Mammalian single membrane-spanning guanylyl cyclases exist in at least seven varieties, including GC-A, B, C, D, E, F, and G. Guanylyl cyclases catalyze the conversion of GTP to cGMP and pyrophosphate. Nitric oxide, bicarbonate, and natriuretic peptides such as ANP and BNP, activate the guanylyl cyclase enzymes, which then form the cyclic GMP. Other activators of guanylyl cyclase enzymes include uroguanylin, guanylin, and guanylyl cyclase activating proteins. The cyclic GMP then serves as an intracellular second messenger that controls blood pressure, cardiac hypertrophy, sexual arousal, gut peristalsis, platelet aggregation, neurotransmission, long bone growth, lipolysis, intestinal fluid secretion, phototransduction, and oocyte maturation.[3]

PDE3 is an enzyme that regulates vascular smooth muscle contractility as well as cardiac myocyte contractility. PDE 3 also regulates the phenotypic switch in vascular smooth muscle and also regulates the response to stress. PDE 3 interacts with L-type calcium channels and the cardiac sarcoplasmic reticulum calcium pump (SERCA2) to modulate cardiac myocyte contractility and relaxation.[6]

PDE 5 is an enzyme found in the smooth muscle of the corpus cavernosum that cleaves and degrades cGMP to 5’GMP. PDE 5 inhibitors and cGMP have similar structures, both bind competitively to PDE 5 and inhibit cGMP hydrolysis, thus enhancing the effects of NO. The erection then prolongs as a result of the increase in cGMP in smooth muscle cells. However, after PDE 5 inhibitor administration, adequate sexual stimulation is still necessary for the erection to occur as PDE 5 inhibitors do not directly affect corpus cavernosum smooth muscle relaxation.[7]

cGMP mediates many physiologic processes and cell types in the cardiovascular system. Dysfunctional signaling at any step of the cascade, including cGMP synthesis, effector activation, or cGMP breakdown, have been present in many cardiovascular diseases such as hypertension and atherosclerosis as well as cardiac hypertrophy and heart failure.

Guanylyl cyclase plays an important role in cardiac muscle relaxation. ANP and BNP are produced and released by cardiac muscle when there is an increase in myocardial wall stretch and/or pressure, an increase in catecholamines, arginine vasopressin, angiotensin 2, endothelin, and glucocorticoids. ANP and BNP are natriuretic peptides and both bind to membrane-associated guanylyl cyclase receptors (also called NPRs). Of the seven mammalian membrane-associated guanylyl cyclases, the NPR A and NPR B participate in natriuretic peptide pathways.  ANP and BNP activate NPR A to regulate body volume homeostasis, blood pressure, and local anti-hypertrophic effects in the myocardium.[8][9]

Guanylyl cyclase plays a prominent role in the process of erection as well. During sexual arousal, nerve terminals and endothelial cells in the corpus cavernosum. NO activates guanylate cyclase, which then converts guanosine triphosphate (GTP) into cyclic guanosine triphosphate (cGTP), triggering a cGMP dependent cascade of events. Smooth muscle relaxation then occurs when cGMP accumulates in the corpus cavernosum to increase blood flow to the penis.[7]

Nitrates can relieve angina by acting as a vasodilator. Nitrates reduce symptomatic and silent ischemic episodes in coronary heart disease patients with ST-segment alterations. These anti-ischemic effects can improve prognosis by infarct prevention and prevention of deterioration of left ventricular function due to chronic myocardial ischemia. Nitrates decrease the frequency of ischemic episodes and reduce the number of anginal attacks that produce clinical symptoms. Nitrates decrease preload, as vasodilation pools blood into distal extremities and decrease the blood returning to the heart.[8]

Sildenafil, vardenafil, tadalafil, and avanafil are PDE 5 inhibitors that are first-line for management of erectile dysfunction in men. PDE 5 is an enzyme found in the smooth muscle of the corpus cavernosum that cleaves and degrades cGMP to 5’GMP. PDE 5 inhibitors bind and inhibit PDE 5, inhibiting cGMP hydrolysis, thus enhancing the effects of NO. The erection then prolongs as a result of the increase in cGMP in smooth muscle cells.[7]

Nitric oxide-cGMP enhancers are also useful in treating primary pulmonary hypertension; these act by dilating the pulmonary arteries and bringing the mean pulmonary artery pressure down, thus reducing right ventricle afterload; this has shown functional class improvement, cardiac index improvement and improvement in 6-minute walking distance. There have been trials in which nitrates have been combined with other agents like endothelin receptor blocker and prostaglandins to show improvements. But only combination therapy which is FDA approved combines ambrisentan (endothelin receptor blocker) and tadalafil (PDE5 inhibitor). There have been trials in which nitrates and sildenafil have been used concomitantly for treating pulmonary hypertension in congestive heart failure.[10]

Nitrates can cause excessive hypotension. Vasodilation increases blood flow to distal extremities, decreasing blood flow returning to the brain, which can cause symptomatic hypotension and headaches, in which case, nitrate therapy should be discontinued. Hypertensive crisis can occur if nitrates are used in patients with acute inferior myocardial infarction associated with right ventricular dysfunction or infarction, or with concurrent use of PDE 5 inhibitor or N-acetylcysteine.[11]

Nitrate tolerance can occur with long term continuous administration as it decreases vasodilatory effects. To prevent tolerance from long-term nitrate therapy, providers should advise a 10 to 12-hour nitrate-free interval; thus nitrates would be administered only for a portion of each day. Also, during the nitrate-free periods, some patients might develop an increase in angina and will require sublingual nitroglycerin for short term therapeutic relief.[12]