Regulation of cardiac rhythm in hibernating mammals

doi:10.1016/S1095-6433(99)00130-0

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology

Volume 124, Issue 4, December 1999, Pages 383-391

https://doi.org/10.1016/S1095-6433(99)00130-0 Get rights and content

Abstract

The dramatic fall in heart rate exhibited by mammals entering hibernation begins before there is any noticeable fall in body temperature. The initial, progressive decrease in heart rate is the result of a cyclic parasympathetic activation that induces skipped beats and regular asystoles as well as slows the even heart beat. As body temperature subsequently falls, the parasympathetic influence is progressively withdrawn and periods of parasympathetic and sympathetic dominance alternate and give rise to regular periods of arrhythmia (tachycardia followed by bradycardia), and occasional long asystoles or periods of highly irregular cardiac activity. Superimposed on this is a vagally-mediated, respiratory sinus arrhythmia that is accentuated in species that breathe episodically. These events give way to a uniform heart rate in deep hibernation at low temperatures where both parasympathetic and sympathetic tone appear absent. The complete absence of tone is not a function of reduced temperature but is reflective of the state of deep, steady state hibernation. The elevation in heart rate that accompanies the onset of arousal is the result of dramatic increases in sympathetic activation that precede any increases in body temperature. As body temperature then rises, sympathetic influence is slowly withdrawn. Arrhythmias are also common during natural arousals or shifts from lower to warmer hibernation temperatures as periods of parasympathetic and sympathetic dominance again alternate en route to re-establishing a steady state in euthermia. The mechanism behind, and the biological significance of, cardiac changes mediated through orchestrated arrhythmias remain unknown.

Introduction

As mammals enter hibernation, their metabolic rates fall, accompanied by proportionate falls in ventilation and cardiac output [24], [30], [31], [41], [50]. The latter is as a result of a dramatic slowing of heart rate. The stroke volume of the heart increases as a result of passive mechanisms arising from the lengthening of diastole and associated increases in venous return [27], [41]. Total peripheral resistance rises, in part as a result of a modest, generalized peripheral vasoconstriction, but primarily as a result of the large increase in the viscosity of the cold blood [27], [35], [36]. While blood pressure falls significantly, the increases in stroke volume and total peripheral resistance result in a slow diastolic run off such that, despite the prolonged diastolic interval and fall in systolic blood pressure, diastolic blood pressure remains relatively high [4], [35]. Perfusion of critical organs is maintained as is autoregulation of coronary flow [3], [5], [7], [21]. The hearts of non-hibernating mammals become arrhythmic and/or fibrillate and cease to function between 10 and 15°C but the hearts of hibernating mammals continue to function at temperatures approaching 0°C, regardless of the season [4], [8], [32].

Many aspects of cardiac function in hibernating mammals have been reviewed previously [6], [11], [24], [32]. In this review, we will focus on the manner in which heart rate changes during entrance into, and arousal from hibernation, as well as on the way in which these changes are produced. This is a fascinating topic that has not received much attention in recent years and for which data is available primarily only for rodent species. While the superficial picture is one of a smooth progressive change in heart rate, the data suggest such changes result from unique, non-stochastic shifts in the balance of sympathetic and parasympathetic cardiac motor outflow. The mechanisms underlying the production of these changes and their biological significance are far from clear.

Section snippets

Control of heart rate during entrance into hibernation

Entrance into hibernation is a carefully regulated process that involves a shift in the set point for temperature regulation to progressively lower temperatures [20], [43]. While metabolism appears to be actively suppressed during entrance [14], [18], [19], shivering is also employed throughout entrance as a brake to the speed of cooling [45]. Thus a complex interaction between reduced heat production and both heat loss and heat gain mechanisms is employed to maintain body temperature near the

Control of heart rate in ‘deep’ hibernation

In all animals in deep hibernation, heart rate appears to be regular and slow. The relative roles of the parasympathetic and sympathetic nervous systems in this state are not yet clear. It is believed by some [32], [34], [35] that parasympathetic influence is now at a minimum and that the system is predominantly under sympathetic control. There is also evidence, however, to suggest that both sympathetic and parasympathetic tone are reduced in proportion to body temperature with parasympathetic

Control of heart rate during arousal from hibernation

It has been proposed that deep hibernation is under autonomic control whereby parasympathetic suppression of sympathetic stimuli maintains hibernation until changes occur in the thresholds of central neurons to sympathetic stimuli (progressive irritability) leading to a sympathetic dominance which allows arousal to ensue [47], [48], [49]. Lyman

Conclusions

Dramatic changes occur in heart rate as part of the events producing entrance into and arousal from hibernation. On entrance, an initial large increase in parasympathetic tone reduces heart rate by as much as 50% before body temperature falls significantly. This increase in parasympathetic tone is slowly replaced by the Q₁₀ effects of temperature such that heart rates of less than 10 beats per min are maintained in deep hibernation at low body temperatures in the apparent absence of any

Acknowledgements

This work was supported by the NSERC of Canada. We are indebted to Dr Hiroshi Tazawa for the invitation to speak at the conference on “Cardiac Rhythms in Animals: Regulation, Development and Environmental Influences” which was the impetus to revisit this intriguing topic and to Dr C.P. Lyman whose pioneering work was the seminal basis for our own observations and research. We would also like to thank Danielle Brochu for her assistance in the preparation of this manuscript.

References (50)

A.R. Dawe et al.
Characteristics of the hibernating heart
Am. Heart J.
(1955)
H.C. Heller et al.
Sleep and torpor-homologous adaptations for energy conservation
S.B. Jones et al.
Functional characteristics and responses to adrenergic stimulation of isolated heart preparations from hypothermic and hibernating subjects
Cryobiology
(1984)
J.E. O’Shea
Temperature sensitivity of cardiac muscarinic receptors of bat atria and ventricle
Comp. Biochem. Physiol.
(1987)
J.W. Twente et al.
Progressive irritability of hibernating Citellus lateralis
Comp. Biochem. Physiol.
(1968)
J.W. Twente et al.
Autonomic regulation of hibernation by Citellus and Eptesicus
G.-A. Biewald et al.
Die chronotrope Vaguswirkung auf das Hamsterherz unter dem Einfluss von Winterschlaf und Hypothermie
Pflügers Arch.
(1959)
S.W. Britton
Effect of partial sympathectomy and vagotomy upon the course of hibernation in heterothermous animals
C. R. Acad. Sci. USSR
(1928)
R.W. Bullard et al.
Estimated regional blood flow by rubidium⁸⁶ distribution during arousal from hibernation
Am. J. Physiol.
(1962)
R.F. Burlington et al.
Low-temperature performance of isolated working hearts from a hibernator and a non-hibernator
Physiol. Zool.
(1988)

R.F. Burlington et al.

Coronary autoregulation and metabolism in hypothermic rat and ground squirrel hearts

Am. J. Physiol.

(1989)

R.F. Burlington et al.

The cardiovascular system in hibernating mammals: recent advances

R.F. Burlington et al.

Differential effects of acetylcholine on coronary flow in isolated hypothermic hearts from rats and ground squirrels

J. Exp. Biol.

(1993)

D.R. Caprette et al.

Isovolumetric performance of isolated ground squirrel and rat hearts at low temperature

Am. J. Physiol.

(1984)

P.O. Chatfield et al.

Circulatory changes during process of arousal in the hibernating hamster

Am. J. Physiol.

(1950)

G. Duker et al.

Monophasic action potentials during induced hypothermia in hedgehog and guinea pig heart

Am. J. Physiol.

(1987)

D.A. Eagles et al.

Cardiac arrhythmias during arousal from hibernation in three species of rodents

Am. J. Physiol.

(1988)

E. Eliassen

Cardiovascular pressures in the hibernating hedgehog, with special regard to the pressure changes during arousal

Arbok Univ. Bergen, Mat.-Naturvitensk. Ser.

(1960)

F. Geiser

Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition?

J. Comp. Physiol. B

(1988)

N.F. Gubinov et al.

Binding of [³H]-dihydroalprenolol to plasma membranes of cardiac cells from a hibernator

Rep. Ukranian SSR Acad. Sci.

(1988)

M.B. Harris et al.

Parasympathetic influence on heart rate in euthermic and hibernating ground squirrels

J. Exp. Biol.

(1995)

M.B. Harris

The Control of Breathing in the Golden-Mantled Ground Squirrel (Spermophilus lateralis)

(1998)

G. Heldmaier et al.

Body temperature and metabolic rate during natural hypothermia in endotherms

J. Comp. Physiol. B

(1992)

G. Heldmaier et al.

Suppression of metabolic rate in hibernation

K. Johansen

Distribution of blood in the arousing hibernator

Acta Physiol. Scand.

(1961)

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ReviewRegulation of cardiac rhythm in hibernating mammals

Abstract

Introduction

Section snippets

Control of heart rate during entrance into hibernation

Control of heart rate in ‘deep’ hibernation

Control of heart rate during arousal from hibernation

Conclusions

Acknowledgements

Am. Heart J.

Cryobiology

Comp. Biochem. Physiol.

Comp. Biochem. Physiol.

Die chronotrope Vaguswirkung auf das Hamsterherz unter dem Einfluss von Winterschlaf und Hypothermie

Pflügers Arch.

Effect of partial sympathectomy and vagotomy upon the course of hibernation in heterothermous animals

C. R. Acad. Sci. USSR

Estimated regional blood flow by rubidium86 distribution during arousal from hibernation

Am. J. Physiol.

Low-temperature performance of isolated working hearts from a hibernator and a non-hibernator

Physiol. Zool.

Coronary autoregulation and metabolism in hypothermic rat and ground squirrel hearts

Am. J. Physiol.

The cardiovascular system in hibernating mammals: recent advances

Differential effects of acetylcholine on coronary flow in isolated hypothermic hearts from rats and ground squirrels

J. Exp. Biol.

Isovolumetric performance of isolated ground squirrel and rat hearts at low temperature

Am. J. Physiol.

Circulatory changes during process of arousal in the hibernating hamster

Am. J. Physiol.

Monophasic action potentials during induced hypothermia in hedgehog and guinea pig heart

Am. J. Physiol.

Cardiac arrhythmias during arousal from hibernation in three species of rodents

Am. J. Physiol.

Cardiovascular pressures in the hibernating hedgehog, with special regard to the pressure changes during arousal

Arbok Univ. Bergen, Mat.-Naturvitensk. Ser.

Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition?

J. Comp. Physiol. B

Binding of [3H]-dihydroalprenolol to plasma membranes of cardiac cells from a hibernator

Rep. Ukranian SSR Acad. Sci.

Parasympathetic influence on heart rate in euthermic and hibernating ground squirrels

J. Exp. Biol.

The Control of Breathing in the Golden-Mantled Ground Squirrel (Spermophilus lateralis)

Body temperature and metabolic rate during natural hypothermia in endotherms

J. Comp. Physiol. B

Suppression of metabolic rate in hibernation

Distribution of blood in the arousing hibernator

Acta Physiol. Scand.

Review
Regulation of cardiac rhythm in hibernating mammals

Estimated regional blood flow by rubidium⁸⁶ distribution during arousal from hibernation

Binding of [³H]-dihydroalprenolol to plasma membranes of cardiac cells from a hibernator