Effect of simvastatin given alone and in combination with valsartan or enalapril on blood pressure and the structure of mesenteric resistance arteries and the basilar artery in the genetically hypertensive rat model.
1. The aims of the present study were to investigate, in the New Zealand genetically hypertensive (GH) rat model, the effects of treatment with simvastatin, alone or in combination with valsartan or enalapril, on blood pressure (BP) and structural remodelling of mesenteric resistance arteries (MRA) and of the basilar artery, an artery that plays a major role in the regulation of cerebral resistance. 2. Genetically hypertensive rats were treated with simvastatin at two dose levels (5 and 10 mg/kg per day) and simvastatin in combination with valsartan or enalapril (also 5 and 10 mg/kg per day) from the age of 7 to 12 weeks. Systolic BP and bodyweight were measured weekly. 3. At the end of the experiment, following fixation by perfusion, MRA and the basilar artery were excised and embedded in Technovit (a glycol methacrylate medium; Heraeus Kulzer, Werheim, Germany). Serial sections were cut and stereological techniques used to determine tunica media width and cross-sectional area (CSA), lumen diameter and the ratio of media width/lumen diameter. 4. Simvastatin monotherapy did not lower BP at either dose. In the high- and low-dose groups, the combination of simvastatin + enalapril lowered BP more than with enalapril alone; this was also true for the simvastatin + valsartan combination in the lower-dose group. 5. The MRA were hypotrophically remodelled by the 10 mg/kg per day dose of simvastatin; the 5 mg/kg per day dose caused hypotrophic remodelling with decreased media/lumen ratio. Valsartan and enalapril caused hypotrophic remodelling together with outward remodelling of the lumen in the 10 mg/kg per day valsartan group and, in all groups, a reduction in the media/lumen ratio, with the greatest effect observed in the high-dose groups. 6. The combination treatments of simvastatin + valsartan and simvastatin + enalapril did not have any consistent extra effect on MRA remodelling. 7. In the basilar artery, high-dose simvastatin had a hypotrophic effect on the media and both doses reduced the media/lumen ratio independently of any change in BP. 8. Simvastatin given in combination with valsartan produced a slight further reduction in medial CSA, media width and ratio. In combination with enalapril, there was little consistent additional effect. 9. Simvastatin monotherapy hypotrophically remodelled the media of the basilar artery in the GH rat model, even in the absence of changes in BP. A similar structural effect may explain, in part, the reduction in stroke seen in patients treated with statins.
Ledingham
Janet M
JM
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. janet.ledingham@stonebow.otago.ac.nz
Laverty
Richard
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology*; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000517:prevention & control; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D019821:Simvastatin / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000068756:Valsartan; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; D019821:Simvastatin; D014633:Valine