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The mesenteric and intestinal blood flow is organized and regulated to support normal intestinal function, and the regulation of blood flow is, in part, determined by intestinal function itself. In the process of the development and adaptation of the intestinal mucosa for the support of the digestive processes and host defense mechanisms, and the muscle layers for propulsion of foodstuffs, a specialized microvascular architecture has evolved in each tissue layer. Compromised mesenteric and intestinal blood flow, which can be common in the elderly, may lead to devastating clinical consequences. This problem, which can be caused by vasospasm at the microvascular level, can cause intestinal ischaemia to any of the layers of the intestinal wall, and can initiate pathological events which promote significant clinical consequences such as diarrhea, abdominal angina and intestinal infarction. The objective of this review is to provide the reader with some general concepts of the mechanisms by which neurohumoral vasoactive substances influence mesenteric and intestinal arterial blood flow in health and disease with focus on transmural transport processes (absorption and secretion). The complex regulatory mechanisms of extrinsic (sympathetic-parasympathetic and endocrine) and intrinsic (enteric nervous system and humoral endocrine) components are presented. More extensive reviews of platelet function, atherosclerosis, hypertension, diabetes mellitus, the carcinoid syndrome, 5-hydroxytryptamine and nitric oxide regulation of vascular tone are presented in this context. The possible options of pharmacological intervention (e.g. vasodilator agonists and vasoconstrictor antagonists) used for the treatment of abnormal mesenteric and intestinal vascular states are also discussed.

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We have previously reported that endothelium-dependent, nitric oxide (NO)-mediated vasorelaxation is impaired in diabetic mesenteric arteries. We hypothesized that vasoconstrictor responses should therefore be enhanced. The purpose of this study was to determine whether diabetic mesenteric arteries exhibit increased vasoconstrictor responses, and to investigate if these changes are receptor and/or NO mediated. Thirty age-matched male Sprague-Dawley rats were divided into control (C) and diabetic (D, streptozotocin: 60 mg/kg) groups and studied after 4 weeks. Terminal branches of ileal mesenteric arteries (300 +/- 9 microns) were isolated, pressurized, and superfused with modified Krebs solution. Changes in vessel internal diameter were measured and dose-response curves (DRC) for each vasoactive agent were determined. Each vessel was initially constricted with 40 mM of KC1 to determine maximal vasoconstriction. Phenylephrine (Phe, 10(-8)-10(-4) M) and UK14304 (10(-9)-10(-5) M) were used to determine alpha 1- and alpha 2-receptor responses, respectively. Similar studies were performed in the presence of N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), a competitive inhibitor of NO synthase. Maximal response (Max), area under the curve (AUC), and vessel sensitivity (ED50) for each DRC were calculated. Comparisons among groups were made using analysis of variance and Student's t test with Bonferroni correction. There were no differences in vasoconstrictor responses induced by KCl (C: 82 +/- 2% vs D: 80 +/- 1%). alpha 1-vasoconstrictor responses to Phe were enhanced in diabetes with significantly higher Max (96 +/- 2% vs 83 +/- 3%), and AUC (1.92 +/- 0.09 vs 1.56 +/- 0.08), but no difference in ED50. The addition of L-NAME enhanced only Phe-induced vasoconstrictor response significantly in control rats. Thus, differences in Phe-induced vasoconstrictor responses between C and D were abolished in the presence of L-NAME. alpha 2-vasodilator responses induced by UK14304 were similar between C and D and unaffected by L-NAME. alpha 1-, but not alpha 2-, vasoconstrictor responses are enhanced in streptozotocin-induced diabetic rats. These enhanced responses can be duplicated by treatment of control vessels with L-NAME.

