Skeletal muscle vascular transport capacity in diabetic rats

Skeletal muscle vascular transport capacity in diabetic rats

William L. Sexton

This study aimed to determine the effect of long-term (17-20 weeks) streptozocin (STZ)-induced diabetes on skeletal muscle vascular transport capacity. Vascular transport capacity was determined from measurements of pressure-flow relationships, capillary filtration coefficient, and permeability-surface area product (PS) for [.sup.51]Cr-EDTA in isolated perfused hindquarters of control (n = 7) and diabetic (n = 6; 65 mg/kg STZ intraperitoneally) rats. Hindquarters were perfused with Tyrode’s solution containing albumin (5 g/dl) and horse serum (10% vol/vol) and were maximally vasodilated with papaverine (30 mM). Hindquarters of diabetic rats weighed 42% less than control rats (86 [+ or -] 3 vs. 147 [+ or -] 4 g; P [less than or equal to] 0.001) because of profound muscle atrophy. Total hindquarters flow (ml [multiplied by] [min.sup.-1] [multiplied by] 100 [g.sup.-1]) was greater in diabetic rats (P [less than] 0.001) at perfusion pressures between 23 and 75 mmHg, indicative of an increased flow capacity relative to control rats. However, absolute flows (ml/min) were not different between control and diabetic rats. Neither capillary filtration coefficient (control = 0.0243 [+ or -] 0.0010 and diabetic = 0.0297 [+ or -] 0.0024 ml [multiplied by] [min.sup.-1] [multiplied by] [mmHg.sup.-1]. 100 [g.sup.-1]) nor isogravimetric PS (control = 3.91 [+ or -] 0.31 and diabetic = 4.39 [+ or -] 0.46 ml [multiplied by] [min.sup.-1] [multiplied by] 100 [g.sup.-1]) were different in control and diabetic rats. However, absolute values for capillary filtration coefficient (ml [multiplied by] [min.sup.-1] [multiplied by] [mmHg.sup.-1]) and PS (ml/min) were less in diabetic rats. These results indicate that muscle atrophy in rats with STZ-induced diabetes is accompanied by a proportional reduction in absolute exchange capacity for water (capillary filtration coefficient) and small solutes PS, such that microvascular exchange capacity per tissue mass is maintained at control levels. In contrast, absolute flow capacity is unchanged in diabetic rats such that hindquarters flow capacity per tissue mass is increased, which results in a greater vascular transport capacity. Diabetes 43:225-31, 1994

Streptozocin (STZ)-induced diabetes in rats causes marked reduction in body weight that is largely the result of atrophy of skeletal muscle [1]. The adaptive response of the skeletal muscle microcirculation to the diabetic state is not well defined. Bohlen and Niggl [2] observed that STZ-induced diabetes in adult mice causes significant atrophy of the cremaster muscle. No change was noted in the number of arterioles in the cremaster of diabetic mice, but a marked loss of capillaries occurred [2]. The greater number of arterioles per cremaster muscle mass in diabetic mice relative to control mice suggests that maximal blood flow per muscle mass would be greater. In contrast, the reduction in capillary number was offset by an equivalent reduction in cremaster mass, suggesting that the capacity for microvascular exchange per muscle mass would be similar in control and diabetic mice.

Vascular transport capacity describes the potential for microvascular transport of water and solutes to and from the tissue parenchyma [3-5]. Vascular transport is a two-step process involving both convective transport of substances to the exchange vessels, flow capacity, and movement of substances across the capillaries and small venules, microvascular exchange capacity. Flow capacity describes the maximal conductance of the vascular bed, whereas exchange capacity is dependent on the microvascular surface area available for exchange and the permeability of the exchange barrier to water and solutes [3-5]. the influence of diabetes on skeletal muscle blood flow and transcapillary exchange have been examined by a number of investigators [6-15]. However, the effects of diabetes on skeletal muscle vascular transport capacity remain unclear, in large part because of the diversity of methods and experimental models used.

This study was conducted to determine if vascular transport capacity is altered in hindlimb skeletal muscle of STZ-induced diabetic rats. Based on previous studies [1,2], it was hypothesized that diabetes-induced muscle atrophy in rats would be accompanied by a proportional reduction in the absolute microvascular exchange capacity but that absolute flow capacity would be maintained. Vascular transport capacity was measured in maximally vasodilated, isolated, perfused hindquarters of control and diabetic rats 17-20 weeks after induction with STZ to determine the nature of vascular adaptations in the skeletal muscle microcirculation associated with long-standing diabetes.

