H. Glenn Bohlen, Ph.D.
Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, Room 371
Indianapolis, Indiana 46202-5120
E-mail: gbohlen @ iupui.edu
Education / Training
- 1968, B.S. in Biology, Appalachian State University, Boone, North Carolina
- 1973, Ph.D. in Physiology, Bowman Gray School of Medicine, Wake Forest University, North Carolina
- 1973-76, Postdoctoral Training in Physiology, University of Arizona, Tucson, Arizona
Intestinal Vascular Regulation
The small intestine during food molecule absorption generates a very high sodium chloride hyperosmolarity in the villi. The hypertonic interstitial fluid both enters the venous drainage and lymphatic systemic of the intestinal wall. Both the hypertonic lymph and venous blood allow the tissue environment around the major intestinal arterioles to become hypertonic and these vessels then dilate to increase blood flow to the mucosal villi to provide oxygen for intestinal absorption. The dilation due to NaCl hypertonic conditions is predominately caused by nitric oxide release from endothelial cells in lymph vessels, venules and arterioles. The nitric oxide in turn relaxes the vascular smooth muscle of the arterioles to allow vasodilation. If the nitric oxide mechanism is suppressed, blood flow can not appreciably increase during food absorption and nutrients are poorly absorbed.
Hypertonic solutions that do not contain sodium only cause a small amount of dilation compared to equivalent hypertonic solutions based on sodium. Current research is focused on how sodium ions enter the endothelial cells and how changes in either the intracellular sodium concentration or membrane electrical status leads to activation of nitric oxide formation by endothelial nitric oxide synthase. At some point in the process, intracellular calcium ion must be increased and this could occur because the cell is preferentially pumping out sodium ions in exchange for potassium ions. In doing so, this mechanism causes hyperpolarization leading to calcium entry into the cells down the electrical gradient. Another possibility is that the normal sodium entry-calcium extrusion pumps are not keeping pace due to the high intracellular sodium concentration and calcium concentration increases by default.
Funding: This research has been supported by NIH Grant HL-20605 and is now in its 23rd year.
Obesity, Diabetes, and Hyperglycemia Effects on Microvascular Regulation
Obesity among adults causes sufficient insulin resistance that some individuals can not reach the high insulin concentrations to maintain glucose regulation. The result is hyperglycemia and Type II diabetes mellitus. Hyperglycemia is associated with a large production of diacylglycerol and activation of protein kinase C is virtually every type of cell in the body. For the microvasculature, the activation of endothelial PKC results in suppression of endothelial nitric oxide synthase to reduce the available nitric oxide and vasoconstriction occurs. The activation of PKC in vascular smooth muscle also contributes to constriction. At the same time, PKC activation of phospholipases floods cells with an over abundance of arachidonic acid leading to various forms of prostaglandins being formed and a large amount of oxygen radical formation. The oxygen radicals damage cells and destroy part of the reduced concentration of nitric oxide available. These processes only require about 30 minutes of 300 mg/dl hyperglycemia to occur in normal rats and the same problems develop at 200 mg/dl in obese Zucker rats. In effect, obesity has primed the vasculature to be damaged at lower glucose concentrations than in normal animals. Blockade of endothelial PKC with an Eli Lilly Company drug (LY333531) partially reverses some of the loss of nitric oxide physiology after hyperglycemia occurs and protects obese animals to a large extent from hyperglycemic effects on lowering nitric oxide. The current studies are designed to determine to what extent the oxygen radical formation during hyperglycemia diminishes the nitric oxide concentration versus a depression of nitric oxide due to suppression of endothelial nitric oxide synthase by PKC. It is likely that both events occur simultaneously and even interact as oxygen radicals damage cell membranes.
Funding: This research has been supported by NIH Grant HL-25824 and is now in its 21st year.
Coworkers: Randy Bills
Selected Recent Publications
Bohlen, H.G. and G.P. Nase. Dependence of Intestinal Arteriolar Regulation on Flow Mediated Nitric Oxide Formation.
Am J Physiol Heart Circ Physiol 279: H2249-H2258, 2000.
Bohlen, H.G. and G.P. Nase. Arteriolar Nitric Oxide Concentration Is Decreased During Hyperglycemia-Induced βII PKC Activation.
Am J Physiol Heart Circ Physiol 280: H621-H627, 2001.
Bohlen, H.G., G.P. Nase, and J.S. Jin. Multiple mechanisms of early hyperglycaemic injury of the rat intestinal microcirculation.
Journal of Experimental Physiology and Pharmacology 29: 138-42, 2002.
