Reactive oxygen species cause endothelial dysfunction in chronic flow overload.

Although elevation of shear stress increases production of vascular reactive oxygen species (ROS), the role of ROS in chronic flow overload (CFO) has not been well investigated. We hypothesize that CFO increases ROS production mediated in part by NADPH oxidase, which leads to endothelial dysfunction. In six swine, CFO in carotid arteries was induced by contralateral ligation for 1 wk. In an additional group, six swine received apocynin (NADPH oxidase blocker and anti-oxidant) treatment in conjunction with CFO for 1 wk. The blood flow in carotid arteries increased from 189.2 ± 25.3 ml/min (control) to 369.6 ± 61.9 ml/min (CFO), and the arterial diameter increased by 8.6%. The expressions of endothelial nitric oxide synthase (eNOS), p22/p47(phox), and NOX2/NOX4 were upregulated. ROS production increased threefold in response to CFO. The endothelium-dependent vasorelaxation was compromised in the CFO group. Treatment with apocynin significantly reduced ROS production in the vessel wall, preserved endothelial function, and inhibited expressions of p22/p47phox and NOX2/NOX4. Although the process of CFO remodeling to restore the wall shear stress has been thought of as a physiological response, the present data implicate NADPH oxidase-produced ROS and eNOS uncoupling in endothelial dysfunction at 1 wk of CFO.

Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation.

The discovery that hemoglobin, albumin, and glutathione carry and release nitric oxide (NO) may have consequences for movement of NO by blood within microvessels. We hypothesize that NO in plasma or bound to proteins likely survives to downstream locations. To confirm this hypothesis, there must be a finite NO concentration ([NO]) in arteriolar blood, and upstream resistance vessels must be able to increase the vessel wall [NO] of downstream arterioles. Arteriolar blood NO was measured with NO-sensitive microelectrodes, and vessel wall [NO] was consistently 25-40% higher than blood [NO]. Localized suppression of NO production in large arterioles over 500-1,000 microm with L-nitroarginine reduced the [NO] approximately 40%, indicating as much as 60% of the wall NO was from blood transfer. Flow in mesenteric arteries was elevated by occlusion of adjacent arteries to induce a flow-mediated increase in arterial NO production. Both arterial wall and downstream arteriolar [NO] increased and the arterioles dilated as the blood [NO] was increased. To study receptor-mediated NO generation, bradykinin was locally applied to upstream large arterioles and NO measured there and in downstream arterioles. At both sites, [NO] increased and both sets of vessels dilated. When isoproterenol was applied to the upstream vessels, they dilated, but neither the [NO] or diameter downstream arterioles increased. These observations indicate that NO can move in blood from upstream to downstream resistance vessels. This mechanism allows larger vessels that generate large [NO] to influence vascular tone in downstream vessels in response to both flow and receptor stimuli.

Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression.

The magnitude of shear stimulus has been shown to determine the level of growth factor expression in cell culture. However, little is known regarding what effect shear level has on specific arterial wall remodeling events in vivo. We have hypothesized that the rate of luminal diameter change and specific remodeling events within the arterial wall layers are dependent on shear level. Selective ligations were made to alter the number of microvascular perfusion units of mesenteric arteries within the same animal to approximately 50%, 200%, and 400% of control. Arterial blood flow and wall shear rate were correlated with the degree of alteration in perfusion units. Luminal diameters were decreased in 50% arteries by day 2 and increased approximately 17% and 33% respectively, in 200% and 400% arteries at day 7. The rate of diameter change was greatest in 50% and 400% arteries. Wall areas (medial +37%; intimal +18% at day 2) and cell densities (intimal +26%; adventitial +44% at day 2) were altered only in the 400% arteries. A positive correlation existed by day 2 between endothelial staining for endothelial nitric oxide synthase and shear level. The results demonstrate that shear level influences the rate of luminal expansion, specific remodeling events within each wall layer, and the degree of endothelial gene expression. A greater understanding of how shear level influences specific remodeling events within each wall layer should aid in the development of targeted therapies to manipulate the remodeling process in health and disease.

Evaluation of the role of intercellular adhesion molecule 1 in a rodent model of chronic venous hypertension.

PURPOSE: To evaluate the role of intercellular adhesion molecule 1 (ICAM-1) in cutaneous leukocyte trapping in venous disease, we used our rodent model of venous hypertension (VH). MATERIALS AND METHODS: VH was created in adult rats by ligation of the inferior vena cava, bilateral common iliac veins, and bilateral common femoral veins. In the Phase I experimental (exptl) group, anti-ICAM-1 monoclonal antibody (1A29) was given intravenously prior to venous ligations. Acute venous pressures were measured in the exptl and control (ctrl) (ligation only) groups. Bilateral forelimb and hindlimb skin specimens were harvested for myeloperoxidase (MPO) assay. In Phase II, VH was created in a chronic group; in a sham-operated group, ties were placed around the same vessels without ligations. Two weeks later, venous pressures were measured and radiolabeled ((125)I and (131)I) monoclonal antibody (mAb) to ICAM-1 was injected and allowed to circulate for 5 min before the level of radiolabeled antibody within forelimb and hindlimb specimens was measured. RESULTS: In the acute study with 1A29, hindlimb pressures were significantly elevated in both the ctrl (n = 4) and exptl (n = 4) hindlimbs (15.4 +/- 0.239 and 13.8 +/- 1.89 mm Hg, respectively) compared with ctrl and exptl forelimbs (1.38 +/- 0.554 and 1.50 +/- 0.612 mm Hg, respectively). However, MPO activity was significantly elevated in the hindlimbs of the ctrl group compared with the hindlimbs of the exptl animals (19.8 +/- 1.54 U vs 6.71 +/- 2.46 U). In the chronic VH rats (n = 5) given radiolabeled anti-ICAM-1 mAb, the hindlimb pressures (10.1 +/- 4.52 mm Hg) were significantly elevated (P < 0.05) compared with forelimb pressures (1 +/- 0.447 mm Hg) and compared with the forelimb and hindlimb pressures in the sham-operated animals (n = 4) (1.63 +/- 0.813 and 4.25 +/- 2.13 mm Hg, respectively). However, there was not a significant difference in the quantity of ICAM-1-hindlimb versus forelimb or chronic VH versus sham. CONCLUSIONS: Anti-ICAM-1 mAb decreased MPO activity in hypertensive hindlimb skin, supporting the instrumental role of ICAM-1 in cutaneous leukocyte trapping. However, the constituent endothelial ICAM-1 is not elevated by VH.

Experimental models to investigate inflammatory processes in chronic venous insufficiency.

Chronic venous insufficiency (CVI) is characterized by leukocyte adhesion and infiltration, venous hypertension and dilatation, and valvular dysfunction. The fact that activated white cells can direct a powerful cytotoxic arsenal at parenchymal cells following their extravasation into the tissues led to the original proposal that leukocytes may play a causative role in the pathogenesis of venous disease. A large body of subsequent work indicates that white blood cells are indeed activated in CVI. However, identification of the factors responsible for initiating leukosequestration and activation in such disorders and determination of whether these activated cells then contribute to the progression of venous disease have been hampered by the lack of appropriate animal models that accurately mimic the human condition. Tantalizing evidence suggesting that cyclical periods of ischemia and reperfusion (I/R) may occur in diseased regions of the skin is beginning to accumulate. As is the case with CVI, leukocyte infiltration is a prominent feature in I/R and activated neutrophils play a causative role in the reperfusion component of tissue injury via the targeted release of reactivate oxygen metabolites and hydrolytic enzymes. In light of these considerations, many investigators have suggested that examining the mechanisms of I/R injury in skin and skeletal muscle, where ischemia is produced by arterial occlusion, may provide a relevant model for studying the pathogenesis of CVI. Others have suggested that venous occlusion may represent a more appropriate model, as this approach also produces the venous hypertension that is characteristic of the disease. The purpose of this review is to summarize the evidence pointing to the involvement of I/R and venous hypertension as causative factors in CVI-induced leukocyte recruitment. In addition, we will describe the evidence in favor of the view that white blood cells contribute to the pathogenesis of CVI. Finally we will describe several different experimental models that have been used to examine the role of I/R-induced microvascular dysfunction as it may pertain to the development of CVI, together with a discussion of the relative advantages and limitations of the various models.

Drag reducing polymers may decrease atherosclerosis by increasing shear in areas normally exposed to low shear stress.

PURPOSE: Drag reducing polymers (DRPs) have been shown to decrease plaque formation. Their mechanism of action is unknown. Atherosclerosis tends to develop in areas of low shear stress. This study investigates whether DRPs increase shear stress in areas normally exposed to low shear stress. METHODS: Six dogs underwent surgical plication of the left half of the aorta. A specially modified 20-MHz Doppler ultrasound probe mounted at a 45-degree angle on a micromanipulator was used to measure blood flow velocity at six 4-mm intervals along both lateral sides of the aorta starting at the aortic wall and then at subsequent 0.1-mm depths moving into the lumen before and after administering DRP. Shear rates were calculated using linear regression and then compared using the paired t test. The blood viscosity remained constant at 0.04 poise during infusions of this amount of DRP. RESULTS: The maximum shear rate occurring during the cardiac cycle on the side of the aortic stenosis (plication) was 9.96 +/- 1.52/sec before the administration of the DRP and 14.27 +/- 2.01/sec after the administration of the DRP (P =.0240). The maximum shear rate on the side of the unstenosed aortic wall was 57.25 +/- 7.93/sec before the administration of the DRP and 44.80 +/- 6.23/sec after the administration of the DRP (P =. 0081). CONCLUSION: One of the ways that DRPs inhibit the development of atherosclerosis appears to be by increasing shear stress in areas normally exposed to low shear stress. Understanding this mechanism may lead to the development of pharmaceutical agents that inhibit the development of atherosclerosis.

Increased hindlimb leukocyte concentration in a chronic rodent model of venous hypertension.

BACKGROUND: The pathophysiologic mechanism for tissue damage in chronic venous insufficiency (CVI) is venous hypertension (VH), the primary mediator behind leukocyte trapping in tissues. We developed a new rodent model of chronic hindlimb VH to allow testing of the microvascular dysfunction that occurs in clinical CVI. MATERIALS AND METHODS: Hindlimb VH was created in adult rats ( approximately 350 g, male, Wistar) by ligation of the inferior vena cava, bilateral common iliac veins, and bilateral common femoral veins. In a sham group, a loose tie was placed around the same vessels. One week later, pressure catheters were placed in the right common carotid artery, right internal jugular vein (forelimb), and right superficial epigastric vein (hindlimb). Measurements were taken 15 min later, to allow for stabilization. Bilateral forelimb and hindlimb skin specimens were harvested. The myeloperoxidase (MPO) assay, an indicator of tissue leukocyte trapping, was performed using a well-described, standard technique. RESULTS: In the chronic rats (n = 8), the hindlimb pressures (12.6 +/- 3.2 mm Hg) were significantly elevated (P < 0.05) when compared to forelimb pressures (1.75 +/- 0.71) and to chronic sham rat (n = 6) hindlimb (3.3 +/- 1.2) pressures. There was a significant (P < 0.05) elevation of MPO activity in hindlimbs of the chronic group (32.9 +/- 13.9 units) when compared to forelimbs (17 +/- 11.3) and sham hindlimbs (18 +/- 10.2). CONCLUSIONS: In our chronic model, as in clinical studies and previous acute investigations, we have demonstrated, using an MPO assay, an increase in the amount of cutaneous leukocytes in the hindlimbs with chronic VH but not in experimental forelimbs or sham hindlimbs or forelimbs.

