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Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 145 records · Page 8Linked to original sources
PubMed1988

Evaluation of the acute hemodynamic effects and pharmacokinetics of coronary thrombolysis produced by intravenous tissue-type plasminogen activator in the anesthetized dog.

The thrombolytic dose-response effectiveness and pharmacokinetics of tissue-type plasminogen activator (rt-PA) was evaluated in anesthetized, open-chest dogs instrumented for the measurement of systemic hemodynamics. Intracoronary thrombi were formed by injecting thrombin (100 U) and CaCl2 (50 microM) into a cannulated, isolated segment of the left anterior descending coronary artery (LAD). Coronary blood flow was measured by placing an electromagnetic flow probe proximal to the LAD thrombus. Thirty minutes after formation of a stable LAD thrombus, intravenous infusion of rt-PA was given at rates of 0.5, 1, 2, 4, or 8 micrograms/kg/min (n = 8/dose) for 60-90 min, and the animals were followed for an additional 30 min. In vehicle-treated animals, residual thrombus wet weight, determined at the end of the experiment, was 30 +/- 4 mg (mean +/- SEM, n = 8) and spontaneous reperfusion did not occur. The rt-PA produced a dose-related increase in the number of animals reperfusing, a decrease in the time to reperfusion, and a decrease in residual thrombus weight, but had no effect on systemic hemodynamics. The increase in infusion rate from 0.5 to 4 micrograms/kg/min resulted in a linear increase in both the steady-state rt-PA plasma concentration and the area under the rt-PA plasma concentration versus time curve (n = 3-5 animals/dose); between the infusion rates of 4 and 8 microgram/kg/min there was a disproportionate increase in both these parameters that was due to a decrease in the total systemic clearance of rt-PA. The postdosing elimination half-life (t1/2 alpha) did not differ significantly at any dose of rt-PA, and the pooled half-life (t1/2 alpha) for all doses of rt-PA was 2.36 +/- 0.12 min (n = 19).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1988

Comparison of the renal and pulmonary hemodynamic effects of fenoldopam, dobutamine, dopamine and norepinephrine in the anesthetized dog.

The renal and pulmonary hemodynamic effects of fenoldopam, dobutamine, dopamine and norepinephrine were compared in the pentobarbital-anesthetized dog. Animals were pretreated with propranolol (1 mg/kg, i.v.) to eliminate beta-adrenoceptor-mediated effects in the renal and pulmonary circulations. Heparinized blood was withdrawn from the right femoral artery and transferred, via a peristaltic pump, to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung. The flow rate of the pump was set so that the perfusion pressure in the lobe was equal to resting diastolic pulmonary artery blood pressure. Under these conditions of constant flow, changes in perfusion pressure reflect changes in pulmonary vascular resistance. Renal blood flow was measured in the same experiments via an electromagnetic flow probe which was placed directly on the left renal artery. Intraarterial administration of fenoldopam resulted in a marked reduction in renal vascular resistance at doses that had virtually no effect on pulmonary vascular resistance. Conversely, dobutamine increased pulmonary vascular resistance slightly, and had no effect on the renal circulation. Dopamine increased pulmonary vascular resistance at all doses, and exhibited a biphasic effect on renal vascular resistance. At low doses, dopamine produced a modest reduction in renal vascular resistance, and at higher doses, dopamine significantly increased renal vascular resistance. Norepinephrine increased both pulmonary and renal vascular resistance at all doses, as expected. These results indicate that fenoldopam may be hemodynamically favorable over dobutamine and dopamine in the management of patients with low output cardiac failure since fenoldopam improves renal hemodynamics at doses that have little or no effect on the pulmonary circulation.

Animals↗
PubMed1988

Alpha adrenoceptor-mediated vasoconstriction in rat hindlimb: innervated alpha-2 adrenoceptors in the saphenous arterial bed.

