Norepinephrine constricts the canine coronary bed via postsynaptic alpha 2-adrenoceptors

The effect of alpha 2-blockade (0.3 mg/kg i.v. rauwolscine) and alpha 1-blockade (1.2 mg/kg i.v. prazosin) on coronary constrictions induced by intracoronary injections of azepexole (B-HT 933, alpha 2-agonist, 0.1-10 microgram/kg), phenylephrine (0.3-3 microgram/kg) and norepinephrine (0.001-0.1 microgram/kg) were studied in dog hearts perfused in situ under beta-blockade. Constrictions by azepexole (antagonized by rauwolscine, yet resistant to prazosin and methysergide) demonstrated coronary alpha 2-adrenoceptors. Norepinephrine-induced constrictions were more attenuated (22-fold) by alpha 2-blockade than by alpha 1-blockade (2.6-fold) and thus were mediated mainly by activation of postsynaptic alpha 2-receptors.     

Postsynaptic alpha 1- and alpha 2-adrenergic mechanisms in coronary vasoconstriction

This study examined the relative importance of postsynaptic alpha 1- and alpha 2-adrenoceptors in mediating coronary vasoconstriction in open chest dogs in which the left circumflex coronary artery was cannulated and perfused at a constant rate. The cervical vagus nerves and central connections of the stellate ganglia were transected, and beta-adrenergic blockade was produced with propranolol. Coronary vasoconstriction occurred in response to intraarterial administration of both the alpha 1-agonist phenylephrine and the alpha 2-agonist BHT 933. The response to phenylephrine was partially blocked with prazosin and nearly completely eliminated by yohimbine. The response to BHT 933 was resistant to prazosin, but almost completely blocked by yohimbine. Coronary vasoconstriction produced by norepinephrine was resistant to prazosin, but was blunted by alpha 2-adrenergic blockade with yohimbine or idazoxan. Prazosin produced some blunting of coronary vasoconstriction in response to small doses of epinephrine, while yohimbine markedly attenuated epinephrine-induced vasoconstriction at all doses used. Measurements of regional myocardial blood flow with radioactive microspheres demonstrated no transmural redistribution of perfusion during vasoconstriction produced by either alpha 1- or alpha 2 stimulation. Thus, although stimulation of both alpha 1- and alpha 2-adrenoceptors is capable of causing coronary vasoconstriction, vasoconstriction in response to norepinephrine and epinephrine is mediated principally by postsynaptic alpha 2-adrenoceptors.     

Dopamine preferentially stimulates postsynaptic alpha 2-adrenoceptors in the femoral vascular bed, but alpha 1-adrenoceptors in the renal vascular bed of the anaesthetised dog

The decrease in blood flow in response to dopamine (DA) injected intraarterially (i.a.) into the femoral or renal vascular beds was examined in the anaesthetised dog. DA or noradrenaline (NA) were 10 times more potent as vasoconstrictor agents in the femoral than in the renal vasculature. In the femoral bed, the DA induced vasoconstriction was completely resistant to antagonism by prazosin (30-300 micrograms/kg i.v.), but was dose-dependently blocked by the alpha 2-receptor antagonist idazoxan (30-300 micrograms/kg i.v.). In the renal bed the vasoconstrictor effects of DA were resistant to blockade by idazoxan, but were prazosin sensitive indicating that alpha 1-adrenoceptors were involved in this response. The alpha-receptor agonist profile for DA was not modified in the femoral bed after blockade of dilatory D1-receptors with SCH 23390 (0.5 mg/kg i.v. and 0.1 mg/kg per h i.v.). However, this antagonist significantly increased the vasoconstrictor potency for DA in the renal bed. The decrease in femoral blood flow induced by an injection of DA, appears to be mediated by alpha 2-adrenoceptors. In the renal vascular bed where the predominant alpha-adrenoceptor corresponds to the alpha 1-subtype and there are few postsynaptic alpha 2-receptors subserving vasoconstriction, DA can stimulate alpha 1-receptors but this action requires higher doses of agonist than those needed for alpha 2-adrenoceptor stimulation.     

