1. ¹Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
2. ²Pharmacology Department, Discovery Research Laboratories, Nippon Shinyaku Co. Ltd, Minami-ku, Kyoto, Japan
3. ³Department of Pharmacology, School of Pharmacy, Shujitsu University, Okayama, Japan
4. ⁴Department of Pharmaceutical Care and Health Sciences, School of Pharmacy, Shujitsu University, Okayama, Japan

Correspondence: Professor H Kawasaki, Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan. E-mail: kawasaki@pheasant.pharm.okayama-u.ac.jp

Received 28 November 2007; Revised 21 December 2007; Accepted 7 January 2008; Published online 4 February 2008.

Abstract

Background and purpose: We previously demonstrated that chronic hyperinsulinaemia induced by drinking high levels of fructose augments adrenergic nerve-mediated vasoconstriction and suppresses vasodilatation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. In this study, the effects of pioglitazone on vascular responses induced by stimulation of adrenergic nerves, CGRPergic nerves and vasoactive agents were investigated in pithed rats given 15% fructose solution to drink (FDR).

Experimental approach: To assess the effect of pioglitazone on the altered vascular responsiveness in the hyperinsulinaemic state in vivo, changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin II and CGRP were evaluated in pithed control rats and FDR either untreated or treated with pioglitazone.

Key results: In the pithed FDR, vasoconstrictor responses to SCS and to injections of noradrenaline and angiotensin II were significantly greater than those of pithed control rats. In pithed FDR with artificially increased blood pressure and blockade of the autonomic ganglia, the vasodilator responses to SCS and CGRP injection were significantly smaller than those of pithed control rats. Oral administration of pioglitazone to FDR for two weeks markedly decreased plasma levels of insulin, triglycerides and blood glucose. In FDR pioglitazone diminished the augmented vasoconstrictor responses to SCS, noradrenaline and angiotensin II, and ameliorated the decrease in vasodilator responses to SCS.

Conclusions and implications: The present results suggest that pioglitazone improves not only insulin resistance, but also the dysfunctions in vascular control regulated by adrenergic and CGRPergic nerves in the hyperinsulinaemic state.