Changes in cardiovascular responsiveness to dopexamine and β₁‐ and β₂‐adrenoceptor function after the chronic treatment of β‐adrenoceptor antagonists and agonists in anaesthetized dogs

Abstract

1. The studies were designed to investigate the changes in responsiveness to beta-adrenoceptor agonists induced by chronic administration of beta-adrenoceptor antagonists and agonists. 2. Dose-response curves for dopexamine, isoprenaline, noradrenaline and impromidine on heart rate, blood pressure and myocardial contractility (dP/dt:integrated isometric tension) were obtained in untreated dogs and compared to those measured in dogs which had been pretreated with propranolol (8 mg kg-1 day-1), atenolol (6 mg kg-1 day-1), isoprenaline (0.5 microgram kg-1 min-1) or noradrenaline (0.5 microgram kg-1 min-1) for 14 days. 3. Propranolol pretreatment significantly enhanced the inotropic and chronotropic responses to isoprenaline. There were noticeable, but non-significant increases in inotropic sensitivity to noradrenaline and dopexamine, especially at higher dose levels. In the atenolol treatment group, there were significant increases in inotropic responses to dopexamine and isoprenaline and in depressor responses to isoprenaline. 4. Thus, chronic administration of propranolol increased responses mediated by both beta 1- and beta 2-adrenoceptors, whereas, atenolol selectively enhanced the inotropic responsiveness to dopexamine, which is mediated mainly by beta 2-adrenoceptors. 5. Isoprenaline pretreatment caused a significant decrease in inotropic sensitivity to dopexamine, isoprenaline and noradrenaline and a significant reduction in chronotropic responses to dopexamine. The tendency to reduced depressor responses to isoprenaline and dopexamine failed to reach significance. Pretreatment with noradrenaline decreased only the inotropic response to noradrenaline. 6. Thus, chronic isoprenaline treatment reduced the responsiveness of both beta 1- and beta 2-adrenoceptors, while chronic noradrenaline infusion only reduced beta 1-adrenoceptor-mediated responses. 7. There was no significant change in any of the dose-response curves to impromidine after any beta-adrenoceptor antagonist or agonist treatment. This indicates that there was no non-specific alteration in responsiveness and that the observed changes were likely to be associated with specific alterations in beta-adrenoceptor number or function.

Nandrolone-pretreatment enhances cardiac β2-adrenoceptor expression and reverses heart contractile down-regulation in the post-stress period of acute-stressed rats

“…Since these effects occur few minutes after stress, it is likely that ND-pretreatment avoids the early mechanisms of ␤1-receptor/G(s)-protein uncoupling, which occurs after acute stress [1][2][3]. How this occur is not known and was beyond the aims of the present study.…”

“…This reduced response that normally occurs after sympathetic over-stimulation has been interpreted as a defense mechanism of the heart against over-stimulation, which has been attributed to a ␤1-receptor down-regulation [1][2][3].…”

“…In case of an acute stress sympathetic over-stimulation induces a subsequent ␤-receptor-pathway down-regulation [1][2][3]. Multiple mechanisms may induce this physiological down-regulation.…”

“…Since steroids may affect the expression of ␤-adrenergic receptors in different tissues [2,4], and stress may alter their function in hearts [1][2][3] we hypothesized that NDpretreatment may affect the cardiac ␤-adrenergic receptor expression and the response to sympathetic stimulation in both stressed and unstressed animals.…”

Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects

“…In mice, reduced inotropic responses to ISO as assessed by echocardiography were noted following 13 days ISO infusion [58]. Likewise, downregulation of b-AR-mediated inotropic responses was observed following daily infusions of ISO or noradrenaline over 2-4 weeks to dogs [80, 170,171]. Interestingly, chronic administration of b-AR antagonist produces the opposite changes as evidenced by increases in chronotropic, inotropic and depressor responses to acute ISO administration [171].…”