Mental stress, hypertension and the baroreflex: what's new?

Blood pressure control during mental stress In the field of hypertension research, the continuing interest in mental stress relates both to its sustained effects on the blood pressure (BP) level [1,2] and to its contribution to the exaggeration of BP variability, which has been established as an independent cardiovascular risk factor [3]. As the arterial baroreceptor reflex is the main short-term controller of BP, it sounds logical to assume that this system plays an important role in modulating BP responses to environmental stressors, including mental and emotional stressors. Since the earliest observations, however, it has been challenging for physiologists to understand the paradox of BP and heart rate rising in parallel during mental stress, which is contradictory to basic baroreflex physiology. The paradox was seemingly solved by studies in anesthetized cats reporting the cardiovascular effects of electrical stimulation within the hypothalamic defence area. Electrical stimulation in this area mimics in almost every respect the responses to emotional stress and was reported to completely suppress the sympathoinhibitory and bradycardic responses to concurrent baroreceptor afferent stimulation [4]. Later on, the anatomical and neurochemical substrates of this inhibitory effect on the baroreflex were proposed by Mifflin et al. [5], who described the selective inhibition of barosensitive neurons of the nucleus tractus solitarius through a mechanism involving GABA receptors during electrical stimulation of the defence area [6]. In the meantime, human studies confirmed that cardiac baroreflex responses were inhibited during emotional stress [7]. These findings established the dogma of stress-induced baroreflex inhibition, and researchers apparently felt confident enough to get out of verifying whether the concept also held true when considering the sympathetic vascular component of the reflex. It should be mentioned, however, that at least one study did not concord with the prevailing opinion. In this study, it was shown that the level of muscle sympathetic nerve activity reached during mental arithmetic combined with phenylephrine infusion was lower than that observed during stress alone, thus suggesting an opposing interaction between stress-induced sympathoexcitation and baroreflex activation [8]. An indirect indication that the sympathetic baroreflex is still operating during emotional stress was also obtained in conscious rats because pressor and regional vasoconstrictor responses to air jet stress were found to be enhanced in chronically sinoaortic baroreceptor denervated rats [9]. It is only recently that the question of stress and the baroreflex was re-examined using direct approaches. First, in anesthetized rats, it was shown that disinhibition of neurons of the defence area with a GABAA receptor antagonist shifted the renal sympathetic baroreflex rightward and increased its sensitivity [10]. This pharmacological approach was more specific than the electrical stimulation, which suffers from the fundamental limitation of potentially activating fibres of passage of unknown nature and function. In another study, renal sympathetic baroreflex function curves were constructed in conscious rats acutely exposed to air jet stress. Similarly, the sympathetic baroreflex was found to be shifted to higher BP levels and its maximum gain was markedly enhanced [11]. In this issue of the journal, Burke and Head [12] report the effect of air jet stress on the sympathetic baroreflex in conscious renovascular hypertensive rabbits. Baroreflex function curves for heart rate and renal sympathetic nerve activity (RSNA) were constructed before and during stress exposure using phenylephrine and sodium nitroprusside infusions. The major novel finding of the study is that the RSNA baroreflex was not suppressed in either control or hypertensive rabbits. On the contrary, it was reset towards higher BP levels and tended to be sensitized, mainly due to an increase in the upper plateau (sympathoexcitation) of the curve. This effect did not reach significance, however, probably because the level of intensity of the stimulus was too mild, as suggested by the authors. Although this finding needs to be confirmed in other forms of hypertension, especially spontaneous hypertension, it suggests that the stress-induced resetting and sensitization of the sympathetic baroreflex might well be preserved in hypertension. Taken together with previous findings in normotensive rats [11], these data seriously challenge the classical view that the sympathetic baroreflex operates around a fixed set point. On the contrary, the baroreflex set point appears to change with the behavioural state, whether this is accompanied or not by changes in the sensitivity of the system [13,14]. From a teleological point of view, a sensitization of the sympathetic baroreflex during stress [11] and exercise [13] might be considered beneficial to the haemodynamic adjustments accompanying the ‘fight or flight’ behaviour, because it would prepare the circulatory system to face strong challenges such as haemorrhage. It has indeed been shown that air jet stress increases the blood loss necessary to produce hypotension in rabbits [15]. Interestingly, rilmenidine, a centrally acting sympatholytic agent, did not compromise this adaptation while reducing the mean level of RSNA and BP in renovascular hypertensive rabbits [12]. Sympathetic baroreflex and blood pressure variability Burke and Head [12] also examined the possible relationships between cardiac and sympathetic baroreflex sensitivities and indices of BP variability, both at rest and during stress. Not surprisingly, there was no relationship between cardiac baroreflex gain and BP variability in either condition, thus confirming that heart rate fluctuations are a minor determinant of short-term BP variability [16]. More surprisingly, there was also no relationship between RSNA baroreflex gain and BP variability. It is worth noting that BP variability was assessed over 30-min periods at rest and 10-min periods during stress, which is probably too short to properly analyze slow and very slow fluctuations. BP variability mainly results from the continuous interplay between haemodynamic perturbations and the baroreflex correction brought about by the sympathetic component of the baroreflex [17]. This stabilizing role of the baroreflex on BP variability is apparent in the low-frequency range (<0.2 Hz in rabbits and rats), where myogenic responses of regional circulations are extremely powerful [18]. At higher frequencies, that is, the mid-frequency band of the present study [12] (up to 0.6 Hz in rabbits and 0.8–1 Hz in rats), the sympathetic baroreflex increases BP variability by generating oscillations, often referred to as Mayer waves [19]. An inverse correlation between RSNA baroreflex gain and low-frequency BP variability is thus expected (a similar inverse correlation is also expected with total BP variability, because low-frequency BP variability contributes the major part of total BP variability [20]). Reciprocally, a positive correlation between RSNA baroreflex gain and mid-frequency BP variability is expected [20]. The lack of correlation between RSNA baroreflex gain and low-frequency BP variability probably derives from the dual origin of the latter [17]. It is only when enlarging the range of RSNA baroreflex gain values by studying rats with partial (aortic) baroreceptor denervation that an inverse correlation with low-frequency BP variability could be observed [21]. The lack of correlation between RSNA baroreflex gain and mid-frequency BP variability might result from the fact that Mayer waves reflect both the feedback from BP to RSNA and the feedforward from RSNA to BP [19,20], that is, vascular reactivity to adrenergic stimulation. The latter is highly variable between subjects, as elegantly demonstrated in humans [22]. In rats, it has been shown that pentobarbital sedation (which alters vascular adrenergic responsiveness) decreases the amplitude of Mayer waves without significantly altering the RSNA baroreflex gain [23]. In conclusion, the study by Burke and Head [12] is important insofar as it provides the first demonstration of a preserved baroreflex control of RSNA during emotional stress in hypertension. The study also brings additional support to the view that changes in the characteristics of the sympathetic baroreflex might accompany changes in the behavioural state. To examine further this question in animals, it might be advisable to use a spontaneous index of sympathetic baroreflex gain that shows a better temporal resolution than the pharmacological method and can be calculated during the performance of common behaviours [21,24]. Furthermore, owing to the recent development of a radiotelemetric method for RSNA recording in rabbits [25], the relationship between RSNA baroreflex gain and BP variability could be assessed over long periods of time with minimal disturbance to the animals.