title: Effect of combination treatment of S-amlodipine with peroxisome proliferator-activated receptor agonists on metabolic and cardiovascular parameters in Zucker fa/fa rats.
abstract: BACKGROUND
  Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, impaired glucose tolerance and insulin resistance associated with dyslipidemia and hypertension. The available drugs are not sufficiently efficacious in reducing cardiovascular risk and restoring normal glucose metabolism associated with type 2 diabetes as a mono- or a combination therapy. The present study examined the combined effects of an antihypertensive (S-Amlodipine) and an insulin-sensitizing agent, peroxisome proliferator-activated receptor (PPAR) agonists (Pioglitazone and Ragaglitazar), on cardiovascular risk factors in aged diabetic and insulin-resistant Zucker fa/fa rats.
  
  
  METHODS
  Following combination treatment for 14 days, blood pressure (BP), serum glucose, total cholesterol and triglycerides were measured. Aortic ring study was conducted to determine the effect of combination treatments on phenylephrine-induced vasoconstriction and acetylcholine (Ach)-induced vasorelaxation.
  
  
  RESULTS
  In combination, S-Amlodipine and Pioglitazone significantly reduced blood glucose (115.1 ± 6.6 vs. 81.7 ± 4.2), BP (184.4 ± 5.0 vs. 155.1 ± 5.0), serum triglycerides (362.5 ± 47.5 vs. 211.1 ± 23.7) and glucose intolerance when compared with vehicle treated Zucker fa/fa rats. Similar results were observed with the combination of S-Amlodipine and Ragaglitazar (Triglycerides, 362.5 ± 47.5 vs. 252.34 ± 27.86; BP, 184.4 ± 5.0 vs. 159.0 ± 8.0) except for serum glucose. ACh-induced vasorelaxation in aortic rings was also superior with both of the combinations compared to individual treatment. Furthermore, there was less body weight gain and food intake with S-Amlodipine and Pioglitazone combination in Zucker fa/fa rats. S-Amlodipine itself caused significant reduction in glucose (115.1 ± 6.6 vs. 89.7 ± 2.7) and BP (184.4 ± 5.0 vs. 156.1 ± 4.0) with improvement in insulin sensitivity observed through oral glucose tolerance test.
  
  
  CONCLUSIONS
  The results suggest that a combination of PPAR agonists and S-Amlodipine has partial benefits in improving the cardiovascular risk factors such as reduction in triglyceride levels, associated with chronic type 2 diabetes, and therefore may be utilized as an approach for addressing some of these devastating metabolic syndrome complications.
authors.affiliation: Department of Clinical Neuroscience, University of Calgary, 3330 Hospital Drive, NW, Calgary, Alberta T2N4N1, Canada. singhb@ucalgary.ca.
authors.forename: Bhagat
authors.initials: B
authors.lastname: Singh
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Sangle
authors.forename: Jeya
authors.initials: J
authors.lastname: Murugan
authors.forename: Rinku
authors.initials: R
authors.lastname: Umrani
authors.forename: Subhasis
authors.initials: S
authors.lastname: Roy
authors.forename: Onkar
authors.initials: O
authors.lastname: Kulkarni
authors.forename: Arvind
authors.initials: A
authors.lastname: Semwal
authors.forename: Mk
authors.initials: M
authors.lastname: Unnikrishnan
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain