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angiotensin II [ 14 ]. These studies support the contention that during hypertension,
baroreflex-mediated suppression of sympathetic outflow is a long-term compensa-
tory mechanism, attenuating the severity of hypertension [ 15 ]. A corollary to this
hypothesis is that the resetting of baroreflexes in hypertension may be incomplete.
Furthermore, baroreflex dysfunction is one irrefutable abnormality commonly
found in hypertension of primary origin [ 15 ]. Mounting evidence documented
impaired (blunted) baroreflex control of heart rate in hypertensive patients. However,
the efficacy of baroreflex buffering of sympathetic nerve traffic in response to phar-
macologically induced, acute changes of blood pressure appears preserved in mild
and even severe hypertension [ 16 ], indicative of resetting with normal dynamic
function. While resetting would maintain the fundamental role of the baroreflex in
the acute regulation of arterial pressure, it would also diminish its ability to chroni-
cally suppress sympathetic activity and counteract the severity of hypertension. To
reconcile these apparently conflicting lines of evidence, a clear distinction should be
made between the dynamic vs. the steady-state domains of operation of the barore-
flex. Baroreflex-mediated acute responses of sympathetic outflow to a sudden
change in blood pressure predominate in the arsenal of investigators assessing
dynamic baroreflex function, but the long-term sympathetic modulation has not
been easily amenable to investigation. Thus, if resetting of the baroreflex is com-
plete, then it would be unlikely that dynamic baroreflex dysfunction could contrib-
ute to the sustained sympathoexcitation that plays a causal role in the pathogenesis
of primary hypertension. On the other hand, if the baroreflex does not entirely adapt
to long-term changes in arterial pressure, baroreflex dysfunction could play a role in
the pathogenesis of primary hypertension.
Patients with resistant hypertension have inadequate blood pressure control
despite treatment with multiple classes of drugs of which some were demonstrated
to activate the sympathetic nervous system [ 17 , 18 ], such as calcium channel block-
ers, diuretics, and even some sympatholytics. Thus, iatrogenically induced sympa-
thetic activation may likely counteract the effects of antihypertensive medication
and contribute to the intractable nature of hypertension in these patients. Peripherally
acting sympatholytic agents such as α1- and β-adrenergic blockers could conceiv-
ably alleviate reflex sympathoexcitation but are rarely administered together and in
concentrations sufficient to completely inhibit peripheral adrenergic responses. As
increased renal sympathetic activity exerts its prohypertensive effects by stimulat-
ing renin and tubular reabsorption of sodium, which are dependent on the activation
of α1- and β-adrenergic receptors, complete and concomitant blockade of these
receptors is necessary in order to counteract neurally induced alterations in renal
function that lead to increased arterial pressure. Centrally acting sympatholytic
agents or non-pharmacological therapies (discussed below) capable of suppressing
global sympathetic outflow, including RSNA, may thus provide an effective thera-
peutic tool to suppress sympathetically mediated increases in blood pressure. Recent
experimental observations are relevant to this issue. Chronic lowering of blood pres-
sure with a commonly used class of antihypertensive drugs, calcium channel block-
ers (amlodipine), was associated with marked sympathetic activation as revealed by
several-fold increases in plasma NE concentration and profound activation of the
R. Iliescu and D.N. Şerban