It is unclear to what extent this observation reflects the protective effects of PDE5 inhibitors against cardiovascular and renal disease. Sildenafil has been shown to be at least as effective as calcium channel blockers in treating severe Raynaud's phenomenon (RP) associated with systemic sclerosis and digital ulceration. When given sildenafil for 4 weeks subjects had reduced mean frequency and duration of Raynaud attacks and a significantly lowered mean Raynaud's condition score. The capillary blood flow velocity also increased in each individual patient and the mean capillary flow velocity of all patients increased significantly. These results came without significant reductions of the systemic blood pressure. However, the therapeutic effects of PDE5 inhibitors in primary (idiopathic) RP are less well defined. Sildenafil has been shown to significantly improve neurovascular coupling without affecting overall cerebral blood flow by increasing brain levels of cGMP, evoking neurogenesis and reducing neurological deficits in rats 2 or 24 hours after stroke. These experimental data suggest that PDE5 inhibitors may have a role in promoting recovery from stroke. However, studies in humans remain inconclusive. Adding PDE5 inhibitors to SSRI drugs (e.g. paroxetine) for the treatment of premature ejaculation could result in better ejaculatory control according to recent studies. Possible mechanism is based on nitric oxide (NO)/cGMP transduction system as a central and peripheral mediator of inhibitory non-adrenergic, non-cholinergic nitrergic neurotransmission in the urogenital system. PDE5 is expressed in clitoral corpus cavernosum and in vaginal smooth muscle and epithelium. Therefore, it is possible that PDE5 inhibitors could affect female sexual arousal disorder but further research is needed. Increased levels of cGMP have been shown to occur in human-cultured vaginal smooth muscle cells treated with a PDE5 inhibitor suggesting involvement of the NO/cGMP axis in the female sexual response. The similarity of many PDE5 inhibitors to the structure of many of the analogs of caffeine that are also suggests that in the future, it may be possible to design an PDE5 inhibitor that, like caffeine, is also an adenosine antagonist. PDE5 is an enzyme that was first purified in 1980 from a rats lung. PDE5 converts intracellular cGMP to the nucleotide GMP. Many tissues contain PDE5, such as lungs, kidneys, brain, platelets, liver, prostate, urethra, bladder and smooth muscles.