A "love triangle" elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes.

THERE ARE THREE MAJOR CARDIOVASCULAR reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative mechanisms of the input signaling from these reflexes, especially involving the regulation of sympathetic outflow in congestive heart failure (CHF) state. CHF is a syndrome that is usually initiated by a reduction in pump function of the heart and characterized by increased sympathetic outflow, which can be measured by both plasma norepinephrine levels and direct sympathetic nerve activity recordings (20). Cardiovascular reflexes play important roles in the control of the circulation, and the three major cardiovascular reflexes include baroreflex, chemoreflex, and CSAR. The baroreceptor reflex is a sympathoinhibitory reflex located in the aortic arch and carotid sinus. It is the primary peripheral regulator of sympathetic outflow, and inasmuch a depressed arterial baroreflex leads to an increase in sympathetic outflow. Consistent with this notion, it is now well established that the arterial baroreflex is depressed in experimental and clinical CHF (20). However, recent studies have revealed that a reduction in baroreceptor sensitivity is the consequence, but not the cause, of a reflex sympathetic excitation, because the extent of elevated plasma norepinephrine is influenced neither by arterial baroreceptor denervation nor by total cardiac denervation in dogs with pacing-induced heart failure (1, 7). The latter findings suggest that one mechanism of sympathetic overactivity in the CHF state could be attributed, at least in part, to the activation of excitatory reflexes, rather than the loss of inhibitory reflexes (i.e., a depression in inhibitory baroreflex only). Accumulating evidence has shown that augmented excitatory reflexes in CHF may contribute to activation of sympathetic outflow. The chemoreflex, composed of chemoreceptors and located in the internal carotid and aortic bodies as well as the brain stem, is sympathetic-excitatory in nature. As such, it exerts powerful influences not only on breathing but also on the regulation of cardiovascular functions. The peripheral chemoreceptors respond primarily to hypoxic stimulation, whereas the central chemoreceptors are highly responsive to hypercapnia. Chemoreflex activation results in increased sympathetic activity, heart rate, blood pressure, and minute ventilation (11). However, these cardiovascular effects can be subsequently attenuated by the chemoreflex response-induced hyperventilation and increased baroreceptor input as a result of increased blood pressure (16, 17). Indeed, a majority of studies has demonstrated an enhanced sensitivity of peripheral and central chemoreflex activity in both animal models and patients with CHF, especially in the late and severe stages (4, 12). In addition, spontaneously hypertensive rats and human subjects with sleep apnea exhibit an increased chemoreflex drive, even under normoxic conditions (13, 15). A second sympathoexcitatory reflex is the so-called CSAR, which consists of sympathetic sensory endings in the cardiac chambers and thoracic aorta. It is sensitive to both mechanical and chemical stimuli, and it is also implicated in the pathogenesis of sympathetic activation in CHF (3, 9). The activation of CSAR results in an increase in arterial pressure, heart rate, and myocardial contraction with positive-feedback characteristics. The sympathetic nerve afferent activity is markedly increased in myocardial ischemia (2). In CHF, increased oxygen consumption contributes to myocardial ischemia, which, in turn, stimulates cardiac sympathetic afferents to increase sympathetic outflow. Consistently, recent studies have shown that CSAR activity is augmented in rats and dogs with CHF (21, 22). The cardiovascular neural regulation is likely to result from a complex interaction of central integration and peripheral inhibitory and excitatory reflexes (Fig. 1). Neurophysiological studies have identified areas of the brain stem where afferent inputs from peripheral baroreceptors, chemoreceptors, and cardiac sympathetic nerves converge, including the nucleus tractus solitarius (NTS) (10, 18). It has been reported that there is a central antagonistic interaction between the peripheral chemoreflex and arterial baroreflex under normal and disease states (14, 16). An important example is that a suppression of chemoreflex activity restores the impaired arterial baroreflex function in CHF patients (14). Recently, it has been shown that