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 Heparinized blood was withdrawn from the left femoral artery and transferred via a peristaltic pump to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung.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)     

Evaluation of the alpha and beta adrenoceptor-mediated activities of the novel, orally active inotropic agent, ibopamine, in the cardiovascular system of the pithed rat: comparison with epinine and dopamine

The alpha and beta adrenoceptor-mediated effects of the novel, orally active inotropic prodrug, ibopamine, have been studied in the pithed rat and compared with those effects mediated by dopamine and the active form of ibopamine, epinine. All three agents produced alpha adrenoceptor-mediated pressor responses in pithed rats, and the vasopressor effects of ibopamine and epinine, but not dopamine, were potentiated by beta adrenoceptor blockade with propranolol (3 mg/kg i.v.). Catecholamine depletion with reserpine (5 mg/kg i.p.) did not affect the vasoconstrictor response elicited by any of these agents, indicating a direct effect in the vasculature. Epinine was 10 times more potent than ibopamine or dopamine. The pressor response to all three agents was antagonized by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and the alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.), suggesting the involvement of both alpha adrenoceptor subtypes in the vasopressor responses elicited by these compounds. After complete blockade of alpha adrenoceptors using a combination of phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.), higher doses of ibopamine, epinine and dopamine produced a propranolol-sensitive, beta-1 adrenoceptor-mediated positive chronotropic response that was significantly reduced in reserpine-pretreated rats, indicating a significant indirect component in the activity of these compounds at the level of the myocardium. Epinine and dopamine were equipotent and were 10 times more potent than ibopamine as directly acting beta-1 adrenoceptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Whether phenylephrine exerts inotropic effects through α- or β-adrenoceptors depends upon the relative receptor populations

Phenylephrine produced concentration-related positive inotropic responses in isolated left atria and papillary muscles of guinea-pigs and rats. In rat tissues, these responses were unaffected by propranolol but antagonized by prazosin and therefore mediated via alpha 1-adrenoceptors. The alpha 1-adrenoceptor agonist methoxamine also exerted positive inotropic effects in these rat tissues. The maximum alpha-adrenoceptor-mediated effect of methoxamine (relative to the isoprenaline maximum) was greater than that of phenylephrine in left atria (in the presence of propranolol), whereas in papillary muscles phenylephrine exerted the greater maximum. In guinea-pig papillary muscles, the response to phenylephrine was unaffected by prazosin but was antagonized by propranolol and therefore caused by stimulation of beta-adrenoceptors. Methoxamine had no effect in guinea-pig papillary muscles. Guinea-pig left atria produced biphasic concentration-response curves for phenylephrine, the lower portion being antagonized by phentolamine and was therefore alpha-adrenoceptor-mediated, while the upper portion was antagonized by propranolol and therefore beta-adrenoceptor-mediated. Methoxamine exerted a small inotropic response, the maximum of which was similar to that of the first component of the phenylephrine response. Phenylephrine was a partial agonist for the cardiac beta-adrenoceptor. The density of rat ventricular alpha-adrenoceptors was 4 times greater than beta-adrenoceptor density, as measured by [3H]-prazosin and [3H]-dihydroalprenolol binding. This explains why the responses of rat papillary muscles were alpha-adrenoceptor-mediated. In contrast, the density of beta-adrenoceptor binding sites in guinea-pig ventricles was 6 times greater than the alpha-adrenoceptor density. This explains why the phenylephrine responses were beta-adrenoceptor-mediated in guinea-pig papillary muscles. In the left atria of guinea-pigs, which displayed both alpha- and beta-adrenoceptor-mediated responses, the densities of alpha- and beta-adrenoceptor binding sites were similar. Thus, phenylephrine exerts positive inotropic effects through alpha- or beta-adrenoceptors depending upon their relative densities.     

