Cardiovascular Effects of Phosphodiesterase 5 Inhibitors

Abstract

Phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil and tadalafil, are now approved for the treatment of erectile dysfunction. They inhibit the cGMP-specific isoform 5 of phosphodiesterase, resulting in cGMP accumulation, which, for example in smooth muscle cells, reduces muscular tone. In the cardiovascular system, they slightly reduce arterial systemic blood pressure. This moderate effect was also shown in combination with many antihypertensive drugs. But the important contraindication is the concomitant use of PDE 5 inhibitors with any drug serving as a nitric oxide donor, as this combination can lead to significant arterial hypotension. Caution is needed in patients on alpha-blocking agents. In general, this class of drugs was not shown to exhibit direct deleterious effects on the myocardium or promote arrhythmias. Furthermore, statistical evaluations did not demonstrate an increased risk for patients taking PDE 5 inhibitors in comparison with an adequate control population. Many patients suffering from erectile dysfunction may be characterized by multiple cardiovascular risk factors or even ischemic heart disease, suggesting an increased baseline risk. While in many forms of erectile dysfunction, these agents seem to be very effective, it becomes clear that endothelial dysfunction is an attractive target of PDE 5 inhibitors and may also be the underlying cause in many types of erectile dysfunction. In addition, these agents seem to be very effective in lowering pulmonary arterial pressure, which might provide the opportunity to treat primary and some forms of secondary pulmonary hypertension, perhaps in combination with inhaled nitric oxide or other pulmonary arterial vasodilators. Sildenafil was approved for treatment of primary arterial hypertension in the U.S. in June 2005. Recently, direct cardioprotective effects were described in animal research, resembling preconditioning-like effects, which may, under certain conditions, also be applicable in clinical research.

Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway

“…36 -38 Sildenafil is a potent antagonist of tissue phosphodiesterase 5 activity and results in the intracellular accumulation of cGMP. 39 Our data indicate that sildenafil significantly increased ischemic tissue cGMP at day 21 but not at day 7. The reason for this is not clear, but could involve changes in tissue consumption of cGMP relative to its production (ie, a greater need and consumption during early periods of ischemia which diminish over time).…”

Nonarteritic anterior ischemic optic neuropathy with PDE-5 inhibitors for erectile dysfunction

“…Several patients with NAION occurring in the context of PDE-5 inhibitor use were noted to have a 'disk at risk' on examination of the fellow eye and other vascular risk factors, such as hypertension and diabetes, suggesting a baseline increased risk of developing NAION ( Table 1). As PDE-5 inhibitors are known to mildly reduce systemic blood pressure, 45 and they are most likely to be taken prior to sexual activity in the evening, it has been postulated that they might increase the risk of NAION by exacerbating nocturnal hypotension. 46,47 This hypothesis is supported by the observation that a considerable number of the patients with NAION following PDE-5 inhibitor use awoke with visual loss the morning after drug ingestion (Table 1).…”

Effects of mirodenafil on the hemodynamics in hypertensive patients taking amlodipine

“…[4,5] Considering that both PDE5 inhibitors and antihypertensive drugs have vasodilatory effects, there is a possibility that co-administration of the two classes of drugs would result in synergistic hemodynamic effects. [6][7][8] When PDE5 inhibitors were administered to hypertensive patients who are on any of the several antihypertensive agents (e.g. β-blockers, calcium channel blocker, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics), there was a synergistic decreasing effect in blood pressure.…”

“…β-blockers, calcium channel blocker, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics), there was a synergistic decreasing effect in blood pressure. [6,9,10] Mirodenafil is a novel PDE5 inhibitor that has been approved in Korea. [11,12] Preclinical studies have shown that mirodenafil has an equivalent pharmacologic effect for the treatment of ED as other PDE5 inhibitors do, and it has a high selectivity for PDE5.…”