Fluvastatin remodels resistance arteries in genetically hypertensive rats, even in the absence of any effect on blood pressure.
1. The aims of the present study were, first, to determine whether, in the genetically hypertensive (GH) rat, fluvastatin would lower blood pressure and remodel mesenteric resistance arteries (MRA) and the basilar artery and, second, to see whether treatment with a combination of fluvastatin and the angiotensin receptor antagonist valsartan would have any extra beneficial effect on blood pressure and vascular remodelling. 2. Male GH rats had tail-cuff systolic blood pressure (SBP) monitored weekly from the age of 7 to 12 weeks. Groups (n = 12-14) were treated with fluvastatin (4 mg/kg per day), valsartan (5 mg/kg per day), both mixed in with chow, or a combination of fluvastatin 4 mg/kg per day + valsartan 5 mg/kg per day. Untreated GH and a group of normotensive Wistar (N) rats served as control groups. 3. At 12 weeks of age, intra-arterial (i.a.) blood pressure was measured by femoral cannulation and rats were then perfused (at the SBP of the animal) with Tyrode's solution containing heparin and papaverine followed by 2.5% glutaraldehyde in Tyrode's solution; MRA and basilar arteries were embedded in Technovit. Serial sections were cut and Giemsa stained and stereological methods used to obtain media width, lumen diameter, medial cross-sectional area (CSA) and the ratio of media width to lumen diameter. Hearts were weighed to determine left ventricular (LV) mass. 4. Fluvastatin had no effect on blood pressure or LV mass, whereas valsartan given alone or with fluvastatin significantly reduced both parameters. 5. In MRA, fluvastatin reduced medial CSA, increased lumen size and, therefore, probably decreased vascular resistance. The media/lumen ratio was reduced to a level below that seen with the combination treatment and to below that of the N group. 6. In the basilar artery, fluvastatin and valsartan showed similar outward remodelling of the lumen and reduction in the media/lumen ratio. The combination treatment group showed, in addition, a reduction in medial CSA and an even lower ratio than the GH group on fluvastatin or valsartan alone or the N group. 7. Although fluvastatin has no effect on blood pressure, it does cause significant remodelling of MRA and the basilar artery. These beneficial structural changes in a peripheral resistance artery bed and in an artery involved in regulating resistance in the brain are worthy of further study.
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. janet.ledingham@stonebow.otago.ac.nz
Janet M
JM
Ledingham
Richard
R
Laverty
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D000077340:Fluvastatin; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D014655:Vascular Resistance / Q000187:drug effects*
D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin