Enhancement of methoxamine-induced contractile responses of rat ventricular muscle in streptozotocin-induced diabetes is associated with alpha1A adrenoceptor upregulation.
OBJECTIVE
To clarify the time-related changes in cardiac function and the mechanism underlying the cardiac dysfunction present in diabetes mellitus, we studied mechanical responses induced by alpha(1)- and beta-adrenoceptors, the Ca(2+)-entry promoter Bay K 8644- and ryanodine (an agent known to inhibit Ca(2+) release from the sarcoplasmic reticulum) in papillary muscles from streptozotocin (STZ)-induced diabetic and age-matched control rats.


METHODS
Male Wistar rats received a single injection of STZ (60 mg kg(-1)) via the tail vein to induce diabetes. For the mechanical studies, papillary muscle preparations were suspended in an organ bath and isometric contractions were measured in 1-, 4-, and 10-week STZ-induced diabetic and age-matched control rats.


RESULTS
In 1-week diabetic rats, the contractions induced by isoproterenol, methoxamine and Bay K 8644 were unchanged (vs. age-matched controls). In 4-week diabetic rats, (a) the isoproterenol- and Bay K 8644-induced contractions were impaired, (b) sensitivity to ryanodine was reduced, whereas (c) the methoxamine-induced contraction was unchanged. In 10-week diabetic rats, the isoproterenol- and Bay K 8644-induced contractile responses were impaired and the sensitivity to ryanodine was reduced, but in sharp contrast the methoxamine-induced contraction was enhanced. Both the mRNA level for the alpha(1A) adrenoceptor (but not the alpha(1B) or alpha(1D) mRNAs) and alpha(1A) adrenoceptor protein were increased in 10-week diabetic rats (vs. age-matched controls).


CONCLUSIONS
These results suggest that impairments of beta-adrenergic and Ca(2+)-handling mechanisms occur early in the development of cardiomyopathy in STZ-induced diabetic rats, and that this is followed by augmentation of alpha(1A) adrenoceptor-mediated inotropy due to alpha(1A) adrenoceptor upregulation.
Kamata
K
K
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan. kamata@hoshi.ac.jp
Satoh
T
T
Matsumoto
T
T
Noguchi
E
E
Taguchi
K
K
Kobayashi
T
T
Tanaka
H
H
Shigenobu
K
K
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012433:Ryanodine / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
C547715:Adra1a protein, rat; D000318:Adrenergic beta-Agonists; D002120:Calcium Channel Agonists; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D012433:Ryanodine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D008729:Methoxamine; D007545:Isoproterenol