Vagal tone dominates autonomic control of mouse heart rate at thermoneutrality

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 (T-a) and that the housing Ta is typically 21-23 degrees C, well below the thermoneutral zone (similar to 30 degrees 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 (beta-less mice), 2) mice deficient in cardiac vagal tone [muscarinic M-2 receptor (M2R-/-) mice], and 3) littermate controls. At a Ta of 30 C, the HR of beta-less mice was identical to that of wild-type mice (351 +/- 11 and 363 +/- 10 beats/min, respectively). However, the HR of M2R(-/-) mice was significantly greater (416 +/- 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, beta-less, and M2R(-/-) mice (Delta HR = 73 +/- 9, 76 +/- 3, and 73 +/- 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 degrees C, did beta-less mice exhibit a HR (442 +/- 14 beats/min) that was different from that of littermate controls (604 +/- 10 beats/min) and M2R(-/-) mice (602 +/- 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.