Thiazolidinediones inhibit the progression of established hypertension in the Dahl salt-sensitive rat.
We evaluated the effects of two thiazolidinediones (TZDs), the potent PPARgamma agonist rosiglitazone currently being used to treat diabetes, and a structurally similar experimental compound that is a poor PPARgamma agonist, in a non-diabetic, established hypertension model with continuous measurement of blood pressure by telemetry. Hypertension was induced in male Dahl salt-sensitive rats by a three-week pre-treatment with 4% salt before initiation of treatment. Fasting blood samples were taken for analysis of a biomarker panel to assess metabolic, anti-inflammatory and antioxidant activity of the treatments. Both TZDs significantly reduced both systolic and diastolic blood pressure. When used at the maximally effective doses established for metabolic improvement, both compounds produced equivalent reduction in lipids and elevation of adiponectin, yet the poorer PPARgamma agonist produced significantly greater reductions in blood pressure. Neither compound had a significant effect on circulating glucose or insulin in this animal model. The data demonstrate that these TZDs lower blood pressure significantly in Dahl rats and that this cardiovascular pharmacology is not directly correlated with the metabolic actions or with the magnitude of PPARgamma activation. These data suggest that it may be possible to find insulin-sensitising agents that have beneficial cardiovascular pharmacology with broad applications for disease prevention.
Bolten
Charles W
CW
Discovery Research, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. charles.w.bolten@pfizer.com
Payne
Maria A
MA
McDonald
William G
WG
Blanner
Patrick M
PM
Chott
Robert C
RC
Ghosh
Sarbani
S
Arhancet
Graciela B
GB
Staten
Nicholas R
NR
Gulve
Eric A
EA
Sullivan
Patrick M
PM
Hromockyj
Alexander E
AE
Colca
Jerry R
JR
D052242:Adiponectin / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020303:Rats, Inbred Dahl; D000077154:Rosiglitazone; D017673:Sodium Chloride, Dietary; D045162:Thiazolidinediones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D052242:Adiponectin; C499920:Adipoq protein, rat; D000959:Antihypertensive Agents; D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; C488474:PNU91325; D047495:PPAR gamma; D011725:Pyridines; D017673:Sodium Chloride, Dietary; D045162:Thiazolidinediones; D000077154:Rosiglitazone