Pharmacologic Modulators of Soluble Guanylate Cyclase/Cyclic Guanosine Monophosphate in the Vascular System - From Bench Top to Bedside

Elias   B.   Jackson; Somnath      Mukhopadhyay; David   A.   Tulis

Abstract

Guanosine-dependent cyclic nucleotide second messenger signaling has been implicated as a pivotal mediator of vascular function under both homeostatic eutrophic conditions as well as in the inimical environs of injury and/or disease. This biological system is highly regulated through reciprocal, complimentary, and often redundant upstream and downstream molecular and cellular elements and feedback controls. Key endogenous factors of the guanosine-dependent cyclic nucleotide cascade include upstream gaseous activating ligands (nitric oxide, carbon monoxide), downstream substrates (cGMP-gated ion channels, cGMP-dependent protein kinases), and cGMP hydrolyzing phosphodiesterases. This intricate system also has capacity to “cross-talk” with parallel adenosine-dependent cyclic nucleotide machinery. Numerous complexes of ligands, enzymes, cofactors, and substrates present significant targets for pharmacologic modulation at the cellular, genetic, and/or molecular level eventuating therapeutically as constructive functional responses observed in vascular physiology and/or pathophysiology. Interestingly, emerging evidence based largely on transgenic mouse models challenges the historically accepted concept that this signaling system functions principally as a therapeutic modality in cardiac and vascular tissues. The general purpose of this update is to provide current information on recently described neoteric agents that impact multifaceted and critical cGMP-dependent signaling in the vascular system. Emphasis will be placed on novel agents that exert significant and often multiple actions on upstream and downstream sites and are capable of eliciting robust effects on guanosine-dependent cellular actions. Individual sections will be devoted to agents that rely on an intact and functional cyclase heme and those that operate independently of the sGC heme. Attention will be placed on the physiologic and pathophysiologic clinical manifestations of these pharmacologic regimens. This review will conclude with some thoughts for future directions for study and continued discovery of novel sGC/cGMP controllers in the vascular system at the basic science and clinical levels.

Keywords: BAY compounds, carbon monoxide, cyclic guanosine monophosphate, nitric oxide, phosphodiesterase, protein kinase, soluble guanylate cyclase, YC-1