Wall remodeling after wall shear rate normalization in rat mesenteric arterial collaterals.

Previous studies have demonstrated endothelial and smooth muscle hyperplasia occur during arterial luminal expansion associated with elevation of arterial wall shear rates. The current study investigated whether remodeling induced by elevated wall shear would ultimately result in a vessel with intimal and medial cell densities and other wall characteristics similar to control arteries. A rat mesenteric model was used in which collateral wall shear is restored to normal 4 weeks after arterial occlusion. Twelve weeks after shear elevation, paired in vivo measurements indicated that the maximum collateral inner diameter was increased 27-75%. Morphometric evaluation of collateral cross sections indicated that, relative to control arteries, luminal and medial areas were increased 79 +/- 22 and 56 +/- 15%. Collateral medial cell density was decreased (1.12 +/- 0.044 vs. 1.35 +/- 0.005 nuclei/1,000 micrometer(2) but intimal cell density was similar (2.86 +/- 0.166 vs. 2.49 +/- 0.102 nuclei/100 micrometer luminal perimeter). Medial thickness to radius ratio was also similar between control and collateral arteries. Thus, for the wall characteristics evaluated, there are many similarities between enlarged collaterals and control arteries. Comparison of nuclear numbers in arterial cross sections of the current and previous studies suggest that intimal and medial cellular regression is correlated with a decrease in wall shear force toward normal levels.

Direct in vivo measurement of flow-dependent nitric oxide production in mesenteric resistance arteries.

PURPOSE: To determine whether the concentration of nitric oxide (NO) at the arterial wall is increased subsequent to the abrupt elevation of blood flow in resistance arteries. METHODS: Eight dogs underwent laparotomy with anesthesia, and their small bowels were exteriorized. NO concentration was measured with NO-specific electrodes (200-micro-tip diameter) at the outer wall of the mesenteric arteries. Flow was increased by occlusion of the adjacent mesenteric arteries. In four animals, flow and NO concentration were measured after the administration of Nomega-nitro-L-arginine-methyl ester (L-NAME) to inhibit NO production. RESULTS: As arterial flow was increased from a baseline of 5.4 +/- 1.3 ml/min to 10.9 +/- 1.8 ml/min (p = 0.001), NO electrode current was elevated in every animal. With repetition of the flow stimulus, the response tended to be attenuated. In the first experimental trial, NO electrode current measured at the arterial wall increased from 2.86 +/- 0.56 to 3.00 +/- 0.60 nA (p = 0.02). L-NAME (10 mg/kg intravenous) effectively inhibited NO synthase as indicated by the elevation of mean arterial pressure (11 +/- 1.7 mm Hg; p = 0.04). After administration of L-NAME, NO electrode current measured at the outer arterial wall fell 0.23 +/- 0.05 nA (p = 0.02). CONCLUSIONS: The data indicate that a doubling of blood flow in the canine mesenteric resistance arteries is associated with an increase in NO concentration of at least 100 nm at the outer arterial wall. This association is probably a substantial underestimation of the actual concentration because of the geometry of the electrode tip. To our knowledge, ours is the first report of direct in vivo measurement of flow-dependent NO release in resistance arteries.

Flow-induced arterial remodeling in rat mesenteric vasculature.

This study was designed to characterize in vivo arterial remodeling of male Wistar rat small mesenteric arteries exposed to varying levels of elevated blood flow in the presence of normal arterial pressure. Through a series of arterial ligations, respective ileal artery and second-order branch blood flows acutely increased approximately 36 and approximately 170% over basal levels. Their respective diameters increased 12 and 38% and their wall area increased 58 and 120% in a time-dependent fashion between 1 and 7 days postlitigation compared with same-animal control vessels. Medical extracellular connective tissue increased concomitantly with medical wall hypertrophy. Immunostaining for proliferating cell nuclear antigen and nuclear profile analyses suggests that both smooth muscle and endothelial cell hyperplasia contribute to flow-induced vascular remodeling. The initial stimulus in this model is flow-mediated shear stress, with possible augmentation by hoop stress, which is increased approximately 7% by the resultant vasodilation. Stable wall thickness-to-lumen diameter ratios at 1, 3, and 7 days, however, suggest chronic hoop stress is tightly regulated and remains constant. The model described herein allows analyses of two arteries with different degrees of flow elevation within the same animal and demonstrates that the magnitude of vessel remodeling in vivo is directly dependent on the duration of flow elevation after abrupt arterial occlusion.

Elevated cutaneous leukocyte concentration in a rodent model of acute venous hypertension.

BACKGROUND: The pathophysiologic mechanism of the skin pathology in chronic venous insufficiency is venous hypertension (VHTN). Microvascular dysfunction involving leukocytes has recently been proposed as the primary mediator of tissue damage from VHTN. We developed a rodent model allowing the investigation of the effects of acute VHTN on tissue leukocyte concentration. MATERIALS AND METHODS: Under general anesthesia, adult male rats underwent transperitoneal isolation of the inferior vena cava and the common iliac veins and arteries. Bilateral thigh incisions allowed isolation of the common femoral veins and superficial epigastric veins (SEV: distal branch of the femoral vein in the thigh). Pressure in the SEV and flow in the iliac artery were measured before (T-Pre), immediately after (T-0), and for 135 min (T-1) after ligation of the cava, iliac, and femoral veins. Sham rats were identical except no venous ligation was performed. After the T-1 pressures were obtained, the distal hindlimb and forelimb skin was harvested and processed to measure myeloperoxidase (MPO) activity, an index of the number of tissue leukocytes. To evaluate the effect of arterial flow reduction known to occur with acute venous ligation, the above measurements were made in an Aortic group of rats in which the aorta was manually stenosed. RESULTS: This venous ligation technique resulted in a significant (P < 0.05) and sustained rise in venous pressure (T-Pre, 9.91 +/- 0.94 and T-1, 26.22 +/- 2.15). Hypertensive rats had significantly elevated hindlimb MPO activity (4.77 +/- 0.36) vs forelimb (0.60 +/- 0.39), Sham (hindlimb, 0.77 +/- 0.41; forelimb, 0.10 +/- 0.05), and Aortic (hindlimb, 0.96 +/- 0.38; forelimb, 0.58 +/- 0.11) controls. CONCLUSIONS: Acute VHTN was successfully created by venous ligation in this newly developed rat model. VHTN, but not arterial flow reduction, was associated with significantly elevated hindlimb skin MPO activity, suggesting that leukocytes may indeed be mediators of skin pathology in VHTN. This model will allow further investigation into the mechanisms of microvascular dysfunction in VHTN.

Femoral artery ligation stimulates capillary growth and limits training-induced increases in oxidative capacity in rats.

OBJECTIVE: The purpose of this study was to assess the interaction of arterial insufficiency and exercise training on soleus and plantaris muscle capillarity and oxidative capacity in adult rats. METHODS: Arterial insufficiency was created by ligation (LIG) of the right femoral artery, and exercise training (TR) was performed on a rodent treadmill. The left hindlimb served as a normally (NORM) perfused control. Capillary:fiber ratio number of capillary contacts per fiber, and citrate synthase activity (CS) were evaluated in the plantaris (Plant) and soleus (Sol) muscles. RESULTS: In sedentary rats, CS was similar between LIG and NORM (Plant: 24.4 vs. 24.3 mumol.min-1.g-1; Sol: 16.6 vs. 16.9 mumol.min-1.g-1), but capillaries per fiber and capillary contacts per fiber were significantly elevated in the plantaris muscle of LIG (2.46 vs. 2.10 caps/fiber, 5.78 vs. 5.03 capillary contacts). CS was elevated in both limbs of TR but was lower in LIG than in NORM (Plant: 28.5 vs. 32.4 mumol.min-1.g-1; Sol: 21.1 vs. 24.9 mumol.min-1.g-1). Treadmill training did not significantly affect capillarity in NORM. However, muscles in the ligated limb of TR tended to have greater capillarity than comparable muscles in either NORM of TR of LIG in SED. CONCLUSIONS: These results demonstrate capillary proliferation in the plantaris but not soleus muscle of rat hindlimbs with femoral artery ligation. Capillarity and CS adaptations were not obligatorily related in LIG, and femoral artery ligation and exercise training appeared to have interactive effects on skeletal muscle capillarity.