The alpha adrenoceptor subtypes mediating vasoconstriction to exogenous agonists and to spinal sympathetic nerve stimulation have been characterized in the autoperfused (constant flow) femoral (predominantly skeletal musculature) and saphenous (predominantly cutaneous) vascular beds of the pithed rat. Intra-arterial infusion of the alpha-1 adrenoceptor agonist, methoxamine, increased perfusion pressure in both vascular beds over the same range of infusion rates, and the maximum responses were similar. The selective alpha-2 adrenoceptor agonist, B-HT 933, also increased perfusion pressure in both beds, although the maximum response to B-HT 933 in the saphenous bed was approximately twice that observed in the femoral bed. Responses to methoxamine were blocked by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg), but not the alpha-2 adrenoceptor antagonist, rauwolscine (1 mg/kg), or by the selective postjunctional alpha-2 adrenoceptor antagonist, SK&F 104078 (1 mg/kg). Conversely, responses to B-HT 933 were blocked by rauwolscine and by SK&F 104078, but not by prazosin. Vasopressor responses to B-HT 933 in both vascular beds of the rat hindlimb also were reduced markedly by the calcium channel blocker, nifedipine (1 mg/kg), whereas responses to methoxamine were relatively resistant to inhibition by nifedipine. In the femoral bed, as in the systemic arterial circulation, responses to sympathetic nerve stimulation were strongly inhibited by prazosin, were potentiated by rauwolscine and were unaffected by SK&F 104078. In contrast, in the saphenous arterial bed, the responses to sympathetic nerve stimulation were inhibited by all three antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1988

Evidence for heterogeneity between pre- and postjunctional alpha-2 adrenoceptors using 9-substituted 3-benzazepines.

A series of alpha adrenoceptor antagonists, including both reference compounds and the novel benzazepine antagonists, SK&F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine) and two of its 9-substituted derivatives, SK&F 101253 and SK&F 104078, were tested in vitro for affinity at central and peripheral alpha adrenoceptor subtypes. Peripheral alpha-1 adrenoceptor antagonist potency of these agents, as assessed by the receptor dissociation constant (KB) against norepinephrine-induced contraction in the rabbit aorta, correlated with the Ki value for inhibition of [3H]prazosin binding to central alpha-1 adrenoceptors in rat brain homogenates. Central alpha-2 adrenoceptor affinity, measured as the Ki for inhibition of [3H]rauwolscine binding to rat brain homogenates, correlated well with antagonist activity at peripheral postjunctional alpha-2 adrenoceptors as reflected by the KB against B-HT 920-induced contraction in canine saphenous vein. The 9-substituted benzazepines, SK&F 101253 and SK&F 104078, produce preferential blockade of postjunctional vs. prejunctional alpha-2 adrenoceptors in peripheral models. The high affinity of SK&F 104078 for postjunctional alpha-2 adrenoceptors in the canine saphenous vein was confirmed by its ability to inhibit [3H]rauwolscine binding to postjunctional alpha-2 adrenoceptors in this tissue. The observation that the Ki values for these antagonists against [3H] rauwolscine binding correlate with their KB values at the postjunctional alpha-2 adrenoceptors, rather than those at the prejunctional neuroinhibitory alpha-2 adrenoceptor, suggests a pharmacologic similarity between the postjunctional vascular alpha-2 adrenoceptors and the central [3H]rauwolscine binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1988

Pharmacologic characterization of SK&F 104078, a novel alpha-2 adrenoceptor antagonist which discriminates between pre- and postjunctional alpha-2 adrenoceptors.

SK&F 104078 has been reported to be a moderately potent antagonist at postjunctional alpha-2 adrenoceptors in canine saphenous vein, rabbit saphenous vein and canine saphenous artery (KB = 76-150 nM). In contrast, SK&F 104078 has been found to have essentially no affinity for prejunctional alpha-2 adrenoceptors in the guinea pig atrium. To characterize further the pharmacology of SK&F 104078 we have examined its effects in several additional alpha-2 adrenoceptor models and on several non alpha adrenoceptor-mediated vascular responses. SK&F 104078 does not block the neuroinhibitory effect of alpha methylnorepinephrine in the guinea pig ileum. In contrast, in the rat vas deferens, high concentrations of SK&F 104078 (3-30 microM) antagonized the neuroinhibitory effect of UK 14,304; however, the antagonism was not competitive. At concentrations up to 1 microM, SK&F 104078 did not potentiate [3H]overflow from guinea pig vas deferens or guinea pig atrium prelabeled with [3H]norepinephrine, indicating no prejunctional alpha-2 adrenoceptor blocking activity in these tissues. SK&F 104078 is a competitive antagonist at alpha-1 adrenoceptors, and at 5-hydroxytryptamine2 receptors, as demonstrated by blockade of norepinephrine- and serotonin-induced contraction in the rabbit aorta, with KB values of 155 and 20 nM, respectively. At concentrations up to 10 microM, SK&F 104078 does not depress angiotensin II-induced contraction of rabbit aorta. At 1 microM, no depression of the response to Ca++ in depolarized rabbit aorta is observed, although a significant inhibition of this response is seen at 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1988

Coronary vascular activity of the novel inotropic pro-drug ibopamine and the de-esterified active form epinine.

