Functional sympatholysis in hypertension

Abstract

Sympathetic vasoconstriction is normally attenuated in exercising muscle by local changes in muscle metabolites and other substances that reduce vascular responsiveness to α-adrenergic receptor activation. Termed functional sympatholysis, this protective mechanism is thought to optimize muscle blood flow distribution to match perfusion with metabolic demand. Emerging evidence from both animal and human studies indicate that functional sympatholysis is impaired in hypertension and may constitute an important underlying cause of skeletal muscle malperfusion during exercise in this common cardiovascular condition. Findings from studies of animal models of hypertension and patients with essential hypertension will be integrated in this review to provide insight into the underlying mechanisms responsible for inappropriate sympathetic vasoconstriction in exercising muscle and the treatment options that may restore functional sympatholysis and improve muscle perfusion during exercise.

Keywords: Exercise; Functional sympatholysis; Hypertension; Sympathetic vasoconstriction.

Figure 1

Left panel, Shows some of the products of skeletal muscle contraction that can diffuse into the interstitium and cause functional sympatholysis by attenuating arteriolar constriction mediated by α₁- and β₂-adrenergic receptors. Right panel, In hypertension, the sympatholytic effect of muscle contraction is impaired by an Ang II-dependent upregulation of NADPH oxidase, increased O₂^–, and reduced NO bioactivity. Antihypertensive treatments that reduce Ang II signaling, ameliorate oxidative stress, or increase NO bioavailability have an added benefit of restoring functional sympatholysis. AR, adrenergic receptor; ARB, angiotensin receptor blocker; AT₁R, angiotensin type 1 receptor; Ang II, angiotensin II; NADPH, nicotinamide adenine dinucleotide phosphate oxidase; NE, norepinephrine; NO, nitric oxide; O₂^–, superoxide; PG, prostaglandins.