicating that vasoconstriction produced by the fluorinated imidazolines was mediated exclusively by postjunctional vascular alpha-1 adrenoceptors. The rank order of potency at the alpha-1 adrenoceptor was: 5-fluoro greater than 2-fluoro greater than desfluoro greater than 6-fluoro. At higher doses, 3,4-dihydroxytolazoline and its fluorinated derivatives produced an alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in animals pretreated with prazosin, with all four compounds being equipotent. In rats with complete alpha adrenoceptor blockade [phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.)] whose blood pressure was elevated by constant infusion of angiotensin II (150 ng/kg/min i.v.), high doses of the 2-fluoro-, but not the 5-, 6- or desfluoro catecholimidazoline derivatives, produced a beta-2 adrenoceptor-mediated vasodepressor response. All four compounds produced a beta-1 adrenoceptor-mediated positive chronotropic response in pithed rats with the rank order of potency being: 2-fluoro = 5-fluoro greater than desfluoro greater than 6-fluoro.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of benzylic hydroxyl substitution on the alpha-adrenoceptor blocking activity of tolazoline.
The R(-)- and S(+)-enantiomers of alpha-hydroxytolazoline, the benzylic hydroxy-substituted derivative of the alpha-adrenoceptor antagonist, tolazoline, were evaluated at alpha 1- and alpha 2-adrenoceptors in canine saphenous vein. Benzylic hydroxyl substitution of tolazoline in either the R(-) or S(+) configuration significantly decreased affinity at both alpha 1- and alpha 2-adrenoceptors. Differences in affinity between the R(-)- and S(+)-enantiomers were small, which is characteristic of imidazolines, but in marked contrast to phenethylamines where enantiomeric differences are large. The rank order of affinities at alpha 1- and alpha 2-adrenoceptors is tolazoline greater than S(+)-alpha-hydroxytolazoline = R(-)-alpha-hydroxytolazoline, which is different from that order predicted by the Easson-Stedman hypothesis (i.e., R(-) greater than S(+) = desoxy). The findings support our contention that phenethylamines and imidazolines interact differently with alpha-adrenoceptors.
Adrenergic beta-Antagonists↗
Differential effect of pertussis toxin on pre- and postjunctional alpha 2-adrenoceptors in the cardiovascular system of the pithed rat.
The role of the pertussis toxin-sensitive guanine nucleotide binding regulatory protein in pre- and postjunctional alpha 2-adrenoceptor-mediated responses has been investigated in the pithed rat. Pertussis toxin (50 micrograms/kg i.v., administered 3 days prior to experimentation) markedly inhibited the alpha 2-adrenoceptor-mediated vasopressor response to B-HT 933, but had no effect on the alpha 2-adrenoceptor-mediated cardiac neuroinhibitory effect of B-HT 933. Thus, postjunctional alpha 2-adrenoceptor activation in vascular smooth muscle, but not prejunctional alpha 2-adrenoceptor activation on sympathetic neurons, utilizes a pertussis toxin-sensitive guanine nucleotide binding regulatory protein.
Adrenergic alpha-Agonists↗
The relationship of alpha-adrenoceptor reserve and agonist intrinsic efficacy to calcium utilization in the vasculature.
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Adrenergic alpha-Agonists↗
Involvement of vascular endothelium in the potentiation of vasoconstrictor responses by neuropeptide Y.
Although neuropeptide Y is not a potent vasoconstrictor in many vascular beds, nanomolar concentrations of this peptide can potentiate the response of isolated blood vessels to sympathetic stimulation or exogenous vasoconstrictors. Potentiation of the response to field stimulation was observed in superfused ring segments of rabbit ear artery or canine saphenous vein, provided that the endothelium was not mechanically damaged. The ability of neuropeptide Y to potentiate the constrictor response to noradrenaline in the ear artery was also dependent on the presence of an intact endothelium. The release of an endothelial-derived vasoconstrictor substance, as yet unidentified, by neuropeptide Y may explain its ability to potentiate the responses to both nerve stimulation and a variety of exogenous vasoconstrictors.
Animals↗
The role of neuropeptide Y in vascular sympathetic neurotransmission may be enhanced in hypertension.
The effect of neuropeptide Y on the contractile response to field stimulation was examined in isolated blood vessels. Exogenous neuropeptide Y at a concentration of 100 nmol/l significantly potentiated the response to field stimulation in rabbit ear artery and canine saphenous vein. Administration of neuropeptide Y antiserum to tissues not previously exposed to neuropeptide Y significantly reduced the response to field stimulation; greater effects were observed in the rabbit ear artery than in the canine saphenous vein. Furthermore, this antiserum depressed the response to field stimulation in caudal arteries from spontaneously hypertensive rats (SHR), but not in those from normotensive Wistar-Kyoto rats (WKY). The depression by the anti-neuropeptide Y antibody did not appear to be produced by a non-specific mechanism, since antiserum against either thyrotrophin-releasing factor or platelet-derived growth factor did not affect the response to field stimulation. It is concluded that endogenous neuropeptide Y can contribute to the vascular contractile response to field stimulation, and that this contribution may be enhanced in hypertensive animals.
Animals↗