The effects of the novel inotropic pro-drug, ibopamine, and the de-esterified active form, epinine (N-methyldopamine), were investigated in isolated canine circumflex coronary arteries in vitro. Both ibopamine and epinine produced concentration-dependent contractions of isolated canine coronary arteries, with epinine being approximately 7-fold more potent than ibopamine. The coronary vasoconstrictor response produced by ibopamine was inhibited completely by the irreversible alpha-adrenoceptor antagonist, phenoxybenzamine, whereas the response produced by epinine was transformed into relaxation which was inhibited by the beta-adrenoceptor antagonist, propranolol. The results indicate that ibopamine has the capacity to produce coronary arterial vasoconstriction, but that this activity may be partially offset by the beta-adrenoceptor-mediated activity of the active form, epinine.

Animals↗
PubMed1988

Coronary thrombolysis with intravenous streptokinase in the anesthetized dog: a dose-response study.

In order to study the in vivo coronary thrombolytic dose-response effectiveness of i.v. streptokinase, pentobarbital-anesthetized, open chest dogs were instrumented for the measurement of lead II ECG, systemic arterial blood pressure, left ventricular developed pressure, left ventricular end-diastolic pressure, left ventricular dP/dt and left anterior descending (LAD) coronary artery blood flow. In some animals, two pairs of ultrasonic dimension gauges were positioned in 1) an area of the left ventricle which would become ischemic after thrombotic occlusion of the LAD and 2) a reference area which would remain unaffected by LAD occlusion. After making an occlusive thrombus by injecting thrombin (50-200 U) and calcium chloride (50-100 mumols) into a cannulated and mechanically occluded side-branch of an isolated segment of the mid- to distal LAD, animals were given either streptokinase (5,000, 10,000, 20,000 or 40,000 U of bolus, followed by 500, 1000, 2000 or 4000 U/min of infusion, respectively) or saline, i.v. At the termination of the experiment, thrombus wet weight and, in some animals, infarct size (measured by tetrazolium staining) were determined. In control animals, thrombus wet weight was 26.7 +/- 5.4 mg (n = 8) and infarct size, as a percentage of the total left ventricle, was 30.1 +/- 4.7% (n = 6). Spontaneous reperfusion (return of LAD blood flow) was not observed in control animals that received saline. Intravenous administration of streptokinase produced a dose-dependent increase in the percentage of animals reperfusing, and a dose-dependent decrease in both thrombus wet weight and the time to reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1988

Systemic and coronary hemodynamic actions of the novel inotropic agent, ibopamine, and the de-esterified metabolite and active form, epinine: relationship to left ventricular performance in the dog.

The relationship between the systemic hemodynamic, inotropic and coronary blood flow actions of the novel inotropic pro-drug, ibopamine, which is the 3,4-diisobutyryl ester derivative of the active form, epinine, was examined in pentobarbital-anesthetized, vagotomized dogs prepared for the recording of systemic arterial blood pressure, heart rate, left ventricular developed pressure and end-diastolic pressure, left ventricular dP/dt, aortic blood flow, left circumflex coronary artery blood flow and lead II ECG. All animals were given i.v. infusions of vehicle followed by 10 min infusions of either epinine (1.1, 3.3, 10 and 30 micrograms/kg/min, n = 4) or ibopamine (3.3, 10, 30 and 100 micrograms/kg/min, n = 4). Both epinine and ibopamine produced dose-dependent increases in mean arterial blood pressure, heart rate, left ventricular developed pressure, left ventricular dP/dt, aortic blood flow, coronary blood flow, left ventricular minute work, stroke work, total peripheral vascular resistance and rate-pressure product. Both epinine and ibopamine decreased coronary vascular resistance, although only the decrease produced by ibopamine achieved statistical significance (P less than .05). Examination of the dose-response curves for epinine and ibopamine showed epinine to be 3- to 4-fold more potent than ibopamine with respect to increasing coronary blood flow, left ventricular stroke work, left ventricular dP/dt and rate-pressure product. However, neither drug increased myocardial work, myocardial oxygen consumption or contractility to a greater extent than the increase in coronary blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078.

