Control of sympathetic activity--new insights; new therapeutic targets?

Abstract

Recently, a large international group of 25 investigators identified a candidate gene for hypertension which codes for phosducin (Pdc) as a novel player in the sympathetic nervous system [1]. In their study, a wide spectrum of findings documented its so-far unrecognized and apparently important role in experimental and human stress-induced hypertension. This conclusion is based on data ranging from detailed analyses of the sympathetic system in genetically manipulated Pdc �/� (knock-out) mice to the demonstration of its relevance in humans: in two separate cohorts, French Canadian and Afro-American individuals, respectively, a correlation was documented between singlenucleotide polymorphisms (SNPs) in the Pdc gene and stress-dependent blood pressure reactions. The target gene identified by the investigators codes for the G-protein regulator phosducin. In mice, targeted Pdc deletion increased blood pressure, increased catecholamine turnover in the peripheral sympathetic system and prolonged action potential firing. This finding suggests that Pdc is a hypotensive principle, explaining why reduced function of Pdc amplifies the hypertensive reaction to stressors. In other words: Pdc puts a brake on sympathetic activity, and conversely Pdc malfunction will lead to hypertension. What is the site of action of Pdc? The Pdc gene and the Pdc protein are expressed in sympathetic ganglia, although to a much lower extent than in the retina and pineal gland, but not in heart, blood vessels and kidney, important players in blood pressure control. To identify the site of action, experimental manipulations sequentially excluded changes in heart function, vascular function or function of the central nervous system as candidates. Early in life, cardiac morphology was not altered in Pdc�/�mice,butleftventricularcontractilitywasincreased despite no change of sensitivity to adrenoceptor agonists (norepinephrine, dobutamine)—consistent with increased sympathetic nerve traffic. In older animals (>4 months), however, significant hypertrophy was seen with expression of fetal genes as evidence of target organ injury.