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 micrograms/kg/min. Noradrenaline and tyramine were administered in the absence and presence of alpha 1-adrenoceptor blockade with doxazosin (2 mg p.o.), alpha 2-adrenoceptor blockade with yohimbine (15 mg p.o.), selective beta 1-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (1.5 micrograms/kg i.v. loading dose followed by 0.15 microgram/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (Pdiast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS2c). I.v. noradrenaline increased Pdiast (delta max 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS2c (delta max -22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by biosprolol. I.v. tyramine reduced Pdiast (delta max -7 mmHg), which was not affected by alpha 1-adrenoceptor blockade, and profoundly shortened QS2c (delta max -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (Psyst) (delta max 57 mmHg). The shortening of QS2c and the rise in Psyst were not influenced by alpha-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 Pdiast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by alpha 1-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by beta 1-adrenoceptor-mediated positive inotropic effects. The rise in Psyst with i.v. tyramine most likely reflects positive inotropism and not a vascular "pressor' response.

Comparative Effects of Carvedilol vs Bisoprolol for Severe Congestive Heart Failure - Special Reference to Atrial Fibrillation -

“…Schafers et al showed that the stimulation of β1-adrenergic receptors induces the inotropic and chronotropic effects of norepinephrine. 21 Similar results were reported by McDavitt, who emphasized that the ability of β1-adrenergic receptor signaling to initiate arrhythmia is illustrated by exercise-induced tachyarrhythmias caused by norepinephrine release from sympathetic nerve ending. 22 Taken together, these results and our results suggest that bisoprolol has greater ability to suppress HR of patients with HF than carvedilol, as the former is a highly selective β1-adrenergic receptor blocker.…”

Endogenously and exogenously increased noradrenaline exerts sex-different responses in humans

“…Our results with tyramine are at variance with Schäfers et al, 11 who reported a reduction in DBP and an increase in SBP and cardiac inotropic performance in healthy males and concluded that the effects of intravenous tyramine are mainly mediated by Figure 1 Effect of intravenous noradrenaline (a) and tyramine (b) given alone or in the presence of propranolol at equivalent noradrenaline plasma concentrations. Percent changes from baseline mean arterial blood pressure, pulse rate and total electromechanical systole QS2c in males (n ¼ 10, hatched columns) and females (n ¼ 9, open columns) are presented as means 7 s.e.m.…”

Diastolic blood pressure is an important determinant of augmentation index and pulse wave velocity in young, healthy males

“…Heart rate (HR) (bpm) was calculated from the RRinterval of the electrocardiogram, which was recorded using a Siemens-Cardirex s multichannel ink jet recorder (Siemens Medizintechnik, Erlangen, Germany) as previously described. 29,30 We used impedance cardiography to measure central haemodynamics. Impedance cardiography agrees closely with measurements obtained by Doppler echocardiography or thermodilution, 31 and is acceptable for clinical use particularly in studies investigating young subjects free from any cardiovascular disease.…”