Wall remodeling during luminal expansion of mesenteric arterial collaterals in the rat.

Wall remodeling associated with rapid luminal enlargement of collateral mesenteric arteries in rats was investigated 1 and 4 weeks after creation of a collateral pathway by ligating three to four sequential arteries. Paired observations were made of inner diameters of collateral and normal arteries in the same animals. Arterial blood flow was measured at the final observation. Sections of arteries were processed for morphological measurements. After 4 weeks, inner arterial diameter was increased more at the beginning (63 +/- 6%) than the end (25 +/- 9%) of the collateral pathway. At 1 and 4 weeks, respectively, cross-sectional areas of collateral relative to normal arteries were increased by 46 +/- 5% and 59 +/- 13% (lumen), 55 +/- 8% and 65 +/- 14% (media), and 89 +/- 18% and 60 +/- 31% (intima). The wall expansion during luminal enlargement resulted in a normal medial thickness:luminal radius relationship. At 1 week postligation, wall shear rate remained elevated and endothelial but not smooth muscle hyperplasia had occurred (intimal nuclei: 40 +/- 1.7 collateral versus 24 +/- 3.0 normal; medial nuclei: 42 +/- 6.8 collateral versus 37 +/- 2.1 normal). At 4 weeks, wall shear rate in collaterals was similar to normal arteries, and smooth muscle hyperplasia had taken place (medial nuclei: 84 +/- 9.4 collateral versus 44 +/- 4.7 normal). The data demonstrate that wall expansion associated with rapid luminal enlargement of these collaterals involves hyperplasia of both endothelial and smooth muscle cells; however, smooth muscle proliferation does not occur until after wall shear rate is reduced. The specific cellular adaptations that occur during collateral development may depend on the level of wall shear and shear-dependent modulation of endothelial growth factors.

Nitric oxide maintains dilation of immature and mature collaterals in rat hindlimb.

The role of nitric oxide (NO) in maintaining collateral dilation was investigated in rats with acute and chronic superficial femoral artery occlusion. Collateral function was evaluated from arterial pressure measurements proximal (mean arterial pressure, MAP) and distal (PD) to the occlusion under resting and hyperemic conditions. For resting and hyperemic conditions, respectively, PD increased with the duration of occlusion from 34 +/- 2.1 and 14 +/- 0.8 mm Hg acutely postocclusion to 37 +/- 2.8 and 19 +/- 3.6, 42 +/- 4.9 and 25 +/- 1.5, and 49 +/- 5.6 and 25 +/- 2.1 mm Hg at 1, 4, and 12 weeks. After NO synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME), PD in control limbs increased but in occluded limbs decreased by 20 +/- 2.0 mm Hg (acute) and 18 +/- 2.1, 15 +/- 4.4, and 20 +/- 8.1 mm Hg at 1, 4, and 12 weeks postligation, respectively. The percent of MAP (%MAP) dissipated by large arteries and collateral vessels decreased during collateral development (from 71 +/- 1.7% acutely to 57 +/- 2.2% at 12 weeks postligation) and was increased approximately 20% by L-NAME at each time point. The rise in PD and decrease in %MAP dissipated by collaterals following chronic occlusion indicates that significant collateral development occurred. The fall in PD and increase in %MAP dissipation after L-NAME administration suggest that NO-mediated vasodilatory tone is maintained throughout the period of collateral development.