Opposing central autonomic actions of alpha 1- and alpha 2-adrenoceptor antagonists on oculomotor tone

Electrical stimulation of the afferent sciatic nerve produces reflex mydriasis in anesthetized rats. The alpha 2-antagonist idazoxan (10-100 micrograms/kg i.v.) inhibited this reflex in a dose-dependent fashion. In contrast, the alpha 1-antagonist prazosin (30-300 micrograms/kg i.v.), produced a dose-related enhancement of the reflex. Single dose administration of the alpha 2-antagonists yohimbine (3.0 mg/kg i.v.), rauwolscine (3.0 mg/kg i.v.) and idazoxan (1.0 mg/kg) also blocked the reflex, whereas the alpha 1-antagonists phenoxybenzamine (3.0 mg/kg i.v.), corynanthine (1.0 mg/kg i.v.) and prazosin (1.0 mg/kg i.v.) potentiated this response. These studies demonstrate that alpha 2-antagonists block and alpha 1-adrenoceptor antagonists potentiate alpha 2-adrenoceptor-mediated inhibition of oculomotor tone.     

Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists

The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.     

Clonidine produces mydriasis in conscious mice by activating central alpha 2-adrenoceptors

Intraperitoneal (i.p.) injection of the alpha 2-adrenoceptor agonist clonidine (1-3000 micrograms/kg) produced dose-dependent pupil dilatation in conscious C57/Bl/6 mice with an ED50 of 54 micrograms/kg (95% confidence limits 40-74 micrograms/kg). This response was rapid in onset and of approximately 30 min duration. The alpha 2-adrenoceptor antagonists idazoxan (1 or 3 mg/kg i.p.) and yohimbine (1 or 3 mg/kg i.p.) both produced dose-related miosis, but the alpha 1- and beta-adrenoceptor antagonists prazosin (1 or 3 mg/kg i.p.) and pindolol (1 or 3 mg/kg i.p.) were without effect. These doses of idazoxan and yohimbine potently reversed the mydriasis induced by clonidine (100 micrograms/kg i.p.), while prazosin and pindolol were again ineffective. Clonidine-induced mydriasis was also unaltered by the 5-HT antagonists, methysergide (2.5 mg/kg i.p.) and ketanserin (0.1 mg/kg i.p.) or 0.1 mg/kg i.p. of the dopamine antagonists, haloperidol, SCH 23390 and BRL 34778. A dose of 0.25 microgram clonidine, which was ineffective when administered i.p., produced marked mydriasis after intracerebroventricular (i.c.v.) injection. In addition, the mydriasis produced by i.p. injection of clonidine (100 micrograms/kg) was abolished by i.c.v. dosing of 2.5 micrograms idazoxan or yohimbine, but again not by prazosin or pindolol. Together, these data provide strong evidence to indicate that clonidine-induced mydriasis is exclusively mediated via central alpha 2-adrenoceptors and that this response provides a useful model for studying the function of these receptors.     

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)     

The pharmacology of pramipexole in the spontaneously hypertensive rat.

Pramipexole (SND-919) administration to spontaneously hypertensive rats resulted in a biphasic response with lower doses (1-30 micrograms/kg) causing a hypotensive response and higher doses (100-1000 micrograms/kg) increasing blood pressure. S-Sulpiride (1 mg/kg i.v.) and domperidone (100 micrograms/kg i.v.) but not SCH 23390(1 microgram/kg per min i.a.), prazosin (0.1 mg/kg i.v.) or rauwolscine (1 mg/kg i.v.) blocked the depressor effect, whereas rauwolscine but not S-sulpiride, SCH 23390 or prazosin blocked the pressor effects. The data indicate that pramipexole stimulates presynaptic DA2 receptors at low doses and postsynaptic alpha 2-receptors at high doses.     

Effects of alpha 1- and alpha 2-adrenoceptor blocking drugs on noradrenaline release rate in anesthetized rabbits

[3H]noradrenaline was infused intravenously into pentobarbitone-anesthetized rabbits to reach a steady-state plasma (3H]noradrenaline level, from which the noradrenaline plasma clearance was calculated. The plasma level of endogenous noradrenaline was determined simultaneously, and the rate of noradrenaline release was then derived. The effects of a series of selective alpha 1- and alpha 2-adrenoceptor blocking drugs on the noradrenaline release rate and noradrenaline clearance were investigated. Yohimbine (1 mg/kg i.v.), rauwolscine (1 mg/kg i.v.), corynanthine (1 mg/kg i.v.), prazosin (0.3 and 1 mg/kg i.v.), phenoxybenzamine (4 mg/kg i.v.), and sodium nitroprusside (10 micrograms/kg/min i.v.) decreased the plasma noradrenaline clearance. The selective alpha 2-adrenoceptor blocking drugs yohimbine and rauwolscine, as well as phenoxybenzamine, increased the noradrenaline release rate more than equihypotensive doses of the directly acting vasodilators hydralazine and sodium nitroprusside. The selective alpha 1-adrenoceptor blocking drugs prazosin and corynanthine increased the noradrenaline release rate less than equihypotensive doses of the vasodilators. These results suggest that, in vivo, blockade of alpha 2-adrenoceptors results in increased noradrenaline release, probably due to blockade of inhibitory presynaptic alpha 2-adrenoceptors at sympathetic nerve endings. Blockade of alpha 1-adrenoceptors, on the other hand, appears to depress baroreceptor-mediated increases in noradrenaline release in response to a fall in blood pressure.     

Alpha-adrenoceptor blockade by phentolamine causes beta-adrenergic vasodilation by increased catecholamine release due to presynaptic alpha-blockade

We tested whether the alpha 1- and alpha 2-blocking agent phentolamine can be used to assess the contribution of alpha-adrenergic constriction in circulatory control. In 15 conscious dogs at rest, phentolamine (2 mg/kg i.v.) caused hypotension (-17 mm Hg mean arterial pressure), vasodilation (-29% total peripheral resistance), tachycardia, and an increase in cardiac output, oxygen consumption, and plasma catecholamines. Following beta-adrenoceptor blockade (2 mg/kg i.v. nadolol), phentolamine still produced hypotension and increased plasma catecholamine levels, but neither vasodilation nor augmented oxygen consumption. During beta-blockade, phentolamine caused a 28-fold decrease in the vasoconstrictor response to norepinephrine infusions. An equihypotensive dosage of the alpha 1-adrenoceptor blocking agent prazosin (1.2 mg/kg i.v.) did not elevate heart rate, cardiac output, plasma catecholamines, or oxygen consumption. The prazosin-induced vasodilation was not attenuated by prior beta-blockade, in contrast to the phentolamine-induced vasodilation. It is concluded that phentolamine increased catecholamine release by presynaptic alpha 2-blockade, thereby suppressing the autoinhibition of transmitter release. This excess of catecholamines causes a rise of oxygen consumption and vasodilation by beta-adrenergic stimulation. Under beta-blockade, this excess competitively counteracts the postsynaptic vascular alpha-blockade. The combination of pre- and postsynaptic effects invalidates the use of phentolamine in the assessment of alpha-adrenoceptor-mediated vasoconstrictor tone.     

Beta 1-adrenoceptor antagonism by urapidil prior to and after the alpha 2-antagonist rauwolscine in anesthetized dogs

The purpose of this investigation was to evaluate the in vivo beta-adrenoceptor antagonistic properties of urapidil, a new antihypertensive alpha 1-adrenoceptor blocking agent. In dogs anesthetized with pentobarbital, the cardioaccelerator nerve was isolated, decentralized and stimulated electrically to elicit adrenergically mediated increases in heart rate. Dobutamine was administered (3-30 micrograms/kg i.v.) to elicit increases in heart rate by the direct stimulation of beta-adrenoceptors. Urapidil 2 mg/kg i.v. had no significant effect on cardioaccelerator nerve-induced tachycardia, but 5 mg/kg i.v. decreased the response by 27%. Heart rate responses to dobutamine were suppressed slightly by the low dose of urapidil and to a greater degree by the high dose of urapidil, whereas the pressor response to dobutamine was markedly attenuated at both dose levels. Neurally or dobutamine-elicited tachycardia remaining after urapidil treatment was eliminated by propranolol (1 mg/kg i.v.). When the selective alpha 2-antagonist rauwolscine was administered (1000 micrograms/kg i.v.), tachycardic responses to nerve stimulation increased 49% above control, and urapidil (5 mg/kg) given subsequently, caused a 48% reduction in the response. These data indicate that urapidil has weak beta 1-blocking activity more clearly seen after blockade of alpha 2-adrenoceptors.     

Mechanism of ketanserin-induced sympatho-inhibition.

Experiments were undertaken to determine if sympatho-inhibition produced by ketanserin is due to antagonism of central nervous system alpha 1-adrenoceptors rather than central 5-HT2 receptors and if (like prazosin) it produces sympatho-inhibition indirectly via a central (presynaptic) alpha 2-adrenoceptor mechanism. Administration of ketanserin (0.03-3.0 mg/kg i.v.) caused a dose-related depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the hypothalamus in pentobarbital anesthetized cats. No effect of ketanserin was observed on electrodermal responses evoked by preganglionic sympathetic nerve stimulation nor did the more specific 5-HT2 receptor antagonist, cinanserin, produce a central sympatholytic effect at dosages up to 3 mg/kg i.v. Pretreatment with alpha 2-adrenoceptor blockers yohimbine, idazoxan, or rauwolscine significantly antagonized ketanserin-induced sympatho-inhibition. Depletion of central nervous system (CNS) monoamines totally prevented ketanserin-induced sympatho-inhibition although clonidine (30 micrograms/kg i.v.) continued to be effective. These results suggest that ketanserin acts in the CNS to reduce sympathetic reactivity by blocking alpha 1-adrenoceptors and not 5-HT2 receptors. In this regard, ketanserin appears to act in a manner similar to other alpha 1-adrenoceptor antagonists (e.g. prazosin and indoramin) by an apparent presynaptic facilitation of alpha 2-adrenoceptor mediated tonic inhibition descending from the lower brainstem.     

3H]idazoxan and some other alpha 2-adrenergic drugs also bind with high affinity to a nonadrenergic site

We compared the pharmacological properties of the alpha 2-adrenergic radioligand [3H]idazoxan with those of [3H]rauwolscine in rat and [3H]yohimbine in human renal cortical membranes. The density of "specific" [3H]idazoxan binding sites (defined by 100 microM tolazoline) was twice as high as that of [3H]rauwolscine in rat kidney and four times as high as that of [3H]yohimbine in human kidney. A variety of structurally different drugs fully competed for specific [3H]rauwolscine and [3H]yohimbine binding, with affinities appropriate for the interaction with alpha 2-adrenergic receptors. Specific [3H]idazoxan binding, however, was only partially competed for by the catecholamines epinephrine and norepinephrine in both tissues. Thus, [3H]idazoxan labels both alpha 2-adrenergic receptors and a nonadrenergic site. Clonidine, B-HT 920, moxonidine, phentolamine, prazosin, yohimbine, dopamine, and serotonin also could not compete for this site. However, UK 14,304, guanabenz, indanidine, tolazoline, oxymetazoline, and SK&F 104,078 competed for the additional [3H]idazoxan sites with affinities similar to those at alpha 2-adrenergic receptors. [3H]idazoxan binding substantially in excess of [3H]rauwolscine or [3H]yohimbine binding was also found in human platelets, myometrium, and erythroleukemia (HEL) cells but not in three cell lines lacking alpha 2-receptors (MDCK, BC3H1, and Jurkat cells). Although we have been unsuccessful thus far in defining the precise nature of the additional [3H]idazoxan binding sites, we hypothesize that these sites may be closely affiliated with alpha 2-adrenergic receptors but clearly distinct from the catecholamine binding site of the receptor. The results indicate that care must be taken in the use of [3H]idazoxan or drugs that are recognized at its nonadrenergic site when studying alpha 2-adrenergic effects and receptor subtypes.     

An alpha-adrenergic coronary constriction during esophageal distention in the dog.

Previous work has shown an increase in sympathetic stimulation of the heart during chemical or mechanical irritation of visceral organs, but the involvement of the coronary circulation in such reflexes is not clear. In five preliminary experiments in anesthetized dogs, esophageal distention produced a sympathetic stimulation of the heart, as evidenced by an increase in heart rate, which was abolished by non-selective beta-adrenergic and muscarinic blockades. On the basis of these preliminary data, we further examined a sympathetic coronary constriction during acute esophageal distension in which any direct adrenergic coronary constriction was unmasked by muscarinic blockade with atropine (100 micrograms/kg, i.v.), and non-selective beta-adrenergic blockade with propranolol (1 mg/kg, i.v.). In seven dogs anesthetized with alpha-chloralose in an open-chest procedure, the esophagus was rapidly distended to a pressure of 36 +/- 2 mm Hg, which was not significantly different from the distending pressure used in the preliminary experiments. During esophageal distention, the mean circumflex blood flow decreased to 77 +/- 10% (SEM) of the predistention value. This decrease was statistically significant (p less than 0.05). There was no change in left ventricular pressure, mean arterial pressure dP/dtmax, or heart rate. Intracoronary administration of the nonselective alpha-adrenergic antagonist phentolamine completely abolished the reduction in mean circumflex coronary blood flow caused by esophageal distention in the presence of beta-adrenergic and muscarinic blockades. These results demonstrate a direct sympathetic coronary vasoconstriction elicited by esophageal distention. This vasoconstriction was due to activation of coronary alpha-adrenergic receptors.     

Coronary artery vasodilation in the canine: physiological and pharmacological roles of beta-adrenergic receptors

The role of beta 1- and beta 2-receptors as modulators of coronary artery vasodilation was studied in the anesthetized dog. The left circumflex coronary artery was cannulated and perfused under constant pressure with blood drawn from the right femoral artery. Coronary blood flow myocardial contractile force were measured with a cannulating electromagnetic flow probe and Walton-Brodie strain gauges, respectively. The left stellate ganglion was isolated distally, and the postganglionic nerves were stimulated with a bipolar electrode. Coronary artery blood flow and regional myocardial contractile force increased in response to stellate nerve stimulation and to the intracoronary administration of norepinephrine (NE), isoproterenol (ISO), and zinterol (ZIN) before selective beta 1-adrenergic receptor blockade with celiprolol (0.3 mg/kg intravenously, i.v.). The administration of celiprolol inhibited the positive inotropic response to both stellate stimulation and to the intracoronary administration of the selected beta-adrenergic receptor agonists. The increase in coronary artery blood flow observed in response to stellate stimulation or to the intracoronary administration of NE was converted to a decrease in flow in the presence of celiprolol. In contrast, however, the intracoronary administration of ISO or ZIN continued to cause coronary vasodilation despite the presence of beta 1-selective adrenergic receptor blockade with celiprolol. Addition of propranolol (1.0 mg/kg i.v.) in the presence of celiprolol completely inhibited the increase in coronary blood flow in response to ISO and ZIN.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prazosin, SGB-1534, dobutamine and isoproterenol on congestive heart failure in dogs

