N. A. Flavahan

α-ADRENOCEPTORS CAN MEDIATE CHRONOTROPIC RESPONSES IN THE RAT HEART

In the pithed rat, amidephrine, a ‘selective’ α1‐adrenoceptor agonist, evokes a positive chronotropic response. This response can be antagonized by prazosin but not by propranolol or by rauwolscine. Similarly, part of the chronotropic response to cardioaccelerator nerve stimulation is resistant to blockade by propranolol but is sensitive to prazosin or WB4101. We conclude that α1‐adrenoceptors can mediate a chronotropic response in the rat heart either to exogenous agonists or to the endogenous neurotransmitter noradrenaline.

Analysis of the α-adrenoceptor-mediated, and other, components in the sympathetic vasopressor responses of the pithed rat

1 The vascular receptors activated following sympatho‐adrenal stimulation were determined by analysing the effects of ‘selective’ antagonists on the vasopressor response to spinal sympathetic nerve activation in the pithed rat. 2 The net vascular response to adrenal stimulation was a balance between α‐adrenoceptor‐mediated vasoconstriction and β‐adrenoceptor‐mediated vasodepression. Part of the α‐adrenoceptor‐mediated response was ‘prazosin‐sensitive’ (α1) and the remainder was abolished by rauwolscine (α2). 3 As with adrenal stimulation, direct sympathetic nerve stimulation of the vasculature evoked pressor responses which were partly resistant to prazosin. Rauwolscine only partly blocked the prazosin‐sensitive component. Reserpine pretreatment led to smaller responses than prazosin plus rauwolscine. Thus, the response resistant to α‐adrenoceptor antagonists could be mediated, in part, by adrenoceptors distinct from α‐adrenoceptors, as currently defined. 4 α, β‐Methylene ATP reduced the nerve‐mediated pressor response after α‐adrenoceptor blockade or reserpine pretreatment but not in drug‐free controls. 5 The results suggest that stimulation of the adrenal medulla can produce a vasopressor response which consists of summating α1 and α2‐adrenoceptor‐mediated components, and is identical to the effect of injected adrenaline. In contrast, the response to vasopressor nerve stimulation appears to be essentially mediated by α1‐adrenoceptors, with a facilitatory influence from α2‐adrenoceptors. A further response obtained after α‐adrenoceptor blockade may contain a purinergic component and another which is adrenergic but not mediated by stimulation of α‐adrenoceptors.

α1‐ADRENOCEPTOR ACTIVATION CAN INCREASE HEART RATE DIRECTLY OR DECREASE IT INDIRECTLY THROUGH PARASYMPATHETIC ACTIVATION

1 The chronotropic effects of α‐ and β‐adrenoceptor agonists were investigated in the pithed rat. 2 The β‐adrenoceptor agonist, isoprenaline, produced only a positive chronotropic response. α1‐Adrenoceptor agonists, phenylephrine and amidephrine, produced positive and negative chronotropic effects. Part of the response to phenylephrine was β‐mediated. 3 A positive chronotropic response to amidephrine and phenylephrine was mediated directly through cardiac α1‐adrenoceptors and had a different time course from β‐adrenoceptor‐mediated responses. 4 A negative chronotropic response to α‐agonists was potentiated by neostigmine and blocked by atropine, tetrodotoxin or hexamethonium as well as by α1‐adrenoceptor antagonists. This may indicate α1‐adrenoceptors on preganglionic parasympathetic nerves, stimulation of these receptors causing release of acetylcholine. 5 The α2‐adrenoceptor agonist, xylazine, produced a direct negative chronotropic effect on the heart, independent of α‐adrenoceptors. No evidence was found for functional post‐junctional α2‐adrenoceptors. At high doses xylazine stimulated cardiac α1‐adrenoceptors.

BLOCKADE BY YOHIMBINE OF PRAZOSIN‐RESISTANT PRESSOR EFFECTS OF ADRENALINE IN THE PITHED RAT

In the pithed rat, following β‐adrenoceptor blockade, the pressor effect of adrenaline can be blocked by phentolamine or by prazosin plus yohimbine but not by prazosin or yohimbine given alone. It is concluded that adrenaline produces its pressor effect by acting on two sets of post‐junctional α‐adrenoceptors, each of which is sensitive to phentolamine, one of which is sensitive to prazosin but resistant to yohimbine and the other of which is sensitive to yohimbine but resistant to prazosin.

Difference in the potency of α2-adrenoceptor agonists and antagonists between the pithed rabbit and rat

1 The subtypes of α‐adrenoceptors which mediate pressor responses to sympathomimetic agonists or to nerve stimulation in pithed rabbits have been classified according to the effects of ‘selective’ antagonists and a comparison has been made, for the α2‐subtype, with corresponding responses in the rat. 2 In the rabbit the dose‐response curve for phenylephrine was shifted to the right in parallel by prazosin (1 mg kg−1) and was unaffected by rauwolscine (1 mg kg−1). The dose‐response curve for noradrenaline was shifted to the right by prazosin (1 mg kg−1) and was shifted to a smaller extent by rauwolscine (1 mg kg−1) or imiloxan (10 mg kg−1). After rauwolscine, prazosin produced a rightward shift larger than when given alone. After prazosin, rauwolscine produced a rightward shift larger than when given alone. 3 The responses to pressor nerve stimulation at low frequencies (< 1 Hz) could be reduced by prazosin, rauwolscine or imiloxan but those at a higher frequency could be reduced only by prazosin. 4 These results indicate that the responses to noradrenaline or to nerve stimulation are mediated by both α1‐and α2‐adrenoceptors. Low doses or frequencies have a proportionately greater component which is α2. 5 Responses to noradrenaline after prazosin (1 mg kg−1), were sufficiently sensitive to rauwolscine to be considered as predominantly α2. A comparison was therefore made of such responses in the rat and rabbit. They were produced by a lower dose per unit body weight in the rat whereas this was less marked for the α2‐adrenoceptor agonist guanabenz. In the rabbit they were more susceptible to blockade by rauwolscine but were less sensitive to Wy 26703 than in the rat. This demonstrates that the α2‐adrenoceptors mediating pressor responses in vivo, like those in other tissues in vitro, are different in rat and rabbit, with regard to antagonists.