Early collateral and microvascular adaptations to intestinal artery occlusion in rat.

The technique to repeatedly observe exactly the same vessels in the rat intestine was used to investigate vascular compensation during the 1st wk after abrupt arterial ligation. A collateral-dependent tissue region was created by ligation of three to four sequential intestinal arteries. At the center of the collateral-dependent region, arterial pressure decreased from 96 +/- 3.7 to 29 +/- 2.5 mmHg, and intestinal blood flow fell approximately 80% during maximal dilation initially postligation. One week later, pressure and blood flow at the center had increased 31 and 250%, respectively. Relative to preligation values, the only compensatory adaptation was an enlargement (31 +/- 11%) of the collateral arteries located between normal tissue and the center; no increase was observed in the diameter or numbers of arterioles or collateral arteries at the center. Wall shear rate was increased 173 +/- 35% initially postligation at the site where luminal enlargement occurred. The selective enlargement of collateral arteries away from the center region is consistent with the hypothesis that collateral enlargement is induced by chronic increases in wall shear rate and can occur independently of tissue ischemia.

Inhibition of NO synthase prevents acute collateral artery dilation in the rat hindlimb.

The role of endothelium-derived nitric oxide (EDNO) in the initial opening and sustained dilation of collateral vessels in the peripheral circulation was investigated. Abrupt arterial occlusion was produced by clamping the rat superficial femoral artery (SFA). Arterial pressures were measured proximal (MAP) and distal (PD) to the occlusion site. In one group (INITIAL DILATION), the clamp was removed after PD reached a plateau, and then the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), was administered and the occlusion repeated in the same limb to evaluate the role of nitric oxide in the initial opening of collateral vessels. In another group (SUSTAINED DILATION), L-NAME was administered after acute compensation to SFA occlusion had occurred to determine if inhibition of nitric oxide synthase would reverse any acute compensation. Collateral dilation was evaluated by recovery in PD relative to MAP (PD-%MAP) and by the percent of total resistance in the collateral-dependent circuit due primarily to collaterals (%Rc). The acute compensation indicated by an increase in PD-%MAP (14 +/- 1.9% to 27 +/- 2.6%) and decrease in %Rc (86 +/- 1.9 to 73 +/- 2.6%) in the INITIAL DILATION group was prevented by L-NAME (P < 0.0005). L-NAME also reversed the compensation in the SUSTAINED DILATION group; PD-%MAP decreased from 28 +/- 2.3% to 11 +/- 1.9% and %Rc increased from 72 +/- 2.3% to 93 +/- 1.1% after administration of L-NAME. Although collateral flow was not measured, the results are consistent with the hypothesis that acute collateral dilation is mediated by increases in flow or shear stress which stimulate the release of EDNO.

Early adaptations in collateral and microvascular resistances after ligation of the rat femoral artery.

Collateral and microvascular (including feed artery) resistances in the rat hindlimb were determined immediately or 1 wk after ligation of the femoral artery. Collateral-to-microvascular resistance ratios were determined from in vivo pressure measurements proximal and distal to the ligation. Microvascular resistance was 32 +/- 2.5 and 41 +/- 1.5% of the total collateral-dependent vasculature in acutely and chronically ligated limbs, respectively, and decreased 20% in both groups during reactive hyperemia. Minimum resistances of collateral vessels and the microcirculation arising from arterial branches proximal and distal to the ligation were determined by using a modification of the standard hindquarter perfusion technique for determining maximum vascular conductance. One week postligation, minimum total hindquarter resistance was decreased by a reduction in the resistance of the collaterals (approximately 50%) and microcirculation (approximately 33%) proximal to the ligation. The results suggest that the microvasculature distal to the occlusion is able to increase flow by dilation both initially and at 1 wk postligation but that collateral adaptations are primarily responsible for decreases in the minimum total resistance of the collateral-dependent region.

