Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats.
The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.
Henriksen
E J
EJ
Department of Physiology, University of Arizona, Tucson 85721-0093, USA. ejhenrik@u.arizona.edu
Jacob
S
S
Fogt
D L
DL
Youngblood
E B
EB
Gödicke
J
J
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D007700:Kinetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker
D000959:Antihypertensive Agents; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007093:Imidazoles; D007328:Insulin; C043482:moxonidine; D005947:Glucose