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.

Adrenergic alpha-Antagonists↗
PubMed1987

Inhibition of plasma cholinesterase prevents the dopamine DA-1 receptor mediated renal vasodilation produced by ibopamine.

We have studied the dopamine DA-1 receptor mediated renal vasodilator response of the inotropic pro-drug, ibopamine, the diisobutyrate ester of epinine. In anesthetized dogs pretreated with phenoxybenzamine and propranolol to eliminate alpha- and beta-adrenoceptor mediated responses, respectively, ibopamine and epinine produced dose-dependent renal vasodilation. Treatment of animals with the cholinesterase inhibitor, physostigmine, markedly inhibited the renal vasodilation produced by ibopamine, but had no effect on the renal vasodilator response of epinine. We conclude that hydrolysis of ibopamine by plasma cholinesterase to yield epinine is necessary for the production of the dopamine DA-1 receptor mediated renal vasodilator response to ibopamine.

Animals↗
PubMed1987

Pharmacologic differentiation between pre- and postjunctional alpha 2-adrenoceptors by SK&F 104078.

Most alpha 2-adrenoceptor antagonists do not discriminate between pre- and postjunctional alpha 2-adrenoceptors, and this has led to the commonly held belief that pre- and postjunctional alpha 2-adrenoceptors may represent one homogeneous population of receptors. SK&F 104078 has been shown to be a potent antagonist at postjunctional alpha 2-adrenoceptors at concentrations that do not block prejunctional alpha 2-adrenoceptors. Thus, SK&F 104078 is a competitive postjunctional alpha 2-adrenoceptor antagonist in canine and rabbit saphenous veins, canine saphenous artery and human platelet with a dissociation constant of approximately 100 nmol/l. Conversely, SK&F 104078 is inactive as a prejunctional alpha 2-adrenoceptor antagonist in atria from dog, guinea pig, rabbit and rat, and in guinea-pig ileum at concentrations up to 10,000 nmol/l. Likewise, SK&F 104078 has the ability to block postjunctional arterial alpha 2-adrenoceptors in vivo in the pithed rat at doses that do not inhibit prejunctional alpha 2-adrenoceptors in the same model. The results suggest that pre- and postjunctional alpha 2-adrenoceptors may not represent one homogeneous class, but rather are discrete subtypes of the alpha 2-adrenoceptor that may be differentiated by SK&F 104078.

Adrenergic alpha-Antagonists↗
PubMed1987

The pharmacology of dobutamine.

Dobutamine is a sympathomimetic amine that was designed as an inotropic agent for use in congestive heart failure. Clinically, dobutamine increases cardiac output by selectively augmenting stroke volume, and this is associated with a decrease in total peripheral vascular resistance that is mediated, in part, by reflex withdrawal of sympathetic tone to the vasculature. This hemodynamic profile of dobutamine makes the drug of value in the management of low output cardiac failure. The inotropic activity of dobutamine has previously been attributed to selective stimulation of myocardial beta 1-adrenoceptors. However, recent studies from a number of laboratories indicate that the mechanism of action of dobutamine is substantially more complex. Dobutamine has the capacity to stimulate beta 1-, beta 2-, and alpha 1-adrenoceptors in the cardiovascular system at doses that approximate those used clinically. It has recently been suggested that the inotropic activity of dobutamine results from combined beta 1- and alpha 1-adrenoceptor stimulation in the myocardium, and that this activity could explain, at least in part, the inotropic selectivity of the compound. Furthermore, in the vasculature, the beta 2-adrenoceptor-mediated vasodilatory effect of dobutamine is exactly offset by the alpha 1-adrenoceptor-mediated vasoconstrictor activity, such that net changes in blood pressure are minimal following the administration of dobutamine. It is concluded, therefore, that the hemodynamic profile of dobutamine in patients with congestive heart failure is derived from a unique and complex series of interactions with alpha- and beta-adrenoceptors in the cardiovascular system.

Dobutamine↗
PubMed1987

Interaction of dopamine, (+/-)-dobutamine and the (-)-enantiomer of dobutamine with alpha- and beta-adrenoceptors in the pulmonary circulation of the dog.

The effects of dopamine, (+/-)-dobutamine (racemic mixture) and (-)-dobutamine on alpha-adrenoceptor-mediated vasoconstriction were evaluated in the pulmonary circulation of the anesthetized dog. The drugs were studied in the absence and presence of propranolol (1 mg/kg, i.v.) in order to assess beta-adrenoceptor-mediated effects in the pulmonary circulation. Intra-arterial administration of dopamine, (+/-)-dobutamine and (-)-dobutamine elicited dose-dependent increases in pulmonary perfusion pressure, reflecting increases in pulmonary vascular resistance. In control animals, dopamine elicited the largest increases in pulmonary perfusion pressure (45% above resting pulmonary pressure) followed by (-)-dobutamine (30% increase) and (+/-)-dobutamine (15% increase). The pressor effects of dopamine in the pulmonary circulation were mediated by both postjunctional vascular alpha 1- and alpha 2-adrenoceptors, since prazosin, (100 micrograms/kg, i.v.), a selective alpha 1-adrenoceptor antagonist, and rauwolscine (100 micrograms/kg, i.v.), a selective alpha 2-adrenoceptor antagonist, both inhibited the vasopressor response elicited by dopamine to roughly equivalent degrees. Pulmonary vasoconstriction produced by (+/-)-dobutamine and (-)-dobutamine was mediated primarily by postsynaptic vascular alpha 1-adrenoceptors, although alpha 2-adrenoceptor-mediated vasoconstriction was observed. In propranolol-pretreated animals, the increase in pulmonary perfusion pressure elicited by dopamine and (-)-dobutamine was qualitatively and quantitatively similar to that observed in control animals, suggesting that these agents have little activity on vascular beta 2-adrenoceptors in the pulmonary circulation. In marked contrast, the maximum pulmonary vasopressor response obtained with (+/-)-dobutamine were greater in propranolol-pretreated animals, indicating that (+/-)-dobutamine also has the capacity to stimulate pulmonary vascular beta 2-adrenoceptors which mediate pulmonary vasodilation that, in part, mask alpha-adrenoceptor-mediated pulmonary vasoconstriction. Since the (-)-enantiomer of dobutamine has little or no beta 2-adrenoceptor agonist activity, the beta 2-adrenoceptor-mediated effect of (+/-)-dobutamine must result from the (+)-enantiomer as has been previously proposed. The results of the present study indicate that dopamine has a greater propensity for increasing pulmonary vascular resistance, and therefore pulmonary arterial blood pressure, relative to (+/-)-dobutamine. This results, at least in part, from the relatively weaker activity of dopamine in stimulating pulmonary vascular beta 2-adrenoceptors which mediate vasodilation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Alpha-2-adrenoceptor-mediated effects of pergolide.

The alpha-adrenoceptor-mediated effects of pergolide were investigated in a number of biochemical and pharmacological test systems. In radioligand binding studies, pergolide more effectively competed for alpha 2-adrenoceptors than for alpha 1-adrenoceptors in membranes prepared from rat cerebral cortex. Consistent with this finding was the observation that pergolide was several orders of magnitude more effective in activating presynaptic alpha 2-adrenoceptors in rat vas deferens to inhibit stimulation-evoked [3H]-norepinephrine release than in activating postsynaptic alpha 1-adrenoceptors in the same tissue to produce a contractile response. Pergolide elicited a potent vasopressor response in pithed rats that was highly sensitive to antagonism by the selective alpha 2-adrenoceptor antagonist, yohimbine, and resistant to blockade by the selective alpha 1-adrenoceptor antagonist, prazosin, suggesting that pergolide selectively activates postsynaptic vascular alpha 2-adrenoceptors. The results of the present study indicate that the alpha-adrenoceptor-mediated effects commonly associated with pergolide result from selective stimulation of alpha 2-adrenoceptors.

Animals↗
PubMed1987

Renal effects of selective alpha-1 and alpha-2 adrenoceptor agonists in conscious, normotensive rats.

