Abstract
Cyclic GMP (cGMP) is a ubiquitous intracellular second messenger that mediates a wide spectrum of physiologic processes in multiple cell types within the cardiovascular and nervous systems. Synthesis of cGMP occurs either by NO-sensitive guanylyl cyclases in response to nitric oxide or by membrane-bound guanylyl cyclases in response to natriuretic peptides and has been shown to regulate blood pressure homeostasis by influencing vascular tone, sympathetic nervous system, and sodium and water handling in the kidney. Several cGMPs degrading phosphodiesterases (PDEs), including PDE1 and PDE5, play an important role in the regulation of cGMP signaling. Recent findings revealed that increased activity of cGMP-hydrolyzing PDEs contribute to the development of hypertension. In this review, we will summarize recent research findings regarding the cGMP/PDE signaling in the vasculature, the central nervous system, and the kidney which are associated with the development and maintenance of hypertension.
Highlights
Hypertension affects more than 1.5 billion people and is the leading risk factor for cardiovascular morbidity and mortality worldwide [1]
Studies in pregnant rat revealed that the natriuretic effect caused by cyclic GMP (cGMP) signaling in the collecting duct is attenuated by increased PDE5 activity
Decrease of cGMP signaling in the blood vessels, in the central nervous system, or in the kidney contributes to the development and maintenance of hypertension
Summary
Hypertension affects more than 1.5 billion people and is the leading risk factor for cardiovascular morbidity and mortality worldwide [1]. Less than 50 % of patients under treatment consistently achieve their blood pressure targets [2]. The reasons for these poor outcomes are complex, but include a relatively limited repertoire of antihypertensive agents and the complex pathophysiology of hypertension involving several physiological key pathways, like the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, the immune system, and the nitric oxide (NO)/cyclic GMP (cGMP) signaling cascade. While the blockade of the RAAS and the sympathetic nervous system have shown to lower blood pressure in the majority patients, we do not have established any effective treatment option targeting the NO/cGMP signaling cascade for the treatment of hypertension and end organ damage.
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