Sildenafil Improves Dynamic Vascular Function in the Brain: Studies in Patients with Pulmonary Hypertension

Abstract

Background: Prostaglandins and nitric oxide play a pivotal role in the regulation of macro- and microcirculatory blood flow distribution. Interference with both mediator systems have been implicated in cerebrovascular dysfunction. Inhaled iloprost (long-acting prostacyclin analogue) and the phosphodiesterase-5 inhibitor sildenafil have recently shown efficacy in the treatment of chronic pulmonary hypertension. We investigated the impact of these agents on cerebral microcirculatory regulation in patients suffering from this disease. Methods: In 11 patients suffering from severe pulmonary hypertension, a functional transcranial Doppler test utilizing a visual stimulation paradigm was undertaken to measure the evoked flow velocity in the posterior cerebral artery. Measurements were performed in parallel to right heart catheterization and pharmacological testing of the pulmonary vasoreactivity. After assessment of baseline measurements, inhaled iloprost and oral sildenafil were given consecutively for testing of cerebral and pulmonary vascular function. The data gained from the Doppler measurements were compared to data from 22 healthy volunteers. Results: Both substances provoked a significant reduction of pulmonary arterial pressure and vascular resistance, accompanied by minor changes in systemic vascular resistance. In contrast to these superimposable hemodynamic profiles opposite effects were observed regarding cerebral vascular tone: cerebral microvascular reactivity, as assessed by attenuation and time rate parameters, was significantly improved by sildenafil, but slightly worsened by iloprost. Conclusions: Sildenafil has beneficial effects on cerebral vascular reactivity indicative of an improvement in neurovascular coupling in patients with pulmonary hypertension. These results warrant further investigations of the influence of sildenafil on dynamic vascular function in the brain independent of the underlying disease.

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

“…Sildenafil may nevertheless increase the blood flow velocity in patients with supposed dysfunctional NO signaling, as measured by transcranial Doppler, with resulting beneficial effects on cerebral vascular reactivity [26]. The cerebrovascular effects of sildenafil are primarily reported in systems with dysfunctional NO signaling [26,44] rather than in systems in which NO-cGMP signalling is normal [25,45]. Interestingly, neuroprotective and neurorestorative effects of sildenafil are reported in animals [46][47][48], though such effect needs to be fully confirmed in humans.…”

“…Recently sildenafil/PDE5 administration was shown to reduce skeletal muscle and cardiac dysfunction and to ameliorate dystrophy in a mouse model of DMD [20][21][22], although no positive effect was found on skeletal or cardiac muscle function and brachial arterial forearm flow in 17 patients with BMD [23] or 15 patients with BMD/DMD [24]. In healthy subjects, including males and females, sildenafil does not change the cerebral blood flow (CBF) after a single oral dose of 100 mg measured by single photon emission computer tomography and transcranial Doppler [25], but it may do so in patients with dysfunctional NO signaling [26], such as patients with BMD.…”

Neurovascular Protective Function of Endothelial Nitric Oxide – Recent Advances –

“…44, 45 Interestingly, a study in patients with pulmonary hypertension suggests that sildenafil treatment improves neurovascular coupling. 46 However, in patients with a history of stroke, sildenafil reduced local or regional perfusion in one or more areas of the brain, thereby suggesting that the safety of sildenafil could be problematic in certain populations of patients. 47 Because a relatively small number of patients has been evaluated, the issue of sildenafil safety in stroke patients remains to be definitively determined.…”

Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension

“…24,25 The present study is the first to suggest that prolonged administration of a selective pulmonary vasodilator improves functional capacity in patients with HF. The improvement in quality of life in patients treated with sildenafil likely reflects enhanced exercise capacity, although other mechanisms related to direct central nervous effects of PDE5 inhibition 26,27 are possible.…”