The effects of the selective alpha-1 adrenoceptor agonist, cirazoline, and the selective alpha-2 adrenoceptor agonist, B-HT 933, were assessed on renal hemodynamics and on water and solute excretion in conscious, chronically instrumented rats. Infusion (i.v.) of equipressor doses of cirazoline and B-HT 933, 0.04 and 4 mg/kg/hr, respectively, decreased renal plasma flow without changing glomerular filtration rate. Cirazoline infusion did not affect urinary excretion of water, electrolytes or total solutes. In marked contrast, B-HT 933 increased urine flow and sodium excretion significantly (P less than .01) but did not significantly alter potassium and urea excretion. Urine osmolality decreased to hyposmotic levels (from 613 +/- 86 to 172 +/- 8 mOsmol/kg of H2O) during the infusion of B-HT 933, suggesting a possible interaction between the alpha-2 adrenoceptor agonist and the vasopressin system. This diuretic action of the selective alpha-2 adrenoceptor agonist was also observed after the i.v. infusion of a subpressor dose (0.4 mg/kg/hr) of B-HT 933. In rats treated with the ganglionic blocker, hexamethonium (10 mg/kg i.v.), the B-HT 933-induced diuresis was not affected, confirming an action in the periphery, possibly at the level of the kidney. These results suggest that stimulation of renal alpha-2 adrenoceptors in conscious, euvolumic rats modulates the reabsorption of water and sodium at the site of the renal nephron.

Adrenergic alpha-Agonists↗
PubMed1987

Comparison of the effects of the novel inotropic agent, ibopamine, with epinine, dopamine and fenoldopam on renal vascular dopamine receptors in the anesthetized dog.

The effect of i.v. administration of the novel, p.o. active inotropic prodrug, ibopamine, on canine renal vascular dopamine DA-1 receptors was determined in the anesthetized dog. These effects were compared with those produced by the active form of ibopamine, epinine, and with the standard DA-1 receptor agonists, dopamine and fenoldopam. After pretreatment of pentobarbital-anesthetized dogs with phenoxybenzamine (10 mg/kg i.v.) and propranolol (2 mg/kg i.v.) to block alpha and beta adrenoceptor-mediated effects, respectively, the renal blood flow responses to i.v. administration of ibopamine, epinine, dopamine and fenoldopam were determined before and after selective blockade of DA-1 receptors by i.v. infusion of SK&F R-83566 (0.5 microgram/kg/min). Under control conditions, ibopamine produced a dose-dependent increase in renal blood flow as a result of renal vasodilation (i.e., decrease in renal vascular resistance), and was approximately 10-fold less potent than epinine in this respect. Epinine elicited qualitatively similar renal hemodynamic changes to ibopamine with the exception of potency. Dopamine was approximately equipotent with epinine as a renal vasodilator, and both compounds were 10-fold less potent than fenoldopam. Concurrent with the renal vasodilation produced by all four compounds, there was a reduction in mean arterial blood pressure and total peripheral vascular resistance. After the administration of SK&F R-83566, the renal vasodilator responses to fenoldopam were antagonized markedly with an approximate 30-fold rightward shift in the log dose-response curve, whereas the renal vasodilator responses to dopamine were abolished completely and converted into small vasoconstrictor responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1987

Comparison of the alpha adrenoceptor activity of dopamine, ibopamine and epinine in the pulmonary circulation of the dog.

The ability of dopamine, ibopamine and epinine to elicit alpha adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog. Animals were pretreated with propranolol to eliminate beta adrenoceptor-mediated relaxation of the pulmonary vasculature. Heparinized blood was withdrawn from the left femoral artery and transferred via a peristaltic pump to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung. The flow rate of the pump was adjusted so that mean pulmonary perfusion pressure in the lobe was equal to resting diastolic pulmonary artery pressure (10 +/- 1 mm Hg). Under conditions of constant left atrial pressure and pulmonary blood flow, intralobar administration of dopamine, ibopamine and epinine elicited dose-dependent increases in perfusion pressure of the lobe, reflecting increases in pulmonary vascular resistance. Prazosin (100 micrograms/kg i.v.), a selective alpha-1 adrenoceptor antagonist, inhibited the pulmonary vasopressor responses to dopamine, ibopamine and epinine. Rauwolscine (100 micrograms/kg i.v.), a selective alpha-2 adrenoceptor antagonist, inhibited pulmonary pressor responses to dopamine and epinine without altering significantly the pulmonary vasoconstrictor response to ibopamine. These data indicate that dopamine and epinine stimulate both postjunctional vascular alpha-1 and alpha-2 adrenoceptors to elicit pulmonary vasoconstriction in the dog, whereas ibopamine, when injected directly into the pulmonary circulation, stimulates primarily postjunctional vascular alpha-1 adrenoceptors. However, when ibopamine was administered intraduodenally, both prazosin and rauwolscine were found to inhibit the resulting pulmonary vasopressor response. This finding is consistent with the hypothesis that ibopamine is converted to its active metabolite epinine, which stimulates both pulmonary vascular alpha-1 and alpha-2 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