Insulin resistance and hyperglycemia are associated with suppressed endothelial mediated dilation in humans. The mechanisms potentially involve oxidant injury and elevation of protein kinase C activity. While a glucose concentration of 250-300 mg/dl induces endothelial injury in normal rats, insulin resistance may lower the concentration to less than 200 mg/dl. In vivo mechanisms by which insulin resistance and acute hyperglycemia impair endothelial microvascular regulation will be studied in normal and insulin resistant Zucker obese rats. Data obtained during normoglycemia in normal and insulin resistant rats will be used to determine whether chronic insulin resistance is associated with dysfunction of nitric oxide production in the intestinal vasculature. Hyperglycemic solution will then be topically applied to the intestine. In normal rats topical 300 mg/dl hyperglycemia causes a rapid and prolonged impairment of endothelial dependent dilation. It is proposed that oxidant injury associated with increased eicosanoid metabolism initially destroy nitric oxide during hyperglycemia. In addition, a mechanism independent of radical formation leads to sustained loss of nitric oxide function. This mechanism may be caused by activation of beta II protein kinase C, and is expressed primarily as increased resistance of small arteries and large arterioles. To confirm this hypothesis, vessel diameter, blood flow and nitric oxide concentration will be measured during flow and agonist mediated stimulation of nitric oxide release. If oxidants initially destroy nitric oxide during hyperglycemia, pretreatment with oxygen free radical scavengers will maintain the nitric oxide concentration during the early phase of hyperglycemia. Further inhibitors of beta II PKC will improve the nitric oxide dependent mechanisms over longer term hyperglycemia. Positive results will confirm that chronic insulin resistance predisposes the microvasculature to abnormalities of endothelial function. However, antioxidants and inhibition of beta II isoenzymes of PKC may protect endothelial function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025824-20
Application #
6182909
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Linder, Barbara
Project Start
1980-08-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
20
Fiscal Year
2000
Total Cost
$138,245
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Bohlen, Harold Glenn (2015) Nitric oxide and the cardiovascular system. Compr Physiol 5:808-23
Zani, Brett G; Bohlen, H Glenn (2005) Transport of extracellular l-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production. Am J Physiol Heart Circ Physiol 289:H1381-90
Bohlen, H Glenn (2004) Mechanisms for early microvascular injury in obesity and type II diabetes. Curr Hypertens Rep 6:60-5
Chu, Shaoyou; Bohlen, H Glenn (2004) High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am J Physiol Renal Physiol 287:F384-92
Bohlen, H G; Nase, Geoffrey P (2002) Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function. Am J Physiol Heart Circ Physiol 283:H391-7
Lash, J M; Nase, G P; Bohlen, H G (1999) Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle. Am J Physiol 277:H1513-20
Bohlen, H G (1998) Mechanism of increased vessel wall nitric oxide concentrations during intestinal absorption. Am J Physiol 275:H542-50
Connors, B; Lee, W H; Wang, G et al. (1997) Aldose reductase and IGF-I gene expression in aortic and arteriolar smooth muscle during hypo- and hyperinsulinemic diabetes. Microvasc Res 53:53-62
Lash, J M; Bohlen, H G (1997) Time- and order-dependent changes in functional and NO-mediated dilation during exercise training. J Appl Physiol 82:460-8
Jin, J S; Bohlen, H G (1997) Non-insulin-dependent diabetes and hyperglycemia impair rat intestinal flow-mediated regulation. Am J Physiol 272:H728-34

Showing the most recent 10 out of 29 publications