Antihypertensive Treatment and Sympathetic Excitation
To the Editor:
The article by Fu et al1 reports that acute and chronic treatment with Hyzaar, while lowering blood pressure (BP), enhances the muscle sympathetic nerve activity (MSNA) without altering the sympathetic baroreflex function. According to the authors’ expectations, the reduction in BP should have been accompanied by a decrease in MSNA, indicating a resetting of baroreflex function. These results are interesting and their interpretation is stimulating.
The old and still promoted hypothesis that sympathetic overactivity, and hence hypertension, is related strictly to an impairment of the baroreflex, in terms of neuroscientific reasoning, is too limited. It would correspond to assigning the most common cardiovascular dysregulation to a dysfunction of a small population of afferent nerve fibers or to the central processing of their functional input. In our opinion, this is an example of a Ptolemaic error.
Quite different and more comprehensive is the view2,3 that an increased sympathetic activity, leading to hypertension and to a rise in cardiovascular morbidity, is the result of lifestyle, emotions, and interactions with an archipelago of bodily functions and genetics. In this conceptual scheme,2,3 the efferent sympathetic activity, far from representing a homogeneous outflow, is regulated at the very least by three main mechanisms consisting in central integration, negative feedback mechanisms (the baroreflex function), and positive feedback mechanisms (reflexes mediated by cardiovascular sympathetic afferents and some somatic afferents). In behavioral conditions, central integration, likely to regulate not only the sympathetic activity but also the gain of the various reflexes, would become the leader in the organization of the pattern to be achieved, well beyond strict homeostatic rules. As to the interplay of reflexes of opposite signs, it has been experimentally demonstrated that in conscious dogs, an excitatory sympathetic cardiovascular reflex can markedly blunt baroreflex function independently of behavioral changes.4 How often has an interaction of opposite reflexes been interpreted as a resetting of a single reflex?
In the article by Fu et al,1 the crucial finding is that a decrease in BP occurs and persists in the presence of an increased MSNA and of an unaltered sympathetic baroreflex function. However, an analysis in the frequency domain of MSNA and of cardiovascular variability would have been advisable. For instance, we reported recently5 that acute administration of atenolol increases MSNA in healthy volunteers without changing BP and baroreflex sensitivity. Power spectrum analysis of MSNA made it clear that the frequency distribution of the increased sympathetic discharge was in part shifted from the low- to the high-frequency component (corresponding to respiration), a frequency that could be too high to be transduced in vascular tone. A central effect of the drug was hypothesized.
It is increasingly recognized that the rhythmicity of neural signals provides crucial complementary information3 that should not be disregarded in our attempts of reading the complexity of neural regulation.
Fu Q, Zhang R, Witkowski S, Arbab-Zadeh A, Prasad A, Okazaki K, Levine BD. Persistent sympathetic activation during chronic antihypertensive therapy—a potential mechanism for long-term morbidity?. Hypertension. 2005; 45: 513–521.
Malliani A. Principles of Cardiovascular Neural Regulation in Health and Disease. Boston, Mass/Dordrecht, the Netherlands/London, UK: Kluwer Academic Publishers; 2000.
Pagani M, Pizzinelli P, Bergamaschi M, Malliani A. A positive feedback sympathetic pressor reflex during stretch of the thoracic aorta in conscious dogs. Circ Res. 1982; 50: 125–132.
Cogliati C, Colombo S, Gnecchi Ruscone T, Gruosso D, Porta A, Montano N, Malliani A, Furlan R. Acute beta-blockade increases muscle sympathetic activity and modifies its frequency distribution. Circulation. 2004; 110: 2786–2791.
We thank Drs Malliani and Montano for their comments on our recent report regarding muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex function during acute and chronic antihypertensive therapy with Hyzaar. We agree entirely that the mechanisms underlying baroreflex resetting are complex, and the ultimate outcome, namely blood pressure control, is likely the result of an interaction among more than one neurohumoral regulatory pathway. It is also likely that an analysis in the frequency domain of MSNA and cardiovascular variability could provide additional information on the effects of Hyzaar on sympathetic baroreflex function, particularly its dynamic regulation. However, in this report, we decided to focus on the data at hand in the most straightforward form and to present our results in a simple way without trying to extrapolate to larger teleological issues. Certainly, we are very interested in the spectral analysis approach and are planning such analyses in future experiments.