Bohlen, H.G. and G.P. Nase. Obesity lowers hyperglycaemic threshold for impaired endothelial nitric oxide function.
Am J Physiol Heart Circ Physiol 283: H391-H397, 2002.
Nase, G.P., J. Tuttle, H.G. Bohlen. Reduced perivascular PO2 increases nitric oxide release from endothelial cells.
Am J Physiol Heart Circ Physiol 285: H507-H515, 2003.
Bohlen, H.G. Protein kinase ßII in Zucker obese rats compromises oxygen and flow-mediated regulation of nitric oxide formation.
Am J Physiol Heart Circ Physiol 286: H492-H497, 2004.
Chu, S. and H.G. Bohlen. High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism.
Am J Physiol Renal Physiol 287: F384-F392, 2004.
2005Zani, B.G. and H.G. Bohlen. Sodium channels are required during in vivo sodium chloride hyperosmolarity to stimulate increase in intestinal endothelial nitric oxide production.
Am J Physiol Heart Circ Physiol 288: H89-H95, 2005.
Zani, B.G., and H.G. Bohlen. 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-H1390, 2005.
Bauser, H.D. and H.G. Bohlen. Cerebral Microvascular Dilation During Hypotension and Decreased Oxygen Tension: A Role for nNOS.
Am J Physiol Heart Circ Physiol 293(4): H2193-H2201, Oct 2007.
Kempson, S.A., N. Thompson, L. Pezzuto, and H.G. Bohlen. Nitric oxide production by mouse renal tubules can be increased by a sodium-dependent mechanism.
Nitric Oxide 17(1): 33-43, Aug 2007. PubMed
Pezzuto, L. and H.G. Bohlen. Extracellular arginine rapidly dilates in vivo intestinal arteries and arterioles through a nitric oxide mechanism.
Microcirculation, Feb;15(2):123-135, 2008. PubMed
Bauser-Heaton, H.D., J. Song, and H.G. Bohlen. Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide-sensitive cotransporter and sodium-calcium exchanger.
Am J Physiol Heart Circ Physiol 294(5): H2166-H2173, May 2008.
Payne, G.A., L. Borbouse, I.N. Bratz, W.C. Roell, H.G. Bohlen, G.M. Dick, J.D. Tune. Endogenous adipose-derived factors diminish coronary endothelial function via inhibition of nitric oxide synthase.
Microcirculation, 15(5): 417-426, July 2008. PubMed
Zhou, X., H.G. Bohlen, S.J. Miller, J.L. Unthank. NAD(P)H oxidase derived peroxide mediates elevated basal and impaired flow-induced NO production in SHR mesenteric arteries in vivo.
Am J Physiol Heart Circ Physiol 295(3): H1008-H1016, Sept 2008. Pubmed
Kim, D.D., T. Kanetaka, R.G. Duran, F.A. Sanchez, H.G. Bohlen, W.N. Duran. Independent Regulation of Periarteriolar and Perivenular Nitric Oxide Mechanisms in the In Vivo Hamster Cheek Pouch Microvasculature.
Microcirculation, 16(4): 323-330, May 2009. PubMed
Payne, G.A., H.G. Bohlen, U.D. Dincer, L. Borbouse, and J.D. Tune. Periadventitial adipose tissue impairs coronary endothelial function via PKC-β dependent phosphorylation of nitric oxide synthase.
Am J Physiol Heart Circ Physiol 297(1): H460-H465, July 2009.
Bohlen, H.G. Microvascular Consequences of Obesity and Diabetes in
Handbook of physiology: Microcirculation 2nd Edition, Ronald F. Tuma, Walter N. Durán, Klaus Ley (Editors), Chapter 19, Amsterdam; Boston: Elsevier/Academic Press, c2008.
Bohlen, H.G., W. Wang, A. Gashev, O. Gasheva, and D. Zawieja. Phasic contractions of rat mesenteric lymphatics increase basal and phasic nitric oxide generation in vivo.
Am J Physiol Heart Circ Physiol 297(4): H1319-H1328, Oct. 2009. PubMed
Bohlen, H.G., X. Zhou, J.L. Unthank, S.J. Miller, and R. Bills. Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation.
Am J Physiol Heart Circ Physiol 297(4): H1337-H1346, 2009.
Zhou, X., H.G. Bohlen, J.L. Unthank, and S.J. Miller. Abnormal Nitric Oxide Production in Aged Rat Mesenteric Arteries is Mediated by NAD(P)H Oxidase-derived Peroxide.
Am J Physiol Heart Circ Physiol 297(6): H2227-H2233, Dec 2009. PubMed