N-hexacosanol prevents diabetes-induced rat ileal dysfunction without qualitative alteration of the muscarinic receptor system.
We evaluated the effects of N-hexacosanol, a cyclohexenonic long-chain fatty alcohol, on muscarinic receptors in diabetic rat ileal dysfunction. Eight-week-old male SD rats were divided into four groups. After induction of diabetes (streptozotocin 50 mg/kg, i.p.), three groups were maintained for eight weeks with treatment by N-hexacosanol (0, 2 or 8 mg/kg, s.c. every day). Ileum function was investigated by organ bath studies using carbachol and KCl, and the expression levels of muscarinic M(2) and M(3) receptors were investigated by real-time polymerase chain reaction. Various concentrations of subtype-selective muscarinic antagonists, i.e., atropine (non-selective), pirenzepine (M(1) selective), methoctramine (M(2) selective), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M(1)/M(3) selective), were used in this study. In the presence and absence of these antagonists, contractile response curves to increasing concentrations of carbachol were investigated. Treatment with N-hexacosanol did not alter the diabetic status of the rats, but did significantly prevent the carbachol-induced hypercontractility in diabetic rat ileum. Estimation of the pA(2) values for atropine, pirenzepine, methoctramine, and 4-DAMP indicated that the carbacholinduced contractile response in the ileum is mainly mediated through the muscarinic M(3) receptor subtype in all groups. Furthermore, N-hexacosanol significantly prevented the diabetes-induced up-regulation of intestinal muscarinic M(2) and M(3) receptor mRNAs in streptozotocin-diabetic rats. Our data indicated that N-hexacosanol exerts preventive effects with respect to carbachol-induced hypercontractility in the diabetic rat ileum without qualitative alteration of the muscarinic receptor system.
Narimatsu
Naho
N
Department of Pathophysiological and Therapeutic Science, Division of Molecular Pharmacology, Tottori University Faculty of Medicine, Nishimachi, Yonago.
Saito
Motoaki
M
Kazuyama
Emi
E
Hisadome
Yoshie
Y
Kinoshita
Yukako
Y
Satoh
Itaru
I
Okada
Shin-Ichi
S
Suzuki
Hiroto
H
Yamada
Masashi
M
Satoh
Keisuke
K
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005233:Fatty Alcohols / Q000494:pharmacology*; D005769:Gastrointestinal Motility; D007077:Ileal Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000502:physiology*
D005233:Fatty Alcohols; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C051942:1-hexacosanol