Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study
Autor: | Miodrag Janić, Mojca Lunder, Alenka France Štiglic, Aleš Jerin, Milan Skitek, Darko Černe, Janja Marc, Gorazd Drevenšek, Mišo Šabovič |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Indoles Time Factors Physiology Aorta Thoracic Blood Pressure 030204 cardiovascular system & hematology Pharmacology Fatty Acids Monounsaturated chemistry.chemical_compound 0302 clinical medicine biology Heart Receptor Endothelin A Vasodilation Nitric oxide synthase Cholesterol Valsartan Molecular Medicine Drug Therapy Combination Female medicine.drug medicine.medical_specialty Endothelin receptor type A Nitric Oxide Synthase Type III Myocardial Reperfusion Injury In Vitro Techniques Arginine Nitric Oxide Nitric oxide 03 medical and health sciences Therapeutic index Coronary Circulation Internal medicine medicine Animals Rats Wistar Fluvastatin Dose-Response Relationship Drug business.industry Myocardium Disease Models Animal 030104 developmental biology Blood pressure Endocrinology chemistry biology.protein Hydroxymethylglutaryl-CoA Reductase Inhibitors business Asymmetric dimethylarginine Angiotensin II Type 1 Receptor Blockers |
Zdroj: | Vascular Pharmacology. 99:45-52 |
ISSN: | 1537-1891 |
Popis: | Background Statins and sartans can, in therapeutic doses, induce pleiotropic cardiovascular effects. Similar has recently been shown also for sub-therapeutic doses. We thus explored and compared the cardiovascular pleiotropic efficacy of sub-therapeutic vs. therapeutic doses. Methods Wistar rats were randomly divided into 7 groups receiving fluvastatin, valsartan and their combination in sub-therapeutic and therapeutic doses, or saline. After 6 weeks, the animals were euthanised, their hearts and thoracic aortas isolated, and blood samples taken. Endothelium-dependent relaxation of the thoracic aortae and ischaemic-reperfusion injury of the isolated hearts were assessed along with the related serum parameters and genes expression. Results Fluvastatin and valsartan alone or in combination were significantly more effective in sub-therapeutic than therapeutic doses. The sub-therapeutic combination greatly increased thoracic aorta endothelium-dependent relaxation and maximally protected the isolated hearts against ischaemia-reperfusion injury and was thus most effective. Beneficial effects were accompanied by increased levels of nitric oxide (NO) and decreased levels of asymmetric dimethylarginine (ADMA) in the serum (again prominently induced by the sub-therapeutic combination). Furthermore, nitric oxide synthase 3 (NOS3) and endothelin receptor type A (EDNRA) genes expression increased, but only in both combination groups and without significant differences between them. In the therapeutic dose groups, fluvastatin and valsartan decreased cholesterol values and systolic blood pressure. Conclusion Sub-therapeutic doses of fluvastatin and valsartan are more effective in expressing cardiovascular pleiotropic effects than therapeutic doses of fluvastatin and/or valsartan. These results could be of significant clinical relevance. |
Databáze: | OpenAIRE |
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