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Emerging Role of Phosphodiesterase 2A in Hypertension.

See related article, pp 190–198 

Phosphodiesterases cleave and, thereby, inactivate the second messengers adenosine cAMP and cGMP.1 Phosphodiesterases are classified according to their preference for cAMP or cGMP. Phosphodiesterase 2 belongs to a class of phosphodiesterases that hydrolyze cAMP and cGMP with similar kinetics.1 Several recent studies point to a hitherto underappreciated pathophysiological and therapeutic relevance of phosphodiesterase 2 in cardiovascular diseases. Specifically, phosphodiesterase 2 upregulation in heart failure desensitizes the heart toward stimulation via β1-adrenergic receptors.2 In engineered connective tissue, phosphodiesterase 2 enhances the conversion of fibroblasts to myofibroblasts, thereby increasing tissue stiffness.3 Finally, phosphodiesterase 2 inhibitors induce relaxation of pulmonary arteries and inhibit proliferation of pulmonary arterial smooth muscle cells, indicating that phosphodiesterase 2 inhibitors may constitute an effective strategy for treatment of pulmonary hypertension.4

On this background, published in this issue of Hypertension , a study by Li et al5 adds a new facet to the emerging roles of phosphodiesterase 2 in the pathophysiology of cardiovascular diseases. In sympathetic neurons, depolarization leads to calcium influx via voltage-dependent calcium channels with subsequent release of norepinephrine (Figure). Enhanced norepinephrine release can worsen hypertension, and there is evidence for defective norepinephrine reuptake into sympathetic neurons in hypertensive rats.6 Li et al5 show that brain-derived natriuretic peptide (BNP), via activation of particulate guanylyl cyclase A increases cGMP levels in sympathetic neurons, and subsequently decreases calcium influx and norepinephrine release (Figure). Ultimately, BNP reduces heart rate. These data are in accord with the …