Effects of selective alpha 1‐, alpha 2‐, beta 1‐and beta 2‐adrenoceptor stimulation on potentials and contractions in the rabbit heart.

Abstract

SUMMARY1. Selective adrenoceptor agonists and antagonists have been used to analyse the effects of stimulation of individual types of adrenoceptor in various parts of the rabbit heart.2. The selective al-and a2-adrenoceptor agonists used were St 587 and BHT 933 respectively, and the antagonists were prazosin (a,) and WY 25309 (a2). 3. The selective 18,-and fi2-adrenoceptor antagonists were atenolol and ICI 118551, respectively. Pirbuterol was a highly selective ,t 2-adrenoceptor agonist. The non-selective agonists noradrenaline, adrenaline and isoprenaline were also employed with various combinations of antagonists. 4. Phenylephrine was found to stimulate fi-as well as ac-adrenoceptors. Rimiterol was a fi-adrenoceptor agonist, partially selective for fl2-adrenoceptors.5. In the sinus node ,1-, but not 8l2-adrenoceptor stimulation increased the fast phase of depolarization (Tfmax).6. Both pj%-and fl2-adrenoceptor stimulation increased the slope of slow diastolic depolarization, accelerated repolarization and increased maximum diastolic potential.7. After blockade of both j,-and fl2-adrenoceptors aL1-adrenoceptor stimulation caused bradycardia, due exclusively to delayed repolarization. ac2-adrenoceptor stimulation had no effect.8. In Purkinje cells and papillary muscle both fi1-and f62-adrenoceptor stimulation accelerated repolarization. Stimulation of c2-adrenoceptors had no effect.9. /%-, not f62-adrenoceptor stimulation augmented peak contractions 3-5-fold, and greatly increased rate of development of tension. After fl-blockade acx-adrenoceptor stimulation moderately increased peak contractions (up to 47 %), but increased time-to-peak and duration of contractions.10. These patterns of adrenoceptor-mediated effects were unchanged in animals pre-treated with sufficient 6-hydroxydopamine to eliminate responses to sympathetic nerve stimulation.11. The results would be consistent with /J1-, not f82-adrenoceptor stimulation increasing inward calcium current, and with stimulation ofacc-adrenoceptors delaying its inactivation, rather than increasing its magnitude.

Effects of sympathetic nerve stimulation on the sino‐atrial node of the guinea‐pig.

“…These receptors were characterized by using selective antagonists of the fl1-type. Although this type of ,3-adrenoceptor is the dominant receptor on cardiac muscle, f82-adrenoceptors are found on pacemaker cells (Dukes & Vaughan-Williams, 1984). Indeed, binding studies indicate that fl2-adrenoceptors are concentrated on sino-atrial cells of the guinea-pig (Jones, Molenaar & Summers, 1989).…”

“…Presumably neurally released noradrenaline has little access to the /l2-adrenoceptors located on sino-atrial node cells. Surprisingly noradrenaline, which is some thirty times more selective as an agonist for /ll-adrenoceptors than it is as an agonist for /82-adrenoceptors (Dukes & Vaughan-Williams, 1984), did not mimic the responses to sympathetic nerve stimulation ( Fig. 6; see also Toda & Shimamoto, 1968).…”

Cardiovascular effects of bevantolol, a selective β1‐adrenoceptor antagonist with a novel pharmacological profile

“…The blocking effect of bevantolol in the pithed rat was much greater on the tachycardia than the hypotension induced by isoprenaline, implying 0,-adrenoceptor selectivity. (Dukes & Vaughan Williams, 1984b APD was lengthened by bevantolol, but the effect of 8 x 106mollI' was less than that of 4 x 10-6molL ', as if a secondary shortening effect was added at the higher concentration. In the preterminal Purkinje cells, APD was actually shortened.…”

“…This activity merits further study, especially in the CNS, since in pithed rats, bevantolol caused hypertension, but did not do so in the anaesthetized dogs studied by Hastings et al (1977), implying that a peripheral vasoconstrictor action might be counteracted by some central effect. Baukema and Bovenkirk (unpublished), however, observed that bevantolol increased stroke volume and peripheral resistance in anaesthetized dogs, effects consistent with a-adrenoceptor agonist action causing a direct positive inotropic effect on the ventricular myocardium (Dukes & Vaughan Williams, 1984b), in addition to peripheral vasoconstriction. Although bevantolol appeared to block is, in the nodes, it had no negative inotropic action, which could be advantageous in hypertensive patients with impaired myocardial function.…”

Indoramin‐prolongation of repolarization time, a mechanism of bradycardia in man?

“…In our study, it is not possible to extrapolate observations on the QT/QTc intervals on the surface ECG to actions on the SA node, but it is possible that indoramin may also prolong SA node repolarisation and hence cause bradycardia. Such activity is not likely to be related to the a-adrenoceptor antagonist properties of indoramin, as a1-adrenoceptor agonists such as noradrenaline and ST587 have also been found to delay SA node repolarisation (Dukes & Vaughan Williams, 1984).…”