The arteriolar response toacetylcholine, mediated by endothelial derived relaxing factorEDRF, isgreatly suppressed. This could be due to inadequate production orinactivation of EDRF as well as competition by constrictor stimuli. Thesuppression of EDRF dilation occurs in about one week in streptozotocindiabetic rats and is duplicated in normal arterioles by one hour oflocal exposure to isotonic hyperglycemia 300-500 mg. Pretreatmentwith superoxide dismutase protects EDRF function during exposure to 500mg glucose, and post-treatment substantially restores EDRF function. These results suggest that oxygen or hydroxyl radicals produced inresponse to hyperglycemia may be the mechanisms responsible for EDRFsuppression. Specific scavengers of oxygen or hydoxyl radicals will beused to determine which radical species is primarily responsible forimpaired EDRF function in acute and chronic hyperglycemia. A potentialsource of radicals is increased ecosanoid synthesis duringhyperglycemia; cycloxygenase, inhibition partially restores EDRFfunction in diabetic rats. If cycloxygenase inhibition substantiallydecreases radical formation during hyperglycemia, eicosanoid synthesiswill be implicated as the primary source of radicals. The extent towhich loss of EDRF function, hyperglycemia, and decreased insulin actioncontribute to the enhanced vasoconstrictor responses in diabetic rats isnot known. The potential contributions of each factor to theconstrictor responses to norepinephrine, angiotensin II, and myogenicpressor stimuli, all of which act directly on vascular smooth musclecells, will be determined. EDRF function of normal arterioles will besuppressed with an arginine analogNMMA or local isotonic hyperglycemiaso that the modulation of constrictor regulation by EDRF andadditionalcomplications caused by hyperglycemia can be determined. Comparison ofEDRF and constrictor functions in Zucker diabetic rats maintained in ahyperglycemic insulin-resistant or normoglycemic insulin-resistant statewill be used to determine whether hyperglycemia or insulin-resistanceprimarily influences altered vascular regulation. In vitro studiesindicate that hyperglycemia increases sorbitol formation by 2 to 3-foldin endothelial cells. Conversion of excess glucose to sorbitol byaldose reductasemay be an attempt to protect the intracellularenvironment from hyperglycemia. Whether aldose reductase expression isincreased in microvascular cells during diabetic hyperglycemia is notknown. Vascular cells may initially increase expression of aldosereductase to compensate for the excess glucose, but eventually, celldamage may attenuate expression, leading to unchecked cytoplasmichyperglycemia. Expression of aldose reductase mRNA in intestinalmicrovessels of early and advanced insulin-resistant and dependentdiabetic rats will be measured using in situ hybridization. Theseresults will be used to determine the time-dependent expression ofaldose reductase, temporal correlation to disturbances in microvascularregulation, and whether the cause of hyperglycemiainfluences aldosereductase expression.
Absorption of food molecules is the major requirement for life. In theintestinal villus, absorption is a complex cellular process supported bythe microvasculature and lymphatic system. During absorption of glucose, amino acids, and lipids, the villus interstitium develops a gradient ofosmolarity from the base to the apex in the range of 450 to over 600mOsm. Even at rest, the villus apex is more hypertonic and has a loweroxygen tension than at the base. Villus hyperosmolarity has implicationsfor regulation of intestinal blood flow during food absorption. Data Iobtained indicate the environment around major resistance arterioles ofthe submucosa becomes hypertonic due to the passage of hypertonic lymphand venular blood from the mucosal tissue. Perfusion of the lymphvessels with hypertonic media causes sustained dilation of the submucosalarterioles and about half of the dilation is linked to a sodium inducedrelease of endothelial derived relaxing factor. The large arterioles andsmall arteries of the small intestine are proposed to be the dominantvessels responsible for decreased resistance and increased blood flowduring absorptive hyperemia. The mechanism of dilation for largearterioles is primarily related to sodiuminduced hyperosmolarity causedby return of hypertonic blood and lymph from the mucosa and this can betested by duplication of same sodium hyperosmolarity as occurs besideeach arteriole during glucose or oleic acid absorption. The processesof counter-current exchange of oxygen and simultaneous counter-currentexchange and multiplication of absorbed materials have been proposed toexplain the origin of the intestinal hyperosmolarity and the higheroxygen tension in the villus base than apex. However, a much simplerexplanation is possible. The fundamental cellular mechanism whichestablishes the gradient of osmolarity and oxygen tension from the villusapex to base may be greater sodium ion absorption at rest and cellularco-transport of amino acids and glucose with sodium molecules in theapical than basal portions of the villus. The hypertonic interstitialfluid produced in the villus apex is moved by the flow of lymph from thevillus apex to base in the lacteal system. The osmolarity at the villusbase and submucosal layer is raised by equilibration with the morehypertonic lymph from the villus apex. The flow of lymph keeps theosmotic gradient from villus apex to base smaller than would expected dueto the proposed major differences in absorptive rates along the villusshaft both at rest and during nutrient absorption. The greaterabsorption rate of sodium at rest and sodium with carbohydrates or aminoacids in the apical than basal portions of the villus is potentiallyresponsible for the reduction in oxygen tension from villus base to apex, rather than counter-current oxygen exchange in the villus. However, counter-current exchange of oxygen between arterioles and venules in thesubmucosa is likely because pilot studies indicate the percent saturationof hemoglobin is 15-25 in small venules compared to 40-60 in largevenules. The efficiency of counter-current exchange of oxygen should bediminished as blood flow increases, which would reduce oxygen loss fromthe arterioles preceding the villus tissue. The overall hypothesis isthat hyperosmolarity generated in the mucosa during nutrient absorptionis a signal for dilation of the resistance vessels and oxygen deliveryto the mucosa is improved by increased oxygen content of arteriolar blooddue to decreased counter-current exchange of oxygen.
Regulation of the microscopic blood vessels in normal and diabetic conditions
- Intestinal Vascular Regulation
- Obesity, Diabetes, and Hyperglycemia Effects on Microvascular Regulation
The arteriolar response toacetylcholine, mediated by endothelial derived relaxing factorEDRF, isgreatly suppressed. This could be due to inadequate production orinactivation of EDRF as well as competition by constrictor stimuli. Thesuppression of EDRF dilation occurs in about one week in streptozotocindiabetic rats and is duplicated in normal arterioles by one hour oflocal exposure to isotonic hyperglycemia 300-500 mg. Pretreatmentwith superoxide dismutase protects EDRF function during exposure to 500mg glucose, and post-treatment substantially restores EDRF function. These results suggest that oxygen or hydroxyl radicals produced inresponse to hyperglycemia may be the mechanisms responsible for EDRFsuppression. Specific scavengers of oxygen or hydoxyl radicals will beused to determine which radical species is primarily responsible forimpaired EDRF function in acute and chronic hyperglycemia. A potentialsource of radicals is increased ecosanoid synthesis duringhyperglycemia; cycloxygenase, inhibition partially restores EDRFfunction in diabetic rats. If cycloxygenase inhibition substantiallydecreases radical formation during hyperglycemia, eicosanoid synthesiswill be implicated as the primary source of radicals. The extent towhich loss of EDRF function, hyperglycemia, and decreased insulin actioncontribute to the enhanced vasoconstrictor responses in diabetic rats isnot known. The potential contributions of each factor to theconstrictor responses to norepinephrine, angiotensin II, and myogenicpressor stimuli, all of which act directly on vascular smooth musclecells, will be determined. EDRF function of normal arterioles will besuppressed with an arginine analogNMMA or local isotonic hyperglycemiaso that the modulation of constrictor regulation by EDRF andadditionalcomplications caused by hyperglycemia can be determined. Comparison ofEDRF and constrictor functions in Zucker diabetic rats maintained in ahyperglycemic insulin-resistant or normoglycemic insulin-resistant statewill be used to determine whether hyperglycemia or insulin-resistanceprimarily influences altered vascular regulation. In vitro studiesindicate that hyperglycemia increases sorbitol formation by 2 to 3-foldin endothelial cells. Conversion of excess glucose to sorbitol byaldose reductasemay be an attempt to protect the intracellularenvironment from hyperglycemia. Whether aldose reductase expression isincreased in microvascular cells during diabetic hyperglycemia is notknown. Vascular cells may initially increase expression of aldosereductase to compensate for the excess glucose, but eventually, celldamage may attenuate expression, leading to unchecked cytoplasmichyperglycemia. Expression of aldose reductase mRNA in intestinalmicrovessels of early and advanced insulin-resistant and dependentdiabetic rats will be measured using in situ hybridization. Theseresults will be used to determine the time-dependent expression ofaldose reductase, temporal correlation to disturbances in microvascularregulation, and whether the cause of hyperglycemiainfluences aldosereductase expression.