Comparison of the cardiovascular actions of dopamine and epinine in the dog

The effects of i.v. infusions of 3 and 6 micrograms/kg/min of dopamine (DA) and epinine on heart rate, arterial blood pressure, regional blood flows and vascular resistances in the renal, mesenteric and femoral vascular beds were compared in pentobarbital-anesthetized dogs. At the 3 micrograms/kg/min infusion rate, neither DA nor epinine changed blood pressure, whereas at the higher infusion rate both increased blood pressure by about 20 mm Hg. DA increased renal blood flow significantly at both infusion rates; whereas, epinine did not change renal blood flow. After administration of phenoxybenzamine, both epinine and DA decreased blood pressure; upon adding propranolol, the vasodepressor effect of epinine, but not of DA, was abolished. However, propranolol did not inhibit epinine-mediated vasodilation in the renal or mesenteric vascular beds, but a marked increase in femoral vascular resistance was observed. The addition of (R)-sulpiride, a DA antagonist, abolished DA and epinine-induced vasodilation in the mesenteric and renal vascular beds. Experiments in animals treated with hexamethonium to block ganglion transmission and propranolol to block beta adrenoceptors revealed that both selective alpha-1 (terazosin) and alpha-2 (rauwolscine) adrenoceptor antagonists inhibited the vasopressor response to DA to a greater degree than the responses to epinine. Thus, although DA and epinine possess significant DA1 activity, the consistent increase in renal blood flow observed with DA is not seen with epinine because of the more potent alpha adrenoceptor activity of the latter, which is mediated by both alpha-1 and alpha-2 adrenoceptors.     

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)     

Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol

The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)     

A study of alpha1- and alpha2-adrenoceptor responsiveness in diabetic insipidus dogs

Summary— The present study was performed to investigate the participation of circulating vasopressin in alpha-adrenoceptor responsiveness. Thus, we compared the pressor responses induced by selective alpha1-or alpha2-adrenoceptor stimulation in two groups of conscious dogs: a) normal animals and b) animals with surgically-induced diabetes insipidus. In addition, platelet alpha2-adrenoceptors labelled with (³H)RX821002 were compared in the two groups. The pressor response to alpha1-adrenoceptor stimulation [ ie successive doses of noradrenaline (0.5, 1, 2, 4 μg/kg iv) after propranolol (1 mg/kg iv) plus yohimbine (0.5 mg/kg iv)] was significantly ( P < 0.05) less pronounced in diabetic insipidus than in normal dogs. In contrast, the magnitude of the pressor effects of alpha2-adrenoceptor stimulation [ ie noradrenaline after propranolol plus prazosin (1 mg/kg iv)] was the same in the two groups of animals. B_max and Kd values for (³H)RX821002 binding on platelets were similar in diabetic insipidus and normal dogs. This study shows that alpha1- (but not alpha2-) adrenoceptor responsiveness is decreased in diabetic insipidus suggesting the involvement of vasopressin in the mechanisms of the vascular alpha1 -adrenoceptor pressor response.     

Cardiac β-adrenoceptor sensitivity and Parkinson''s disease

Certain clinical manifestations of Parkinson's disease (PD) (speech or/and balance disturbances) are not linked to brain dopamine deficiency. The purpose of the present study was to search for a possible relationship between those so-called "non-dopamine-dependent" extrapyramidal manifestations and the sensitivity of cardiac beta-adrenoceptors. Fourteen patients aged 51 to 69 were included in the study after having given their informed consent. Any factor or pathology susceptible to modify receptor sensitivity entailed exclusion. In the absence of a reference model for measuring the reactivity of central beta-adrenoceptors, a computation of the isoprenalin dose necessary to increase the resting heart rate by 20 bpm was used as an index for beta-adrenergic system reactivity. In addition to that test, other parameters were recorded: disease duration, motor status scale (Columbia), some cognitive functions (MMS and image differed recall). The cardiac beta-receptor decrease in reactivity to isoproterenol is correlated to PD duration (r = 0.8, P less than 0.001). Conversely, the sensitivity of these receptors appeared to be unrelated to the extrapyramidal severity of the disease, hence to the degree of the so-called "non dopamine-dependent" disturbances. Furthermore, such results raise the meaning of the impairment of peripheral aminergic receptors in the cognitive disturbances linked to ageing and/or PD.     

