In vivo demonstration of alpha-adrenoceptor-mediated positive inotropy in pithed rats: evidence that noradrenaline does not stimulate myocardial alpha-adrenoceptors.
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.
Broadley
K J
KJ
Department of Pharmacology, Welsh School of Pharmacy, Cardiff University, UK.
Williamson
K L
KL
Roach
A G
AG
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D009638:Norepinephrine; D011224:Prazosin; D004837:Epinephrine