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
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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