A lack of synergistic interaction between insulin and pioglitazone on reactivity of rat aorta from chronically high dose insulin-treated diabetic rats.
Our goal was to determine whether hyperinsulinaemic and diabetic state can affect vaso-depressor effects of insulin and pioglitazone (PIO), an insulin-sensitizing thiazolidinedione drug. For this purpose, we established an experimental type 2 diabetic model (streptozotocin-nicotinamide model) in adult male rats (DIA group) and some of them were treated with chronically high-dose insulin for 14 weeks (INS-T DIA group). Blood pressure, glucose, HbA(1C), triglyceride, cholesterol, plasma insulin levels and body weight were measured. Endothelium-denuded aortic rings were suspended in tissue baths for reactivity studies. Cumulative concentration-response curves of serotonin (5-hydroxytryptamine; 5-HT) were evaluated before and after 1 h incubations with insulin (10(-7) or 10(-4) U/l), or PIO (10 micromol/l) or insulin plus PIO. PIO or higher concentration of insulin (10(-4) U/l), each alone, attenuated 5-HT induced contractions in both groups of aortae. Vasodepressor effect of insulin was diminished by 12% +/- 4% in aortae from INS-T DIA group. The presence of PIO in the bath did not affect impaired vasodepressor response of insulin. Contractions induced by KCl, or Bay K 8644 were partly inhibited after PIO incubations, with similar E(max) and pD(2) values in both groups of aortae. The results indicate that PIO does not modulate directly vasodepressor effect of insulin in hyperinsulinaemic/diabetic state. But, the direct vasodepressor effect of PIO, partly by Ca(2+) channel inhibition, may be beneficial by improving insulin utilization due to increasing blood flow to the insulin-sensitive tissues in hyperinsulinaemic/diabetic state.
Sahilli
M
M
Ankara University, Faculty of Pharmacy, Department of Pharmacology, Tandogan, Ankara, Turkey.
Irat
A M
AM
Işik
A C
AC
Karasu
C
C
Ozansoy
G
G
Ari
N
N
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D014280:Triglycerides; D014662:Vasoconstrictor Agents; D012701:Serotonin; D002784:Cholesterol; D005947:Glucose; D000077205:Pioglitazone