Augmentation of insulin-stimulated ANP release through tyrosine kinase and PI 3-kinase in diabetic rats.
The aim of present study was to define the effects of insulin on atrial dynamics and ANP release and its modification in diabetic rats. An isolated perfused beating atrial model was used from control and diabetic rats. Insulin was perfused with and without an inhibitor for tyrosine kinase or phosphatidylinositol 3-kinase (PI 3-kinase). Insulin increased the release of ANP and decreased atrial contractility in a dose-dependent manner. During the perfusion of 10(-10)M insulin, the release of ANP abruptly increased within 8min by approximately 40% and then decreased with time despite of continuous perfusion. In terms of increasing the dose of insulin, the time to reach the peak effect became faster and the slope to decrease became slower. In contrast, atrial contractility was gradually decreased with time. These effects were independent upon extracellular glucose. Genistein (10(-5)M) or lavendustin C (10(-5)M), a tyrosine kinase inhibitor, attenuated the release of ANP stimulated by insulin (10(-8)M). Wortmannin (10(-7)M) or LY294002 (10(-5)M), a PI 3-kinase inhibitor, also attenuated insulin-stimulated ANP release. However, both inhibitors for PI 3-kinase and tyrosine kinase did not cause any significant effects on negative inotropism by insulin. Insulin-stimulated ANP release was augmented in streptozotocin-treated rat atria. The density of insulin receptor markedly increased in diabetic hearts. These results suggest that insulin stimulates the release of ANP through PI 3-kinase and tyrosine kinase, and augmentation of insulin-stimulated ANP release in diabetic rat atria may be partly due to an upregulation of insulin receptor.
Bai
Guang Yi
GY
Department of Physiology, Center for Healthcare Technology Development, Chonbuk National University Medical School, 2-20 Keum-Am-Dong-San, Jeonju 561-180, Republic of Korea.
Piao
Feng Lian
FL
Kim
Sun Young
SY
Yuan
Kuichang
K
Kim
Sung Zoo
SZ
Kim
Suhn Hee
SH
D000818:Animals; D016279:Atrial Function, Left; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis*; D003920:Diabetes Mellitus / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D007328:Insulin; D009320:Atrial Natriuretic Factor; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases