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

Kolettis, T. M./ Kontaras, K./ Spartinos, I./ Maniotis, C./ Varnavas, V./ Koutouzis, M./ Mourouzis, I./ Papalois, A./ Pantos, C./ Kyriakides, Z. S.


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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: Animals,Cardiotonic Agents/*administration & dosage/adverse effects/*pharmacology,Dose-Response Relationship, Drug,Heart/drug effects/physiopathology,Ischemic Contracture/prevention & control,Male,Myocardial Ischemia/*physiopathology,Myocardial Reperfusion Injury/physiopathology/*prevention & control,Phosphodiesterase Inhibitors/administration & dosage/adverse effects/pharmacology,Piperazines/*administration & dosage/adverse effects/*pharmacology,Purines/administration & dosage/adverse effects/pharmacology,Random Allocation,Rats,Rats, Wistar,Sulfones/*administration & dosage/adverse effects/*pharmacology,Vasodilator Agents/administration & dosage/adverse effects/pharmacology,Ventricular Dysfunction, Left/etiology/physiopathology/prevention & control,Ventricular Function, Left/*drug effects,Ventricular Pressure/drug effects
URI: http://olympias.lib.uoi.gr/jspui/handle/123456789/22350
ISSN: 2042-7158
Link: http://www.ncbi.nlm.nih.gov/pubmed/20487218
http://onlinelibrary.wiley.com/store/10.1211/jpp.62.03.0009/asset/jpp.62.03.0009.pdf?v=1&t=h0oxy28o&s=2c50232837c3f51f8d38e6254501434eca45f032
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