Effects of prazosin, dobutamine, isoproterenol and SGB-1534, a new alpha-blockade, on congestive heart failure (CHF) in dogs were investigated. The model was made by protease injection into the left ventricular free wall, saline loading, and dextran and methoxamine infusions. By this maneuver, left atrial pressure (LAP), systemic vascular resistance (SVR) and left ventricular end-diastolic pressure (LVEDP) were markedly increased, aortic blood flow (AoBF) was decreased, and systemic blood pressure was unchanged. In this model, the intravenous administration of prazosin (0.1 approximately 10.0 micrograms/kg, i.v.) increased AoBF and decreased LAP in a dose-dependent manner. The improvement of the CHF by prazosin was considered to result from its vasodilating action. SGB-1534 (0.1 approximately 10.0 micrograms/kg, i.v.) improved the CHF mainly through its vasodilating and positive inotropic actions, which is because SGB-1534 decreased SVR and increased Vmax. The magnitudes of vasodilation by SGB-1534 was greater than those by prazosin. These data indicate that SGB-1534 is useful in the treatment of CHF. Both dobutamine (5 approximately 100 micrograms/kg, i.v.) and isoproterenol (0.001 approximately 0.1 micrograms/kg, i.v.) improved the CHF through their vasodilating and positive inotropic actions in the canine CHF. The ratio of positive inotropism/vasodilation was greater for dobutamine than isoproterenol. The vasoconstriction by the large dose of dobutamine might participate in this difference between dobutamine and isoproterenol.     

Sympathetic control of myocardial oxygen balance in dogs mediated by activation of coronary vascular alpha 2-adrenoceptors

Recent observations on sympathetic constriction of the poststenotic coronary bed without dilatory reserve indicate the involvement of postsynaptic alpha 2-adrenoceptors, which are commonly regarded as noninnervated, hormonal receptors. Therefore, we characterized the vascular alpha-adrenoceptor activated during the competition between sympathetic constriction and metabolic dilation of the nonstenosed coronary bed by analyzing myocardial oxygen balance. In 39 anesthetized, spinalized open-chest dogs with bilateral cervical vagotomy, the left decentralized stellate ganglion was stimulated while mean aortic pressure was kept constant. Stimulation at 1 and 10 Hz lowered coronary venous oxygen saturation by 2.5 +/- 0.3 (SEM) and by 11.1 +/- 0.8 saturation %, respectively, in experiments under beta-blockade (4 mg/kg nadolol, n = 21). In experiments without beta-blockade (n = 18), the saturation response was similar. Under beta-blockade, alpha 2-blockade by rauwolscine (0.03 and 0.3 mg/kg) attenuated the decline in saturation induced by 10 Hz stimulation to 0.56 +/- 0.08 (p less than 0.01) of the control response and to 0.30 +/- 0.06 (p less than 0.001), respectively, whereas alpha 1-blockade by prazosin (0.012 and 0.12 mg/kg) modified this response only to 0.94 +/- 0.06 (NS) and to 0.75 +/- 0.08 (0.1 greater than p greater than 0.05). Without beta-blockade, similar attenuations to 0.36 +/- 0.07 (p less than 0.001) by 0.3 mg/kg rauwolscine and to 0.80 +/- 0.09 (NS) by 0.12 mg/kg prazosin were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Turnover in vivo of alpha 1-adrenergic receptors in rat submaxillary glands

In submaxillary glands, vas deferens, and cerebral cortex, [3H]prazosin labeled one homogeneous population of alpha 1-adrenergic receptors having a KD of 0.1 nM. Intravenous injections of phenoxybenzamine blocked these receptors in a dose-dependent manner without changing the affinity of the remaining sites for [3H]prazosin. The phenoxybenzamine efficiency was highest in submaxillary glands: 1 mg/kg completely blocked the alpha 1-adrenergic receptors but did not affect alpha 2-adrenergic, beta-adrenergic, and muscarinic receptors in this organ. After this blockade, the alpha-adrenergic receptors reappeared in the glands following a monoexponential time course. Analysis of this time course allows the determination of the rate constant for receptor degradation (k = 0.02 hr-1) and the rate of receptor production (r = 1.86 fmoles/mg of protein per hour). The half-life of the receptor was 33 hr. The reappearing receptors corresponded to newly synthetized receptors since their reappearance was blocked by i.p. injections of cycloheximide. Blockade of alpha 1-adrenergic receptors with phenoxybenzamine (2 mg/kg) did not affect receptor reappearance. In contrast, higher doses (4-20 mg/kg) decreased the velocity of receptor reappearance.     

Beta-adrenergic activation of the renin-angiotensin system following alpha 2-, alpha 1-, or nonselective alpha-blockade in conscious dogs: no relation to the changes in blood pressure

We analyzed the role of the renin-angiotensin system following alpha 2-, alpha 1-, or nonselective alpha-blockade in an intact organism in which both postsynaptic alpha-adrenoceptor types contribute to adrenergic vasoconstriction. In conscious dogs, alpha 2-blockade (0.3 mg/kg rauwolscine, n = 10) increased mean arterial pressure by 40 mm Hg, while hypotension by 8 mm Hg occurred following nonselective alpha-blockade (1.5 mg/kg phentolamine, n = 9) and by 20 mm Hg following alpha 1-blockade (1.2 mg/kg prazosin, n = 10). Plasma angiotensin II (pg/ml) rose by 103 +/- 28 (SEM), 143 +/- 48, and 58 +/- 15 following alpha 2-, nonselective alpha-, or alpha 1-blockade, respectively. While alpha 2- or nonselective alpha-blockade induced tachycardia and substantial elevations of plasma catecholamines, alpha 1-blockade did not. Beta-Blockade (2 mg/kg nadolol) attenuated the elevations of angiotensin following alpha 2- or nonselective alpha-blockade by 100 and 88%, respectively, without affecting the alpha 1-blockade-induced elevation, which is mainly mediated by the hypotension. Pretreatment with 3 mg/kg captopril reduced the pressure increase induced by alpha 2-blockade from 40 to 13 +/- 10 mm Hg and aggravated the decline in blood pressure induced by nonselective alpha-blockade from 8 to greater than 50 mm Hg. In anesthetized, spinalized dogs, both types of alpha-blockade competitively antagonized the pressor effect of the alpha 2-agonist azepexole by the same degree. It is concluded that, in the intact animal, the central and peripheral presynaptic augmentation of sympathoexcitation induced by alpha 2- or nonselective alpha-blockade leads to a strong beta-adrenergic activation of the renin-angiotensin system, independent of the concomitant changes in blood pressure. The constrictive action of the activation contributes substantially to the compensation of the vascular adrenoceptor blockade induced by nonselective or alpha 2-selective blockade in the intact organism.     

Clonidine-induced hypoactivity and mydriasis in mice are respectively mediated via pre- and postsynaptic alpha 2-adrenoceptors in the brain

Since brain alpha 2-adrenoceptors occur both pre- and postsynaptically, experiments were carried out to determine the synaptic locations of those receptors mediating clonidine-induced hypoactivity and mydriasis. Intraperitoneal (i.p.) injection of clonidine (1-3000 micrograms/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED50 values were: 120 micrograms/kg for hypoactivity (95% confidence limits 103-140 micrograms/kg), 54 micrograms/kg for mydriasis (95% confidence limits 40-74 micrograms/kg) and 18 micrograms/kg for MHPG reduction (95% confidence limits 8-36 micrograms/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose dependently produce mydriasis, but not hypoactivity, after peripheral (0.1-5 mg/kg i.p.) or central (0.5-10 micrograms i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 micrograms idazoxan or yohimbine, but not 2.5 micrograms prazosin or pindolol, showing this effect was mediated by central alpha 2-adrenoceptors. Methamphetamine (1-10 micrograms i.c.v.) potentiated the mydriasis induced by clonidine (50 micrograms/kg i.p.) suggesting this was a postsynaptic alpha 2-adrenoceptor response. By contrast, methamphetamine (1-10 micrograms i.c.v.) dose dependently reversed clonidine (100 micrograms/kg i.p.) hypoactivity indicating this response was mediated by presynaptic alpha 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. x 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 micrograms/kg i.p.) and markedly attenuated clonidine (100 micrograms/kg i.p.) hypoactivity.