In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo. Immunohistology has shown that PDE5 localizes in heart cells at the sarcomere z-disk, but can also be found in diffuse amounts in the cytosol. Increased expression of PDE5 has also been measured in hypertrophic disease and has been linked to oxidative stress, and PDE5 inhibition has shown beneficial effects in the failing heart. In an experiment, PDE5 overexpression was found to contribute to worsened pathological remodeling after mouse cardiomyocytes experienced myocardial infarction. The role of PDE5 in heart failure and cardiac treatment involving PDE5 inhibitors have been major areas of focus for both lab and clinical studies. PDE5-inhibiting drugs There are now four oral erectile dysfunction (ED) drugs: Viagra (sildenafil) by Pfizer, Levitra (vardenafil) by Bayer Pharmaceutical and Glaxo-Smith-Kline-Beecham/Schering Plough, Cialis (tadalafil) by Lilly-ICOS, and Stendra (avanafil) by Auxilium Pharmaceuticals. For all practical purposes, these drugs including Viagra, Levitra, and Cialis are the first line of oral treatment for males with erectile dysfunction. In certain circumstances in which the males are young, no comorbidities are recognized, and laboratory tests are normal, one should look for the underlying cause of their erectile dysfunction before instituting treatment since the disease process may be more serious than the ED itself. In some cases, treatment of the underlying cause may resolve the sexual dysfunction. Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction for patients receiving protease inhibitors, including Reyataz. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. PDE5-inhibiting drugs are very effective. PDE5 inhibitor drugs appear to work in men regardless of why they have erectile dysfunction — including vascular disease, nerve problems, and even psychological causes. PDE5-inhibiting drugs can cause a number of minor side-effects, including headache, lightheadedness, dizziness, flushing, nasal congestion, and changes in vision. In 2011, the Food and Drug Administration (FDA) issued additional guidance on regulations related to cGMP manufacture and packaging.