Preservation of postprandial intestinal hyperemic response after small bowel transplantation.

Postprandial intestinal hyperemia (PIH) is a normal physiological phenomenon and is thought to accommodate the increased intestinal metabolic demand during food digestion. Lack of such a response could lead to malabsorption. The purpose of this study was to determine whether transplanted intestine retains the ability to mediate PIH. Nineteen rats with syngeneic orthotopic small bowel transplantation (SBT) and 13 normal controls were further divided into two subgroups to receive gastric gavage of either 2 mL of Ensure Plus (EP) high-calorie liquid nutrition or 2 mL of normal saline. Intestinal blood flow was determined before, and 20 and 45 minutes after the gavage, employing a colored microsphere technique. The results showed that basal blood flow to the transplanted intestine (56.7 +/- 26.7 mL/min/100 g) was similar to that of normal intestine (64.2 +/- 35.8 mL/min/100 g; P > .1). EP feeding elicited a marked increase in intestinal blood flow (PIH phenomenon) in both normal and SBT animals. The magnitudes of flow increase were similar for the two groups (249 +/- 99% versus 241 +/- 76% of baseline 45 minutes after EP feeding in the normal and transplanted intestine, respectively; P > .1). The results indicate that hyperemic response to feeding is normal in syngeneic orthotopic SBT.

Current theories of pathogenesis and treatment of nonocclusive mesenteric ischemia.

Nonocclusive mesenteric ischemia (NOMI) is a poorly understood condition marked by progressive intestinal ischemia leading to infarction, sepsis, and death in a high proportion of patients. The mortality rate for this intestinal disorder remains high, even when the diagnosis is made early in the disease course. This paper presents a comprehensive review of NOMI with a detailed discussion of its history, pathophysiology, diagnosis, and treatment.

Exercise training effects on collateral and microvascular resistances in rat model of arterial insufficiency.

Experiments were performed to determine if exercise training reduces collateral or microvascular resistances in the hindlimb of rats with arterial insufficiency. After right femoral arterial ligation (age 10 wk), rats were divided into sedentary (Sed) and treadmill-trained (Tr) groups (7-9 wk, final intensity: 27 m/min, 6 degree grade, 60 min/day). Minimal resistances (mmHg.ml-1.min.100 g) of the total limb (RT), collateral vessels (RC), and the microcirculations distal (Rfmc) and proximal (Rimc) to the ligation site were determined during pump perfusion of the hindlimbs. RT was lower in nonligated (open) and acutely ligated limbs of Tr than Sed rats (open: 0.69 +/- 0.011 vs. 0.93 +/- 0.071; acute: 0.92 +/- 0.028 vs. 1.18 +/- 0.070 mmHg.ml-1.min.100 g) but not in chronically ligated limbs (chronic: 0.88 +/- 0.072 vs. 1.00 +/- 0.046 mmHg.ml-1.min.100 g). RC was similar between the chronically ligated limbs of Sed and Tr rats (1.69 +/- 0.165 vs. 1.97 +/- 0.227 mmHg.ml-1.min.100 g) and was approximately 70% lower than in acutely ligated limbs of both groups. Rfmc and Rimc were not affected by arterial ligation, but Rimc was significantly lower in Tr than in Sed rats (acute: 1.05 +/- 0.026 vs. 1.54 +/- 0.163; chronic: 1.24 +/- 0.071 vs. 1.81 +/- 0.202 mmHg.ml-1.min.100 g). These results indicate that the primary site of vascular adaptations to chronic arterial ligation is in the collateral vessels. Exercise training does not significantly alter the collateralization process but may provide protection against acute arterial occlusion by stimulating microvascular growth.