Pressure to change? Re-evaluating the role of baroreceptors in the long-term control of arterial pressure

Abstract

A clear conceptual framework for the long-term control of arterial pressure is required for a full mechanistic understanding of normal cardiovascular regulation as well as changes in arterial pressure that occur in such states as primary and secondary hypertension, congestive heart failure, and pregnancy. For the purpose of this editorial focus, long-term control is defined as those mechanisms that set the average level of arterial pressure of an unstressed individual at rest, though it is recognized that there is no clear consensus on this “theoretical” definition; normal daily routines can alter this level, and the 24-h mean pressure is sometimes used operationally to define the set point. Despite a considerable amount of research over many years, there is much that remains unclear. One key area of dispute is whether brain control of the autonomic nervous system or renal control of sodium balance dominates long-term arterial pressure control, although their role in control of arterial pressure may be interrelated. A long-standing argument against a critical role of the brain and the sympathetic nervous system in the long-term control of arterial pressure has been that the predominantly short-acting control system that adjusts sympathetic activity and heart rate in response to pressure perturbations, the baroreceptor reflex, cannot be involved. Two key pieces of evidence are typically evoked to support this contention. First, the average level of arterial pressure in dogs and other experimental animals housed in a standard controlled environment is chronically unaltered by baroreceptor deafferentation. Second, arterial baroreceptors, in particular myelinated A-fibers, adapt or reset to sustained changes in arterial pressure in the direction of the pressure change. Importantly, this baroreflex resetting refers to an action of a change in pressure per se on the afferents, and possibly also within the brain, such that the initial changes in baroreflex afferent or efferent activity wane with time. Abundant evidence indicates that complete resetting of baroreflex control of heart rate occurs in human and experimental hypertension (although whether there is complete resetting of sympathetic activity throughout the vasculature is unclear). Despite these two sizeable pools of data and the long-heralded view that the baroreflex is only involved in short-term control of arterial pressure, recent experiments from the laboratories of Thrasher, Lohmeier, and Malpas, have revitalized an interest in understanding the potential role of baroreflex in long-term control of arterial pressure. The four Invited Reviews that follow ([3][1], [23][2], [36][3], [42][4])[1][5] examine the evidence in favor of a role of baroreceptors in the long-term control of arterial pressure as well as opposing views. Obviously, this issue of the role of baroreceptors in the long-term control of arterial pressure is far from settled, and it is hoped that these reviews will stimulate further discussion and experimentation in this important area. The renewed discussion of this issue revolves around three new experimental approaches. A key approach used by Lohmeier and colleagues has been chronic electrical stimulation of carotid baroreceptor afferent nerve fibers in dogs. They find that with the stimulation parameters they use there is a decrease in arterial pressure, accompanied by a decrease in plasma norepinephrine concentration that presumably reflects a decrease in sympathetic activity, which is maintained for at least 7 days ([24][6]). Conversely, Thrasher has shown that chronic unloading of carotid baroreceptors (with other carotid and aortic baroreceptors surgically removed) increases arterial pressure for at least 7 days in dogs ([41][7]). Thus, both of these preparations suggest that increasing or decreasing the activity of baroreceptors can lead to decreases or increases in arterial pressure, respectively, for at least 1 wk and therefore support the hypothesis that altered baroreceptor function can chronically alter arterial pressure. A third approach, used by Malpas and colleagues, has been chronic recording of renal sympathetic nerve activity (RSNA) during chronic increases in arterial pressure with ANG II infusion in rabbits. They find that ANG II infusions for a week, which result in sustained increases in arterial pressure, produce sustained reductions in RSNA ([4][8]). Lohmeier et al. also have indirect data to suggest that ANG II infusion chronically reduces RSNA in dogs ([25][9]). The observations are most readily consistent with baroreceptors contributing to the chronic control of arterial pressure and RSNA. Another older observation that is being interpreted as supporting a role for baroreceptors in the long-term control of blood pressure is that sinoaortic baroreceptor-denervated (SAD) rats fed a diet with a high salt content show an increase in arterial pressure ([19][10], [35][11]). Thus, in contrast to previous research, these data seem, at face value, to make a strong case in favor of baroreceptors contributing to the long-term control of arterial pressure. The key issue would then seem to be how the recent observations from the laboratories of Lohmeier, Malpas, and Thrasher can be reconciled with the numerous studies documenting that animals lacking arterial baroreceptor afferents exhibit normal blood pressure. Moreover, if the baroreflex chronically restrains sympathetic outflow in animals with hypertension, then why is arterial pressure not even higher in hypertensive animals subjected to sinoaortic denervation ([13][12])? Indeed, in one model (chronic NOS blockade), hypertension was actually reversed by sinoaortic denervation ([37][13]). Clearly the answers are not yet available, and the four reviews present the approaches and biases of four laboratories that have been important contributors to this area. In doing so, the authors cover many, if not all, of the points that should be...