Absorption of food molecules is the major requirement for life. In theintestinal villus, absorption is a complex cellular process supported bythe microvasculature and lymphatic system. During absorption of glucose, amino acids, and lipids, the villus interstitium develops a gradient ofosmolarity from the base to the apex in the range of 450 to over 600mOsm. Even at rest, the villus apex is more hypertonic and has a loweroxygen tension than at the base. Villus hyperosmolarity has implicationsfor regulation of intestinal blood flow during food absorption. Data Iobtained indicate the environment around major resistance arterioles ofthe submucosa becomes hypertonic due to the passage of hypertonic lymphand venular blood from the mucosal tissue. Perfusion of the lymphvessels with hypertonic media causes sustained dilation of the submucosalarterioles and about half of the dilation is linked to a sodium inducedrelease of endothelial derived relaxing factor. The large arterioles andsmall arteries of the small intestine are proposed to be the dominantvessels responsible for decreased resistance and increased blood flowduring absorptive hyperemia. The mechanism of dilation for largearterioles is primarily related to sodiuminduced hyperosmolarity causedby return of hypertonic blood and lymph from the mucosa and this can betested by duplication of same sodium hyperosmolarity as occurs besideeach arteriole during glucose or oleic acid absorption. The processesof counter-current exchange of oxygen and simultaneous counter-currentexchange and multiplication of absorbed materials have been proposed toexplain the origin of the intestinal hyperosmolarity and the higheroxygen tension in the villus base than apex. However, a much simplerexplanation is possible. The fundamental cellular mechanism whichestablishes the gradient of osmolarity and oxygen tension from the villusapex to base may be greater sodium ion absorption at rest and cellularco-transport of amino acids and glucose with sodium molecules in theapical than basal portions of the villus. The hypertonic interstitialfluid produced in the villus apex is moved by the flow of lymph from thevillus apex to base in the lacteal system. The osmolarity at the villusbase and submucosal layer is raised by equilibration with the morehypertonic lymph from the villus apex. The flow of lymph keeps theosmotic gradient from villus apex to base smaller than would expected dueto the proposed major differences in absorptive rates along the villusshaft both at rest and during nutrient absorption. The greaterabsorption rate of sodium at rest and sodium with carbohydrates or aminoacids in the apical than basal portions of the villus is potentiallyresponsible for the reduction in oxygen tension from villus base to apex, rather than counter-current oxygen exchange in the villus. However, counter-current exchange of oxygen between arterioles and venules in thesubmucosa is likely because pilot studies indicate the percent saturationof hemoglobin is 15-25 in small venules compared to 40-60 in largevenules. The efficiency of counter-current exchange of oxygen should bediminished as blood flow increases, which would reduce oxygen loss fromthe arterioles preceding the villus tissue. The overall hypothesis isthat hyperosmolarity generated in the mucosa during nutrient absorptionis a signal for dilation of the resistance vessels and oxygen deliveryto the mucosa is improved by increased oxygen content of arteriolar blooddue to decreased counter-current exchange of oxygen. Animal Physiology/Morphology, Cardiovascular System, Diabetes, Digestive System, Hypertension, Lymphatic System, Physiological Controls and Systems, USA, Southeast