α1 and α2-adrenergic control of large and small coronary arteries during exercise in conscious dogs under β-blockade

Summary— The aim of this study was to determine the relative roles of α₁-and α₂-adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise in conscious dogs. The responses of left circumflex coronary artery diameter and blood flow were investigated at rest and during graded treadmill exercise (5, 10 and 12 km/h) in six chronically instrumented dogs during control conditions (saline) and after administration of propranolol (1 mg/kg) either alone or in combination with either prazosin (50 μg/kg), or idazoxan (300 μg/kg), or the association of prazosin + idazoxan (same doses). In control conditions, graded treadmill exercise resulted in a progressive increase in coronary artery diameter (+ 3.8 ± 0.6% from 3479 ± 80 μm) and in a decrease in coronary vascular resistance (- 46.0 ± 4.5% from 8.49 ± 1.51 mmHg/cm/s). Propranolol significantly constricted large (- 4.4 ± 0.6% from 3486 ± 87 μm) and limited dilation of small coronary arteries during exercise. These coronary effects of propranolol remained unchanged following additional α₂-adrenoceptor blockade by idazoxan but were abolished following α₁-adrenoceptor blockade by prazosin, given either alone or combined with idazoxan. Thus, α₁- but not α₂-adrenoceptors are responsible for propranolol-induced constriction of large coronary arteries and limitation of small coronary arteries dilation during exercise in conscious dogs.     

Effect on the endocrine system of a new dopaminergic agent, ibopamine

Ibopamine, an oral dopaminergic and adrenergic agent, was given to 19 healthy men to investigate the effect of this dopamine analogue on carbohydrate metabolism. In a three-part study six subjects received ibopamine alone, seven subjects were pretreated with metoclopramide (a dopamine antagonist), and six subjects received phentolamine (an alpha-receptor antagonist) and propranolol (a beta-receptor antagonist) to study the specific mechanisms involved. In these single-blind, controlled, randomized studies, effects on fasting glucose, insulin, glucagon, and prolactin were evaluated. Ibopamine, 300 mg, produced a statistically significant increase in fasting glucose and insulin levels but had no effect on glucagon or prolactin levels. Pretreatment with metoclopramide or phentolamine did not block these effects, but pretreatment with propranolol significantly (P less than 0.05) blunted the increase in fasting glucose and insulin levels. These findings indicate that, unlike other dopaminergic agonists, administration of ibopamine results in increased glucose levels without affecting glucagon. The effect on glucose is mediated through stimulation of beta-adrenergic receptors.     

Peripheral α2-adrenoceptor-mediated sympathoinhibitory effects of mivazerol

Summary— Mivazerol is a new compound that could potentially reduce perioperative cardiovascular morbidity and mortality in patients with or at risk of coronary disease and submitted to surgery. This action of mivazerol depends on a well documented centrally mediated reduction in sympathetic nerve activity, but a direct peripheral decrease in sympathetic neurotransmitter release induced by activation of prejunctional α₂-adrenoceptors located on sympathetic nerve endings could also contribute. To investigate this issue, the effects of mivazerol on the pressor, systemic and regional hemodynamic (pulsed Doppler technique) as well as on the cardiac responses to electrical stimulation of the spinal cord (SCS) were measured in pithed rats in the absence and in the presence of mivazerol. Mivazerol exerted strong sympathoinhibitory effects: SCS-induced increases in blood pressure, total peripheral resistance and heart rate were dose-dependently reduced by mivazerol, but among the regional vascular beds investigated, only the hindlimb vasoconstrictor responses were significantly drug-affected. All these sympathoinhibitory effects of mivazerol were abolished by prior yohimbine administration. Simultaneously, mivazerol did not induce any postjunctional adrenoceptor blockade as it did not affect noradrenaline cardiac and hemodynamic effects. On the contrary, through postjunctional α₂-adrenoceptor stimulation, mivazerol, in this pithed preparation, dose-dependently increased blood pressure, total peripheral and hindlimb vascular resistances, but heart rate was not affected. We conclude that, in the pithed rat, mivazerol exerts strong peripheral sympathoinhibitory effects. The mechanism involved is prejunctional α₂-adrenoceptor activation as i) mivazerol does not display any postsynaptic α-adrenoceptor blocking effect — it even behaves as a postsynaptic α₂-adrenoceptor agonist — and ii) yohimbine abolishes mivazerol's sympathoinhibitory effects. Thus, direct peripheral together with central mechanisms contribute to mivazerol's sympathoinhibitory effects and ultimately to its cardioprotective action.     

Evaluation of alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction in the in situ, autoperfused, pulmonary circulation of the anesthetized dog

Alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog utilizing selective alpha adrenoceptor agonists and antagonists. Animals were pretreated with propranolol (1 mg/kg i.v.) to eliminate beta adrenoceptor-mediated effects in the pulmonary circulation. 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 pressure (10 +/- 1 mm Hg). Under conditions of constant left atrial pressure and pulmonary blood flow, intralobar administration of alpha adrenoceptor agonists elicited increases in perfusion pressure of the lobe, reflecting changes in pulmonary vascular resistance. Intralobar administration of the selective alpha-1 adrenoceptor agonist methoxamine and the selective alpha-2 adrenoceptor agonist B-HT 933 elicited dose-dependent increases in lobar perfusion pressure, as did the nonselective alpha adrenoceptor agonist norepinephrine. Prazosin (100 micrograms/kg i.v.), a selective alpha-1 adrenoceptor antagonist, inhibited pulmonary vasopressor responses to methoxamine and norepinephrine without altering significantly the response to B-HT 933. Rauwolscine (100 micrograms/kg i.v.), a selective alpha-2 adrenoceptor antagonist, inhibited the response to B-HT 933 and norepinephrine with little effect on methoxamine. Intralobar administration of tyramine to evoke the release of endogenous norepinephrine resulted in dose-dependent increases in lobar perfusion pressure. The response to tyramine was inhibited selectively by prazosin with little effect of rauwolscine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in plasma glucose and lactate evoked by α and β2-adrenoceptor stimulation in conscious fasted rabbits

In conscious fasted rabbits, the iv infusion of salbutamol (3 micrograms/kg per min) and clonidine (2 micrograms/kg per min) induced a blood glucose increase amenable to blockade, respectively by ICI 118551 (1 micrograms/kg per min) and idazoxan (20 micrograms/kg per min). Amidephrine (10 micrograms/kg per min) and salbutamol mediated an increase in plasma lactate which was attenuated by prazosin (50 micrograms/kg, sc) and ICI 118551 respectively. Clonidine did not alter basal plasma lactate. The iv infusion of adrenaline (0.3 micrograms/kg per min) evoked an increase in plasma lactate more sensitive to blockade by ICI 118551 than by prazosin. ICI 118551 also shortened the hyperglycaemic response to adrenaline, 3-Mercaptopicolinic acid (25 mg/kg) reduced salbutamol- and adrenaline-mediated hyperglycaemia and increased at the same time the lactate/glucose ratio. Our data show that plasma lactate levels may be regulated by alpha 1- and beta 2-excitatory adrenoceptor stimulation. However, only the increase in blood lactate derived from beta 2-adrenergic stimulation seems to contribute to the overall catecholamine-mediated hyperglycaemia.     

