Effects of glitazones on blood pressure and vascular structure in mesenteric resistance arteries and basilar artery from genetically hypertensive rats.
1. The effects of two of the glitazone (thiazolidinedione) class of drugs, namely rosiglitazone and pioglitazone, on blood pressure and vascular remodelling in the New Zealand genetically hypertensive (GH) rat model were investigated. 2. In the first study, a GH group given rosiglitazone (5 mg/kg per day) from the age of 7 to 12 weeks was compared with a GH control group. In the second study, GH rats were given either pioglitazone, simvastatin, valsartan or combinations of pioglitazone with simvastatin or valsartan (all drugs at a dose of 10 mg/kg per day). 3. Tail-cuff systolic blood pressure was measured weekly. At the end of the experiment, blood vessels were fixed by perfusion and samples of mesenteric resistance arteries (MRA), second-order branches and basilar artery were embedded in Technovit and serial sections were cut and stained with Giemsa for stereological analysis. Media width, medial cross-sectional area and lumen diameter were determined and the ratio of media width/lumen diameter was calculated. 4. Rosiglitazone significantly reduced blood pressure in GH rats. 5. In MRA, rosiglitazone had a hypotrophic effect on media, reduced lumen diameter and reduced media/lumen ratio (P<0.001). 6. In basilar artery, there was also a hypotrophic effect of rosiglitazone on media and reduced media/lumen ratio (P<0.001). 7. Pioglitazone slowed down the rate of blood pressure increase with age in GH rats and had a greater effect on blood pressure when given in combination with simvastatin. 8. Pioglitazone had a hypotrophic effect on the media of MRA and basilar artery. The hypotrophic effect was enhanced when pioglitazone was given in combination with simvastatin. The media/lumen ratio was reduced by pioglitazone; in MRA, combination treatment with simvastatin reduced the ratio further to normal and, with valsartan, to below normal. In basilar artery, the media/lumen ratio was reduced further by both combination treatments, but was lowest in the pioglitazone-valsartan combination group. 9. The significant effects on MRA and basilar artery structure (and, thus, haemodynamics) seen after rosiglitazone monotherapy and after pioglitazone, given alone and in combination with simvastatin or valsartan, may well indicate a glitazone class effect on vascular structure and, hence, cardiovascular function.
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
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000473:pathology; D000077205:Pioglitazone; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D000077154:Rosiglitazone; D019821:Simvastatin / Q000008:administration & dosage; D013777:Tetrazoles / Q000008:administration & dosage; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013777:Tetrazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000068756:Valsartan; D019821:Simvastatin; D014633:Valine; D000077205:Pioglitazone