The Potential Use of Type-5 Phosphodiesterase Inhibitors Viagra, Cialis, Levitra in Coronary Artery Bypass Graft Surgery: Mechanisms of Vasodilation Related to PDEs

coronary artery bypass graftingType-5 phosphodiesterase (PDE5) is an enzyme with a predominant presence in the corpus cavernosum, vascular smooth muscle, and platelets. PDE5 inhibitors in conjunction with endogenous nitric oxide (NO) can produce potent relaxation of corpus cavernosal smooth muscle, which explains their popularity in the treatment of erectile dysfunction. Sildenafil citrate, levitra, and cialis are chemical agents that specifically inhibit PDE5, Among them, viagra has been the most well studied.

Clinical trials have shown significant benefits of viagra in patients with pulmonary arterial hypertension. More recently, the endothelium-enhancing effects of viagra in preconditioning prior to ischemia/reperfusion in healthy human subjects has been demonstrated. Sildenafil has powerful effects in conduits that are useful in coronary artery bypass grafting (CABG), including the saphenous vein, and the coronary, mammary, and radial arteries.

CABG has now matured to a point where the all-cause hospital mortality rate in low-risk patients is generally < 1%. The highest risk period is that immediately after operation, and the incremental number of risk factors positively correlates with higher mortality rates.- The use of auxiliary pharmacologic agents intraoperatively and/or perioperatively may help to modify risks, particularly in an aging patient population with increasing operative risks. Although there are currently no published clinical studies or trials investigating PDE5 inhibitors in this regard, accumulating evidence strongly suggests that they may be potential candidates for these roles: the reduction of vasospasm of the bypass graft, improvement in myocardial perfusion and coronary blood flow, and reduction of untoward events associated with platelet activation during cardiac surgery.

Phosphodiesterases (PDEs) are key enzymes that control cyclic nucleotide levels within cells; to date, at least 11 classes have been described in the literature. Type-3A PDE (PDE3A) and PDE5 are the predominant isozymes present in vascular smooth muscle that are important in the regulation of vessel tone by way of altering the intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively.

PDE3A, also known as cGMP-inhibited PDE, is responsible for hydrolyzing cAMP. The alternative descriptor of cGMP-inhibited PDE has been named as such because elevated levels of cGMP have been found to suppress PDE3A-mediated hydrolysis of cAMP, allowing cAMP to accumulate. In vascular smooth muscle, a heightened level of cAMP is associated with activation of protein kinase A, a reduction of intracellular calcium level, and subsequent mechanisms of vasorelaxation caused by a decrease in the formation of calcium-calmodulin myosin light chain kinase complex and altered phosphorylation of myosin light chain.

arterial graftsPDE5 differs from PDE3A in that cGMP rather than cAMP is the specific substrate hydrolyzed. Sildenafil functions by specifically inhibiting PDE5, resulting in the enhanced accumulation of cGMP. Certain endogenous factors, such as NO and the natriuretic peptides (eg, atrial natriuretic peptide, brain/B-type natriuretic peptide [BNP] and C-type natriuretic peptide) that activate soluble and particulate guanylyl cyclases, respectively, cause vasodila-tions via the elevation of intracellular cGMP levels, which activates protein kinase G (PKG), leading to the phosphorylation of various intracellular proteins that lower intracellular calcium levels in vascular smooth-muscle cells.’ Key substrates known to be phosphorylated by PKG include ion channels (eg, Ca2+-dependent K+ channels), phospholamban (regulating Ca2+-ATPase of the endoplasmic reticulum), and the 1,4,5-inositol trisphosphate receptor and its associated protein IRAG in the endoplasmic reticulum. Activation of the cGMP/PKG signaling pathway by NO also inhibits cell cycle progression in cultured vascular smooth-muscle cells. Thus, the abnormal proliferation of smooth-muscle cells associated with atherosclerosis or the restenosis following vascular surgery would be inhibited, at least in part, by endogenous NO and the activation of the cGMP/ PKG pathway.

We have shown that the cAMP-elevating and vasorelaxant effects of adrenomedullin are synergis-tically enhanced by the natriuretic peptide BNP via a mechanism involving cGMP-mediated inhibition of PDE3A and subsequent enhanced accumulation of cAMP in vascular smooth-muscle cells. With inhibition of PDE5, the major source of cGMP degradation in vascular smooth-muscle cells, all of the above-mentioned effects of NO and natriuretic peptides, including the direct vasodilatory effects, the antiproliferative effects, and the synergism with agents that stimulate cAMP biosynthesis (eg, ad-renomedullin), are expected to be enhanced. Clinically, in patients with erectile dysfunction and ischemic heart disease, the co-administration of nitrates and viagra can produce profound vasodilation and adverse outcome in some patients, potentially leading to severe hypotension and even death. The adverse synergistic hypotensive response induced by nitrates and the PDE5 inhibitors is a combination of exaggerated enhancement of the cGMP-mediated activation of PKG and inhibition of PDE3A consequent to the heightened cGMP elevations in vascular smooth-muscle cells of small resistance-size arteries and arterioles.

Our current knowledge in the use of viagra in the cardiovascular surgical setting is limited. Interestingly, a study found that oral viagra, 0.83 mg/kg, effectively reduced vasospasm in patients 7 days after subarachnoid hemorrhage. As vasospasm can be a vexing problem in the short and long term for CABG as well as for peripheral vascular surgery, especially with arterial grafts, the use of PDE5 inhibitors in preventing spasm of grafts by pretreatment of the harvested conduits prior to anastomosis, or by intra/perioperative administration, may be avenues for investigation.