Mechanism of the pressor action of LY171555, a specific dopamine D2 receptor agonist, in the conscious rat

Administration of LY171555, a specific dopamine D2 receptor agonist, (10-1000 micrograms/kg i.v.) produced dose-related increases in mean arterial pressure in conscious Sprague-Dawley rats. Pretreatment with metoclopramide (5 mg/kg i.v.) abolished the pressor action of LY171555, whereas pretreatment with domperidone (2.5 mg/kg i.v.) and propranolol (10 mg/kg i.p.) did not affect the pressor action of LY171555. The vasopressor antagonist of arginine vasopressin (AVP), d(CH2)5Tyr(Me)AVP (10 micrograms/kg i.v.) and phenoxybenzamine (1 mg/kg i.v.) partly blocked and hexamethonium (25 mg/kg i.v.) enhanced the pressor action of LY171555. After combined treatment with both d(CH2)5Tyr(Me)AVP and phenoxybenzamine, LY171555 induced a depressor response which was completely blocked by pretreatment with domperidone. LY171555 administration induced a rapid, short-acting depressor response followed by a pressor response in conscious adrenomedullectomized Sprague-Dawley rats which was smaller in magnitude than that seen in intact Sprague-Dawley rats. LY171555 administration increased plasma norepinephrine, epinephrine and AVP in conscious Sprague-Dawley rats. These results suggest that the pressor action of LY171555 in conscious rats is dependent on activation of sympathetic outflow and AVP release through the central D2 dopaminergic system and that the central pressor effects of LY171555 could mask a depressor effect of LY171555 at the peripheral D2 dopamine receptor.     

Central effects of quinpirole on blood pressure of spontaneously hypertensive rats.

The i.v. administration of the dopamine D-2 receptor agonist quinpirole induced a rapid increase in blood pressure in spontaneously hypertensive rats (SHR). Heart rate showed little change. The pressor response to quinpirole was similar in SHR and normotensive Wistar-Kyoto rats (WKY) at doses of 0.03 to 0.3 mg/kg but, at 1 mg/kg, quinpirole induced a greater increase in blood pressure in SHR than in WKY. In contrast, although both strains showed a decreased locomotor activity after administration of 0.01 to 0.05 mg/kg of quinpirole, only in WKY was activity enhanced by 0.25 to 1.25 mg/kg of quinpirole. The i.v. administration of the dopamine agonists apomorphine, N-propylnorapomorphine and (R)-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine, but not the putative presynaptic D-2 agonist (S)-(-)-3-(3-hydroxyphenyl)-N- propylpiperidine, induced pressor responses in SHR comparable to those after quinpirole administration. The pressor effect of quinpirole was enhanced by pretreatment with the peripheral D-2 antagonist domperidone, but blocked by the centrally acting dopamine antagonists haloperidol or sulpiride. In SHR, which were pretreated centrally with pertussis toxin, quinpirole induced a significantly smaller increase in blood pressure than in control SHR. Pretreatment centrally with 6-hydroxydopamine had no effect on the pressor action of quinpirole in SHR. Thirty minutes after i.v. administration of quinpirole, an additional injection of quinpirole did not significantly change blood pressure. Increasing the interval between two subsequent injections of quinpirole showed that this desensitization slowly reversed, but only after 24 hr had the pressor response to quinpirole fully recovered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog

Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.     

Amiodarone: influence of the route of administration on thyroid status and cardiac β-adrenoceptors in the rat

The influence of 2 different routes of amiodarone (AMIO) administration, oral gavage (OG) and subcutaneous injection (SC), on the density of cardiac beta-adrenoceptors (Bmax), hepatic type I 5' iodothyronine deiodinase (5' DI) and thyroid hormone serum concentrations was studied. Compared with respective control values, AMIO treatment (50 mg/kg per day, 7 days) via both OG and SC routes significantly lowered Bmax (OG: 14.6 +/- 1.92 vs 18.2 +/- 1.03 fmol/mg and SC: 16.6 +/- 2.34 vs 19.1 +/- 2.05 fmol/mg) and 5' DI activity (from 409 to 85 and 340 to 47 fmol I-/mg per min, respectively). The SC route induced a fall in thyroid secretion and a generalized hypothyroidism (decreased serum FT4 and FT3, inhibition of body weight gain. The OG route did not modify thyroid secretion. These results demonstrated that the effects on cardiac beta-receptor density in the SC group might be due to the generalized hypothyroidism and that AMIO produced its specific cardiac effects only after oral route medication, suggesting that the oral route is the best choice for studying AMIO cardiac effects on beta-receptor density.     

