Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function

Abstract

Abstract-Cyclic GMP (cGMP) made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an importantregulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals. The ability of smooth muscle cells (SMCs) to utilize different combinations of phosphodiesterase (PDE) isozymes allows cGMP to mediate these multiple processes. For example, PDE5 as a major cGMP-hydrolyzing PDE effectively controls the development of smooth muscle relaxation. In order for contraction to occur, PDE5 is activated and cGMP falls. Conversely, blockade of PDE5 activity allows the relaxation cycle to be prolonged and enhanced. A recently shown direct activation of PDE5 by cGMP binding to the GAF A domain suggests that this regulatory site might be a target for new drug development. The calcium surge associated with vasoconstrictor initiated contraction also activates a calcium/calmodulin-dependent PDE (PDE1A). Together, PDE5 and PDE1A lower cGMP sufficiently to allow contraction. Longer term, both PDE5 and PDE1A mRNA are induced by chronic stimulation of guanylyl cyclase. This induction is a major cause of the tolerance that develops to NO-releasing drugs. Finally, high levels of cGMP or cAMP also act as a brake to attenuate the proliferative response of SMCs to many mitogens. After vessel damage, in order for SMC proliferation to occur, the levels of cGMP and cAMP must be decreased. In humans, this decrease is caused in large part by induction of another Ca 2ϩ /calmodulin-dependent PDE (PDE1C) that allows the brake to be released and proliferation to start. Key Words: cyclic GMP Ⅲ smooth muscle function T he cyclic nucleotide second messengers, cAMP and cGMP, have been shown to regulate a wide variety of processes in many different tissues of the body and have been suggested to regulate many more. In fact, they have been proposed to modulate so many different processes that, until recently, it has been difficult to understand how these simple, small, second messenger molecules could provide both the specificity of action and the diversity of function necessary for such regulation. Particularly problematic has been an understanding about how both very rapid and very slow processes can be modulated by the same mechanisms.A major conceptual advance in our understanding of the mechanisms by which such temporally and spatially disparate processes can be controlled was the realization that many different isozymes for synthesis (cyclases) and degradation (phosphodiesterases, PDEs) of cAMP and cGMP are present Original

Inhaled Nitric Oxide

“…The physiological actions of cGMP are limited to its area of synthesis by its hydrolysis to GMP by cyclic nucleotide phosphodiesterases (PDE) or by its export from the cell. Of the 11 reported PDE isozymes, PDE5 is considered to be the most active cGMP-hydrolyzing PDE in smooth muscle (for review, see the work by Rybalkin et al 8 ). PDE5 has a high affinity for cGMP and is selectively inhibited by compounds such as zaprinast, sildenafil, and verdenafil.…”

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus

“…The cyclic nucleotides cAMP and cGMP are considered the main intracellular secondary messengers involved in smooth muscle relaxation (Omori and Kotera 2007;Rybalkin et al 2003). These molecules are degraded by a family of enzymes known as phosphodiesterases (PDEs).…”

“…There are now known to be 11 diVerent PDE families expressed in mammalian tissues. Depending on the species, the major PDEs present in vascular smooth muscle are PDE1, PDE3 and PDE5 (Moreno et al 2004;Omori and Kotera 2007;Rybalkin et al 2003). PDE3 s are termed cGMP-inhibited cAMP PDEs, whereas PDE5 speciWcally hydrolyzes cGMP (Moreno et al 2004;Omori and Kotera 2007;Rybalkin et al 2003).…”

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.…”