Endothelin A-receptor blockade in experimental diabetes improves glucose balance and gastrointestinal function.
Secondary complications of diabetes mellitus often involve gastrointestinal dysfunction. In the experimental Goto Kakizaki rat, a model of Type II diabetes, hyperglycaemia and reduced glucose clearance is associated with elevated plasma endothelin (ET)-1 levels and selective decreases in nitric oxide synthase in circular muscle, longitudinal muscle and neuronal elements of the gastrointestinal tract. Functionally, this is accompanied by decreased nitrergic relaxatory responses of jejunal longitudinal muscle to tetrodotoxin-sensitive electrical field stimulation. Long-term treatment with a selective ET A-type receptor antagonist, markedly reduced hyperglycaemia and restored plasma glucose clearance rates towards normal. This was associated with a restoration of N(G)-nitro-L-arginine methyl ester-sensitive relaxatory responses of jejunal longitudinal muscle to electrical field stimulation. The results indicate that beneficial effects of ETA receptor blockade on gastrointestinal function may result from an improvement in insulin sensitivity with concomitant reduction of the severity of hyperglycaemia. ETA receptor blockade may represent a new therapeutic principle for improving glucose tolerance in Type II diabetes and could be beneficial in alleviating or preventing hyperglycaemia-related secondary complications in this condition.
Clinical Pharmacology, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
Bruno
B
Balsiger
Andreas
A
Rickenbacher
Penelope Jane
PJ
Boden
Erwin
E
Biecker
Janice
J
Tsui
Michael
M
Dashwood
Jürg
J
Reichen
Sidney George
SG
Shaw
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004558:Electric Stimulation; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects / Q000503:physiopathology*; D009252:NADPH Dehydrogenase / Q000032:analysis; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors; D010646:Phentolamine / Q000494:pharmacology; D010666:Phenylpropionates / Q000627:therapeutic use*; D011433:Propranolol / Q000494:pharmacology; D011724:Pyridazines; D051381:Rats; D011919:Rats, Inbred Strains; D044022:Receptor, Endothelin A
D001786:Blood Glucose; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011724:Pyridazines; D044022:Receptor, Endothelin A; D001285:Atropine; D011433:Propranolol; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; C467894:ambrisentan; D019331:NG-Nitroarginine Methyl Ester; D010646:Phentolamine