Dose-dependent effects of sildenafil on post-ischaemic left ventricular function in the rat isolated heart

Abstract

Abstract Objectives Sildenafil may be beneficial during myocardial ischaemia/reperfusion, but this effect may be dose-dependent, accounting for previous conflicting results. We have explored the effects of two acute and one chronic administration regimen on left ventricular function. Methods The study was conducted on 36 Wistar rats (290 ± 7 g). Sildenafil was administered 30 min before ischaemia at a low (0.7 mg/kg, n= 8) or high (1.4 mg/kg, n= 8)dosage. The chronic treatment arm (n= 8) consisted of two daily injections of sildenafil (0.7 mg/kg) for three weeks. The control group was formed by 12 rats. Ischaemic contracture, post-ischaemic recovery and hypercontracture were measured in isolated, Langendorff-perfused preparations. Key findings Ischaemic contracture tended to be lower after high-dose sildenafil, while remaining unchanged after low-dose or chronic sildenafil administration. Compared with controls (62.9 ± 2.0% of baseline developed pressure), post-ischaemic recovery was higher (P= 0.0069) after low dose (75.1 ± 2.4%), unchanged (P= 0.13) after high dose (69.1 ± 2.1%), but lower (P < 0.001) after chronic (42.9 ± 4.5%) sildenafil administration. Compared with controls (71.8 ± 3.9 mmHg), hypercontracture was higher (P= 0.0052) after chronic sildenafil administration (89.5 ± 4.1 mmHg), but similar after acute low dose (65.7 ± 3.3 mmHg, P= 0.33) or high dose (67.1 ± 4.7 mmHg, P= 0.43). Conclusions The effects of sildenafil after ischaemia/reperfusion were strongly dose-dependent. Beneficial actions on left ventricular function were evident after acute pretreatment with a low dosage, but were lost after doubling the dose. Chronic sildenafil administration deteriorated left ventricular function during ischaemia and reperfusion.