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BACKGROUND: Diabetes and uremia are comorbid conditions that have significant effects on cardiovascular physiology. These studies were designed to examine the effects of diabetes and uremia on vascular reactivity. METHODS: Sprague-Dawley rats were divided into control (C), diabetic (D), uremic (U), and diabetic/uremic (D + U) groups. Diabetes (D, D + U groups) was induced with an injection of streptozotocin. Uremic (U, D + U groups) was produced by seven-eighths nephrectomy. Serum glucose, blood urea nitrogen, creatinine, creatinine clearance, and protein excretion were measured at baseline and before microvascular studies at 4 or 8 weeks after injection. Vascular reactivity was studied in isolated, pressurized, and superfused segments of mesenteric arterioles (300 microns). Changes in internal vessel diameter were measured in response to phenylephrine (10(-8) to 10(-4) mol/L), acetylcholine (10(-9) to 10(-5) mol/L), and nitroprusside (10(-9) to 10(-2) mol/L). RESULTS: Results at 4 and 8 weeks were similar in all groups. Vasoconstrictor responses to phenylephrine and endothelium-independent vasodilator responses to nitroprusside were not altered in any experimental group. Endothelium-dependent vasodilator responses to acetylcholine were significantly depressed in both diabetic groups (D and D + U, p < 0.01 versus control), and there were no differences between the two diabetic groups. CONCLUSIONS: Streptozotocin-induced diabetes results in impairment of endothelial-dependent (nitric oxide mediated) vasodilator responses in mesenteric resistance vessels, which are unaffected by coexisting uremia. Uremia has little effect on mesenteric vascular reactivity in this model.

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OBJECTIVES: The aims of this study were to determine if angiographic findings can be used to predict successful nonoperative therapy of splenic injury and to determine if coil embolization of the proximal splenic artery provides effective hemostasis. METHODS: Splenic injuries detected by diagnostic imaging between 1981 and 1993 at a level I trauma center were prospectively collected and retrospectively reviewed after management by protocol that used diagnostic peritoneal lavage, computed tomography (CT), angiography, transcatheter embolization, and laparotomy. Computed tomography was performed initially or after positive diagnostic peritoneal lavage. Angiography was performed urgently in stabilized patients with CT-diagnosed splenic injuries. Patients without angiographic extravasation were treated by bed rest alone; those with angiographic extravasation underwent coil embolization of the proximal splenic artery followed by bed rest. RESULTS: Patients (172) with blunt splenic injury are the subject of this study. Twenty-two patients were initially managed operatively because of associated injuries or disease (11 patients) or because the surgeon was unwilling to attempt nonoperative therapy (11 patients) and underwent splenectomy (17 patients) or splenorrhaphy (5 patients). One hundred fifty of 172 consecutive patients (87%) with CT-diagnosed splenic injury were stable enough to be considered for nonoperative management. Eighty-seven of the 90 patients managed by bed rest alone, and 56 of 60 patients treated by splenic artery occlusion and bed rest had a successful outcome. Overall splenic salvage was 88%. It was 97% among those managed nonoperatively, including 61 grade III and grade IV splenic injuries. Sixty percent of patients received no blood transfusions. Three of 150 patients treated nonoperatively underwent delayed splenectomy for infarction (one patient) or splenic infection (two patients). CONCLUSIONS: (1) Hemodynamically stable patients with splenic injuries of all grades and no other indications for laparotomy can often be managed nonoperatively, especially when the injury is further characterized by arteriography. (2) The absence of contrast extravasation on splenic arteriography seems to be a reliable predictor of successful nonoperative management. We suggest its use to triage CT-diagnosed splenic injuries to bed rest or intervention. (3) Coil embolization of the proximal splenic artery is an effective method of hemostasis in stabilized patients with splenic injury. It expands the number of patients who can be managed nonoperatively.

