Influence of adrenoceptor and muscarinic receptor blockade on the cardiovascular effects of exogenous noradrenaline and of endogenous noradrenaline released by infused tyramine

Abstract

This study aimed firstly to compare the in vivo cardiovascular effects of exogenously administered and of endogenously released noradrenaline; secondly to characterize the adrenoceptors mediating these responses; thirdly to assess the influence of parasympathetic tone on the cardiovascular effects of noradrenaline. In two randomised placebo-controlled studies, healthy, young, male volunteers received intravenous (i.v.) infusions of noradrenaline at six incremental doses of 10–160 ng/kg/min and – in order to release endogenous noradrenaline – tyramine at four incremental doses of 5–20 μg/kg/min. Noradrenaline and tyramine were administered in the absence and presence of α₁-adrenoceptor blockade with doxazosin (2 mg p.o.), α₂-adrenoceptor blockade with yohimbine (15 mg p.o.), selective β₁-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (15 μg/kg i.v. loading dose followed by 0.15 μg/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (P_diast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS₂c). I.v. noradrenaline increased P_diast (Δmax 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS₂c (Δmax –22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by bisoprolol. I.v. tyramine reduced P_diast (Δmax –7 mmHg), which was not affected by α₁-adrenoceptor blockade, and profoundly shortened QS₂c (Δmax -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (P_syst) (Δmax 57 mmHg). The shortening of QS₂c and the rise in P_syst were not influenced by α-adrenoceptor blockade but were antagonized by bisoprolol. Atropine potentiated the blood pressure rise and the shortening of QS₂c induced by i.v. noradrenaline and converted the fall in P_diast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by α₁-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by β₁-adrenoceptor-mediated positive inotropic effects. The rise in P_syst with i.v. tyramine most likely reflects positive inotropism and not a vascular ‘pressor’ response.