Swoap SJ, Li C, Wess J, Parsons AD, Williams TD, Overton JM. Vagal tone dominates autonomic control of mouse heart rate at thermoneutrality. Am J Physiol Heart Circ Physiol 294: H1581-H1588, 2008. First published February 1, 2008 doi:10.1152/ajpheart.01000.2007.-It is generally accepted that cardiac sympathetic tone dominates the control of heart rate (HR) in mice. However, we have recently challenged this notion given that HR in the mouse is responsive to ambient temperature (Ta) and that the housing T a is typically 21-23°C, well below the thermoneutral zone (ϳ30°C) of this species. To specifically test the hypothesis that cardiac sympathetic tone is the primary mediator of HR control in the mouse, we first examined the metabolic and cardiovascular responses to rapid changes in Ta to demonstrate the sensitivity of the mouse cardiovascular system to Ta. We then determined HR in 1) mice deficient in cardiac sympathetic tone ("-less" mice), 2) mice deficient in cardiac vagal tone [muscarinic M2 receptor (M2R Ϫ/Ϫ ) mice], and 3) littermate controls. At a Ta of 30°C, the HR of -less mice was identical to that of wild-type mice (351 Ϯ 11 and 363 Ϯ 10 beats/min, respectively). However, the HR of M2R Ϫ/Ϫ mice was significantly greater (416 Ϯ 7 beats/min), demonstrating that vagal tone predominates over HR control at this Ta. When these mice were calorically restricted to 70% of normal intake, HR fell equally in wild-type, -less, and M2R Ϫ/Ϫ mice (⌬HR ϭ 73 Ϯ 9, 76 Ϯ 3, and 73 Ϯ 7 beats/min, respectively), suggesting that the fall in intrinsic HR governs bradycardia of calorically restricted mice. Only when the Ta was relatively cool, at 23°C, did -less mice exhibit a HR (442 Ϯ 14 beats/min) that was different from that of littermate controls (604 Ϯ 10 beats/min) and M2R Ϫ/Ϫ mice (602 Ϯ 5 beats/min). These experiments conclusively demonstrate that in the absence of cold stress, regulation of vagal tone and modulation of intrinsic rate are important determinants of HR control in the mouse. telemetry; intrinsic heart rate; cold stress; caloric restriction; sympathetic nervous system THE FREQUENCY OF CARDIAC CONTRACTION in mammals is achieved through modulation of heart rate (HR) around its intrinsic rate (IHR). HR is slowed by parasympathetic nervous system activity via the muscarinic M 2 receptor (M 2 R) (17) and elevated by sympathetic nervous system activity via the  1 -adrenergic receptor (39). Blockade of these autonomic inputs indicates that murine IHR is typically about 500 beats/min, well below the generally reported resting HR of about 600 beats/min [reviewed in Ref. 27, supporting the concept that cardiac sympathetic tone predominates at rest in the mouse (19,27)]. However, some recent studies indicate that resting mouse HR is lower than 500 beats/min at rest, calling into question the sympathovagal balance controlling HR in mice (6,11,35).Our laboratories (48, 54 -56) and others (8, 52) have demonstrated that mouse HR is markedly reduced when experiments are conducted in thermoneutral conditions [ambient ...