Enhanced pulmonary alpha-2 adrenoceptor responsiveness under conditions of elevated pulmonary vascular tone

Alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog under conditions of normal and elevated pulmonary vascular tone. Under conditions of normal pulmonary vascular tone (10 +/- 1 mm Hg), methoxamine, a selective alpha-1 adrenoceptor agonist, and B-HT 933, a selective alpha-2 adrenoceptor agonist, elicited maximal increases in lobar perfusion pressure of 5 and 2 mm Hg above resting pulmonary tone, respectively. When pulmonary vascular tone was elevated progressively with the thromboxane mimetic, U-46619, serotonin or PGF2 alpha, alpha-1 adrenoceptor-mediated pulmonary vasoconstrictor responses to methoxamine were unaffected, whereas alpha-2 adrenoceptor-mediated pulmonary pressor responses to B-HT 933 were enhanced. Overall the response to B-HT 933 was enhanced 4-fold when pulmonary perfusion pressure was elevated to 19.8 +/- 0.8 mm Hg with U-46619 and almost 5-fold when elevated to 27.0 +/- 1.2 mm Hg. Pulmonary vasoconstrictor responses to angiotensin II were unaffected by elevated pulmonary vascular tone. Enhanced responsiveness of B-HT 933 to elevated pulmonary vascular tone was antagonized by the selective alpha-2 adrenoceptor antagonist, rauwolscine (100 micrograms/kg i.v.), and unaffected by the selective alpha-1 adrenoceptor antagonist, prazosin (100 micrograms/kg i.v.). When canine intralobar pulmonary veins were studied in vitro they contracted to B-HT 933 whereas intralobar pulmonary arteries did not respond. These data indicate that alpha-2 adrenoceptor responsiveness is enhanced markedly and selectively under conditions in which pulmonary vascular tone is elevated.     

Ibopamine in Patients with Congestive Heart Failure and Different Degrees of Renal Function

Following a 1-week placebo run-in phase, 20 patients with congestive heart failure (New York Heart Association class II) were treated orally for 7 days with 100 mg ibopamine t. i. d. Ten subjects had a normal renal function, whereas 10 patients suffered from chronic renal insufficiency (mean creatinine clearance 36 plus minus 3.9 ml min(minus sign1)). Ibopamine significantly increased stroke volume and cardiac output, but only 45 and 90 min after administration. After 7 days of ibopamine treatment, urine output rose significantly in both patient groups by about 400--500 ml per 24 h. The glomerular filtration rate (inulin clearance) and urine osmolality remained nearly unchanged, whereas renal plasma flow (PAH clearance) increased on ibopamine administration. Urinary sodium and potassium excretion were slightly but insignificantly elevated. Pharmacokinetic parameters of ibopamine were unaltered in impaired renal function, both on the first and seventh treatment day. Maximum plasma levels of the active metabolite epinine were achieved after 45 min and were higher on the first as compared with the seventh treatment day in both groups. In conclusion, ibopamine caused a relevant increase in stroke volume and cardiac output associated with a rise in renal perfusion and urine output in patients with normal and with impaired renal function. Ibopamine is an orally active derivative of dopamine and is used for treatment of patients with congestive heart failure, who frequently have an impaired renal function. Therefore, in the present study, the hemodynamic effects and kinetic behavior of ibopamine should be investigated in patients with different degrees of renal function.