Effects of cholinergic and β-adrenergic blockade on orthostatic tolerance in healthy subjects

Abstract

Cardiovascular responses during a graded lower body negative pressure (LBNP) protocol were compared before and after atropine and propranolol administration to test the hypothesis that both sympathetic and parasympathetic control of cardio-acceleration are associated with syncopal predisposition to orthostatic stress in healthy subjects. Eleven men were categorized into two groups having high (HT, N = 6) or low (LT, N = 5) tolerance based on their total time before the onset of presyncopal symptoms. HT and LT groups were similar in physical characteristics, fitness, and baseline cardiovascular measurements. Atropine treatment had no effect on LBNP tolerance or mean arterial pressure at presyncope, despite an atropine-induced increase in heart rate. Propranolol treatment reduced (p<0.05) LBNP tolerance in both groups. Diminished LBNP tolerance after propranolol administration was associated with reductions in cardiac output, whereas increase in systemic peripheral resistance from baseline to presyncope was unaffected by propranolol. Reduction in cardiac output and LBNP tolerance after beta blockade reflected a chronotropic effect because lower LBNP tolerance for the HT (-50%) and LT (-39%) groups was associated with dramatic reductions (p <0.05) in the magnitude of LBNP-induced tachycardia without significant effects on stroke volume at presyncope. Absence of an atropine-induced difference in cardiac output and systemic peripheral resistance between HT and LT groups failed to support the notion that cardiac vagal withdrawal represents a predominant mechanism that could account for differences in orthostatic tolerance. Because a reduction in LBNP tolerance in both HT and LT groups after propranolol treatment was most closely associated with reduced tachycardia, the data suggest that a primary autonomically mediated mechanism for maintenance of mean arterial pressure and orthostatic tolerance in healthy subjects is beta adrenergic-induced tachycardia.

Autonomic mechanisms associated with heart rate and vasoconstrictor reserves

“…We, and others, define the maximum response from baseline levels (e.g., HR, peripheral vasoconstriction) to a reduction in central blood volume as the physiological 'reserve' [24,27]. Using an experimental model of progressive hemorrhage in humans [15,20] that is designed to induce hemodynamic decompensation (i.e., severe hypotension and pre-syncope) has revealed that subjects with high tolerance (HT) to reduced central blood volume display higher HR [16] and peripheral vasoconstriction [17,38] than low tolerant (LT) subjects [16,38]. These observations suggest that greater physiological reserve is associated with greater tolerance to central hypovolemia.…”

The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia

“…Two recent studies reported comparable hemodynamic responses to LBNP and blood loss up to 1,000 ml in humans (21, 36) and 25% loss of total blood volume in baboons (17). It is well established that during the initial stages of progressive central hypovolemia, reflex cardiovascular responses are initiated (e.g., tachycardia, peripheral vasoconstriction) (5,6,15,19,24,38), protecting the vital organs from hypoperfusion. Although traditionally protection of absolute CBF was thought to be essential in determining tolerance to central hypovolemia (24), recent studies have indicated a disconnect between tolerance to LBNP and protection of absolute flow [predominantly assessed by middle cerebral artery velocity (MCAv), an index of global cerebral blood flow] (20, 27, 28, 37).…”

Heart rate and orthostatic stress

“…There is one further observation, seen in earlier work and confirmed in the article of Convertino and Sather, that links heart rate to orthostatic tolerance: in all subjects, both healthy volunteers and patients, there is a positive correlation between orthostatic tolerance and maximal heart rate before presyncope [1,4,5,15,16]. However, a correlation does not prove cause and effect.…”

“…The article in this issue [1] had the aim of assessing the importance of autonomic control of heart rate in determin- Figure 1. 'Diagram to explain the small effect on cardiac output of changes in heart rate when venous filling pressure is not increased.…”

“…There is little doubt that vasomotor responses are of fundamental importance in preventing hypotension, but there is also a concomitant increase in heart rate, and the significance of this is much less clear. The article by Convertino and Sather [1] in this issue attempts to clarify the role of the orthostatic tachycardia using healthy volunteer subjects in whom the autonomic nerves were blocked using either atropine (muscarinic block) or propranolol ([3-adrenergic block). In this editorial, I will discuss the physiologic significance of changes in heart rate in the context of orthostatic stress and attempt to interpret the results of Convertino and Sather in the light of existing physiologic knowledge.…”