Phosphodiesterase regulation of nitric oxide signaling

Abstract

Nitric oxide regulation of the cardiovascular system involves both cGMP-dependent and independent mechanisms. The former directly interacts with the family of catabolic phosphodiesterases (PDEs) that control cGMP levels and thus distal effects such as protein kinase G stimulation. Growing evidence supports an important role of several PDEs, including PDE1, PDE2, and PDE5, in the regulation of cGMP in both vascular smooth muscle and cardiac myocytes. These PDEs have relatively little impact on resting function, but they can potently modulate acute contractile tone in cells stimulated by external agonists such as angiotensin or catecholamines. Regulation by PDEs is compartmentalized, with selective interactions occurring between a given source of cGMP and PDE hydrolysis. PDE1 and/or PDE5 are also reportedly up-regulated in chronic disease conditions such as atherosclerosis or cardiac pressure-load stress and heart failure as well as in response to long-term exposure to nitrates. Such up-regulation is thought to contribute to vascular and cardiac pathophysiology and to drug tolerance. Recent studies utilizing selective PDE5 inhibitors support significant cross-signaling with NO-cGMP synthetic pathways that may be particularly helpful in treating certain disease states.

Positive effect of tadalafil, a phosphodiesterase-5 inhibitor, on fracture healing in rat femur

“…Intracellular levels of cGMP can be increased by NO or by inhibiting the breakdown through PDEs. [27] The release of NO induces dilation of the blood via accumulation of cGMP. Sildenafil and tadalafil are inhibitors of PDE5 and decrease the breakdown of cGMP, leading to enhancement of the vasodilatory effect of NO.…”

Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors

“…FRETbased cGMP indicators are also limited in resolving possible compartmentalized intracellular cGMP signaling events using confocal microscopy. It was recently suggested that in VSM cells and cardiac myocytes cGMP signaling may be spatially segregated and that this functional compartmentalization may be the cause of the unique actions of ANP and NO (19)(20)(21)(22)(23). The goal of this study was to develop previously undescribed non-FRET biosensors suitable to monitor the temporal changes of [cGMP] i in response to low-nanomolar NO or ANP, and to investigate the spatial patterning of [cGMP] i , using real-time, confocal imaging techniques.…”

Relax

“…In fact, the scenario might be much more complicated because an increase in cAMP, as a result of the inhibition of the pump, might also impinge on the activity of other PDEs, PDE1 and PDE3, and cross-regulate cGMP signaling. Although PDE1 is known to be expressed in smooth muscle cells, 19,20 its inhibition had no impact on NO-generated cGMP in this investigation. The lack of commercially available specific PDE1 inhibitors and the fact that PDE1 activity is largely dependent on intracellular Ca 2+ might explain these results.…”