Effect of clonidine, prazosin and phentolamine on heart rate and coronary sinus catecholamine output during cardioaccelerator nerve stimulation in spinal dogs. Br J Pharmacol 67: 283-292

British Journal of Pharmacology (Impact Factor: 4.84). 11/1979; 67(2):283-92. DOI: 10.1111/j.1476-5381.1979.tb08678.x
Source: PubMed


1 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.2 Clonidine (20 mug/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.3 Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.4 On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.5 Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).6 These results show that in spinal dogs the clonidine-induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic alpha-adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic alpha-adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.

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    ABSTRACT: This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.
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    ABSTRACT: The pre- and post-junctional effects of five -adrenoceptor agonist drugs were examined in the pithed rat. On pre-junctional receptors on the cardioac-celerator nerves, oxymetazoline, guanabenz and xylazine had effects which were qualitatively similar to the established effects of clonidine; phenylephrine had not. These pre-junctional effects could be antagonised by yohimbine. Post-junctional effects of the agonists, assessed as the diastolic arterial pressor response or contraction of the anococcygeus, showed an unexpected pattern. The effects of phenylephrine were almost abolished by prazosin (1 mg/kg) whereas the effects of the other four agonists, clonidine, oxymetazoline, guanabenz and xylazine were only moderately antagonised, guanabenz and xylazine being particularly resistant; this resulted in an order of agonist potency for the prazosin-resistant responses which was similar to that for pre-junctional -adrenoceptor agonism on the cardiac or vas deferens sympathetic nerves. Yohimbine (1 mg/kg) produced greater antagonism of the pressor effects of guanabenz and xylazine than did prazosin. It is postulated that at least two types of post-junctional -adrenoceptors exist in rat tissues, one of which is similar to 1-adrenoceptors previously demonstrated and another which has similarities to the prejunctional 2-adrenoceptors. Noradrenaline released from vasopressor nerves or administered intravenously could be shown to produce post-junctional effects which were partly resistant to prazosin, suggesting a physiological role for each of these -adrenoceptors.
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    ABSTRACT: In addition to its well known actions on postsynaptic adrenoreceptors, noradrenaline released at the sympathetic nerve endings is now believed to modulate subsequent transmitter release through its actions on presynaptic receptors1-7. Much evidence in support of this hypothesis has been obtained from overflow studies in which labelled noradrenaline and metabolites released into the bathing solution are used as an assay of transmitter release. According to Langer4 and Rand, McCulloch and Story6, evidence to favour the existence of such a presynaptic mechanism includes the demonstration that alpha-adrenoreceptor antagonists produce enhanced transmitter overflow in steady-state conditions of sympathetic stimulation. They also suggest that alpha-adrenoreceptor-mediated potentiation of transmitter release would not be expected in response to a single pulse, as a threshold concentration of released noradrenaline is required to activate presynaptic inhibition of further release. In the myocardium both conditions have been obtained in the presence of phenoxybenzamine5,6. Surprisingly, although phentolamine is also a potent alpha-adrenoreceptor antagonist, the potentiation of transmitter release was less than the increase due to phenoxybenzamine6. Studies of transmitter overflow have generally been made with supraphysiological sympathetic stimulation of 5 Hz continuously for 30s or 4 Hz for 60s (refs 6,7). We have used more closely physiological stimulation parameters delivered only during the atrial refractory period. We have now shown that phenoxybenzamine markedly potentiates the chronotropic response to a single pulse and also responses up to maximum stimuli. By contrast, phentolamine and yohimbine were totally without effect even at high concentration. The action of phenoxybenzamine was largely accounted for by its effect on uptake blockade. Taken together, our studies provide evidence against a physiological role of presynaptic alpha-adrenoreceptors in the heart
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