In vivo demonstration of α‐adrenoceptor‐mediated positive inotropy in pithed rats: evidence that noradrenaline does not stimulate myocardial α‐adrenoceptors

Abstract

1. This study examines whether positive inotropy via alpha-adrenoceptors could be observed in vivo in pithed rats. Cardiac contractility was measured as the maximum rate of rise of left ventricular pressure (dP/dt(max)). Heart rate and aortic blood pressure were also recorded. 2. The selective alpha1-adrenoceptor agonists, methoxamine, cirazoline, amidephrine and phenylephrine caused dose-related increases in dP/dt(max). This response was progressively reduced by increasing doses of the alpha1-adrenoceptor antagonist prazosin. However, since the concomitant increase in diastolic blood pressure (DBP) was also blocked, the changes in dP/dt(max) may have been a consequence of increased after load. 3. Adrenaline and noradrenaline also increased dP/dt(max), accompanied by pressor responses. Propranolol (1 mg kg(-1)) antagonized the increase in dP/dt(max) in response to noradrenaline, suggesting beta-adrenoceptor involvement, but not that to adrenaline. The additional presence of prazosin (1 mg kg(-1)) further shifted the dose-response curves for both noradrenaline and adrenaline to the right. 4. Analysis of the increases in dP/dt(max) at predetermined increases in DBP by each agonist revealed three groups of regression lines. Adrenaline in the presence of propranolol and the four selective alpha1-adrenoceptor agonists occupied a common central position. Above this group were adrenaline and noradrenaline in the absence of antagonists; their additional effects on contractility were beta-adrenoceptor-mediated since the regression lines were lowered by propranolol. Clearly below the main group of agonists was noradrenaline in the presence of propranolol. 5. Thus, for a given increase in DBP, adrenaline (in the presence of beta-blockade) and the alpha1-adrenoceptor agonists exert an additional inotropic effect to noradrenaline (also in the presence of beta-blockade). This is concluded to be an alpha-adrenoceptor-mediated increase in cardiac contractility which is not shared by noradrenaline.

Possible involvement of GLP‐1(9–36) in the regional haemodynamic effects of GLP‐1(7–36) in conscious rats

“…In this study, as previously with exendin‐4, the enhanced pressor effect of GLP‐1(7–36) seen with propranolol treatment did not occur when the animals were treated with phentolamine together with propranolol. Because this could not be explained by a marked diminution by phentolamine of the vasoconstrictor effects, we suggest it is due to inhibition of a cardiac α‐adrenoceptor‐mediated positive inotropic effect (Broadley et al ., 1999). It was interesting that there was no evidence for a major contribution from α‐adrenoceptors to the vasoconstrictor effects of GLP‐1(7–36).…”

Testosterone-augmented contractile responses to α1- and β1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart

“…A negative inotropic effect of ␣ 1 -adrenoceptor stimulation in the mouse myocardium has been reported (37). On the other hand, positive inotropic responses have been observed in rats both in vivo (6) and in vitro (14) upon ␣ 1 -adrenoceptor stimulation. In the present study, we showed that ␣ 1 -adrenoceptor stimulation with PE increased contractility and accelerated relaxation, which were accompanied, respectively, with an increased amplitude of Ca 2ϩ release from the SR and faster removal of Ca 2ϩ from the cytosol.…”

“…It is well documented that ␤ 1 -adrenoceptor activation increases contraction and accelerates relaxation (10, 64). There is also evidence showing that ␣ 1 -adrenoceptor activation triggers positive inotropic responses in the rat myocardium (6,14). We recently demonstrated that testosterone enhances injury responses and contractile recovery to stimulation of both ␣ 1 -and ␤ 1 -adrenoceptors as well as enhances the expression of both adrenoceptor subtypes (56).…”

Mesenteric Vasoconstriction and Hindquarters Vasodilatation Accompany the Pressor Actions of Exendin-4 in Conscious Rats

“…However, we do not believe this additional effect of phentolamine on the pressor response was due only to suppression of the hindquarters vasoconstrictor action of exendin-4 because there was no hindquarters vasoconstrictor response to exendin-4 in the presence of ICI 118551, when the pressor effect of exendin-4 was augmented to a similar extent. Hence, the most likely explanation of the ability of phentolamine to suppress the increase in the pressor effect of exendin-4 caused by propranolol is that this was due to inhibition of another mechanism, e.g., a cardiac ␣ adrenoceptor-mediated positive inotropic effect, most likely attributable to adrenaline (Broadley et al, 1999). So, our results are consistent with the sympathoadrenal activation caused by exendin-4 resulting in substantial adrenaline release causing activation of cardiac ␣ and ␤ adrenoceptors and (largely) hindquarters ␤ 2 adrenoceptors, with little evidence of activation of vascular ␣ adrenoceptors, either through this mechanism or through mediation of sympathetic efferent noradrenergic vasoconstrictor activity.…”