Chronic Sildenafil Treatment Corrects Endothelial Dysfunction and Improves Hypertension

Background: Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3′5′-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension. Methods: Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months. Results: As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR. Conclusions: These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.