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Cyclosporine-induced decreases in renal blood flow (RBF) and glomerular function are well documented. Glomerular filtration and tubular function may be affected by changes in both total renal blood flow and cortical blood flow distribution (CBFD). The effect of CsA on RBF, CBFD, glomerular filtration rate, and tubular function was studied in conscious ewes receiving a mean CsA dose of 30 mg/kg/day for 28 days with mean CsA trough levels of 344 +/- 45 ng/ml. RBF and CBFD were determined by the injection of 15 microns radioactive microspheres before and after one month of treatment with CsA or its vehicle, olive oil. RBF decreased by 24% from 7.65 +/- 0.87 to 5.79 +/- 0.42 ml/min/g of kidney in CsA-treated ewes (P = 0.014), while no decrease was noted in the control group (7.92 +/- 1.10 vs. 7.62 +/- 0.71). Intracortical blood flow decreased in proportion to the fall in total renal blood flow--thus CsA treatment did not change the cortical distribution of flow. There was a 25% decrease in GFR, as determined by inulin clearance, in the CsA-treated group (80 +/- 6 vs. 62 +/- 3 ml/min; P = 0.027) while there was a nonsignificant increase in control animals (62 +/- 11 vs. 92 +/- 7 ml/min). There was no evidence of tubular dysfunction in either group. There were also no changes in urinary excretion rates of prostaglandins PGE2, 6-keto-PGF1 alpha or thromboxane B2, nor were there changes in plasma renin activity. CsA induced decreases in RBF occur red without redistribution of cortical blood flow, indicating that altered cortical distribution of blood flow is not responsible for the changes in GFR or tubular function that have been reported. The changes in renal blood flow and glomerular filtration rate are independent of changes in renal prostaglandin production, and are likely not associated with altered plasma renin activity.

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Cyclosporine may have deleterious effects on glucose metabolism. This study was designed to characterize more precisely cyclosporine-induced alterations in glucose homeostasis in a large animal model with hyperglycemic and euglycemic clamp studies in addition to simple bolus glucose (IVGTT) and insulin (IVITT) tolerance tests. In experiment 1, IVGTTs and hyperglycemic clamp studies were performed in eight ewes before and after 4 weeks of cyclosporine treatment. Studies were repeated 4 weeks after cessation of therapy. In experiment 2, IVITTs and euglycemic clamp studies were performed in seven ewes before and after 4 weeks of cyclosporine treatment. Fasting glucose and insulin levels were not affected by cyclosporine treatment. In experiment 1 cyclosporine did not alter IVGTTs; however, during sustained hyperglycemia, cyclosporine caused a 37% decrease in net glucose disposal (p less than 0.001) and a 39% decrease in plateau plasma insulin levels (p less than 0.05). In experiment 2 cyclosporine had no effect on IVITTs. Plateau insulin values in euglycemic clamp studies were lowered by 27% (p less than 0.05) after cyclosporine treatment. In addition, the metabolic clearance rate of insulin was increased by 25% (p less than 0.05), and the steady-state insulin clearance rate was increased by 16% (p less than 0.003). Measurements of insulin sensitivity were unchanged by cyclosporine. These experiments suggest that cyclosporine treatment results in impairment of sustained synthesis and secretion of insulin, increased insulin clearance, and unaltered insulin sensitivity.

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This study was performed to examine the effect of transplantation, and thus extrinsic denervation, of the small intestine on intraluminal release of serotonin and substance P. Heterotopic 40-cm-long proximal (jejunal) small intestinal isografts were performed in six 200- to 250-g adult male Lewis rats under general anesthesia. Bowel ends were exteriorized as ostomies. Six Lewis rats with neurovascularly intact 40-cm proximal small bowel Thiry-Vella loops exteriorized as ostomies served as the control animals. On the seventh postoperative day, the intestinal loops were perfused at 0.5 ml/min for three 10-min periods with normal saline followed by an equilibrium period and then for three 10-min periods with 20% dextrose. Perfusates were collected for each period and levels of serotonin and substance P were determined by radioimmunoassay. Intraluminal serotonin levels rose from 29 +/- 9 ng/ml during saline perfusion to 115 +/- 28 ng/ml during intestinal perfusion with 20% dextrose in the innervated loops and from 21 +/- 7 ng/ml to 94 +/- 26 ng/ml in the transplanted loops. While there was a statistically significant increase in mean intraluminal serotonin levels following perfusion with 20% dextrose in both the control and transplant groups, there was no difference in the intraluminal serotonin response between controls and transplant recipients. In contrast, 20% dextrose had no effect on luminal release of substance P in either group. These results indicate that extrinsic denervation of the small intestine has no effect on the intraluminal serotonin response to stimulation and suggest that serotonin and substance P are not released into the intestinal lumen by the same regulatory mechanisms.

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