RESEARCH DESIGN AND METHODS

Sixteen male Sprague-Dawley rats (Hilltop, Scottsdale, PA) initially weighing 250-275 g were used in these studies. The rats were randomly divided into control (n = 8) and diabetic (n = 8) groups. Rats in the diabetic group received a single intraperitoneal injection of STZ (65 mg/kg) dissolved in sterile saline, whereas rats in the control group received an equivalent volume of the saline vehicle. The onset of diabetes was confirmed 24-48 h later with the use of urine test strips for glucose (Diastix, Ames, Elkhart, IN). The rats were housed in pairs in hanging wire cages (24 x 8 x 12 inches) under controlled temperature (23 [degrees] C) and light conditions (12-h light-dark cycle). The rats were allowed free access to water and commercial rat chow. Experiments were conducted 17-20 weeks after induction of diabetes to examine the effects of long-standing diabetes on the adaptive response of the skeletal muscle microcirculation.

Hindquarters preparation. The effect of STZ-induced diabetes on capillary exchange capacity and flow capacity of rat skeletal muscle was determined with the use of the vascularly isolated, perfused rat hindquarters preparation as described previously [3-5,16,17]. Rats were fasted overnight before the experiment. After delivering pentobarbital sodium anesthesia (65 mg/kg intraperitoneally), the trachea was cannulated to ensure a patent airway during the surgical procedure, and the tail artery was cannulated (PE-50) for monitoring of perfusion pressure. Plasma samples were collected during surgery and frozen for later determination of fasting plasma glucose (FPG) concentration (Glucose Analyzer 2, Beckman, Fullerton, CA).

After making a midline abdominal incision by using thermocautery, the intestines, colon, and testes were resected, and flow to the seminal vesicles, prostate, and bladder was occluded with a mass ligature. The abdominal aorta and vena cava were isolated between the renal and iliolumbar vessels. The skin and abdominal muscles were separated circumferentially by using thermocautery. Heparin (1,000 U) was administered via the tail artery. Ten minutes later the inferior vena cava and the abdominal aorta were cannulated, and the hindquarters were perfused with the use of a peristaltic pump (minipuls 2, Gilson, Middleton, WI). A tight ligature was placed around the lumbar musculature at the level of the catheters, and the hindquarters were separated from the body cephalad to the ligature. The spinal canal was plugged with cotton and sealed with cyanoacrylate adhesive to prevent seepage.

Arterial pressure was monitored from the tail artery catheter and venous pressure was monitored from a side branch of the venous catheter with the use of pressure transducers (P23AC, Statham, Hato Rey, Puerto Rico). The hindquarters preparation was placed on a grid suspended from a strain gauge transducer (FT03C, Grass Quincy, MA) to monitor changes in weight during the experiments. Arterial and venous pressures and hindquarters weight were recorded continuously with the use of a Grass model 7 polygraph. The sensitivity of the weight-recording system was calibrated so that 1 g of weight produced a pen deflection of 20 mm on the recording paper. Rectal temperature was monitored with a thermistor (YSI, Yellow Springs, OH) and was maintained at 37 [degrees] C by using an infrared heat lamp.

Perfusate. Hindquarters of control and diabetic rats were perfused with Tyrode’s solution containing 10 mM D-glucose, bovine serum albumin (5 g/dl; Sigma, St. Louis, MO), and horse serum (10% vol/vol; Pel-Freeze, Rogers, AR). A cell-free, artificial perfusate was used in these experiments to eliminate the potential influence of different rheological properties of blood cells in control and diabetic animals [14] and to eliminate the potential impact of circulating vasoactive factors that might influence the results [9]. A small amount of horse serum is required to maintain the integrity of the exchange barrier during perfusion with artificial perfusates [16]. Papaverine (Sigma) was added to the perfusate at a concentration known to produce maximal vasodilation (0.2 mM) [5]. The perfusate was bubbled with 95% [O.sub.2] and 5% [CO.sub.2] to yield [PO.sub.2] of |400 mmHg and [PCO.sub.2] of |40 mmHg, and the pH was adjusted to 7.4. The perfusate was maintained at 37 [degrees] C with the use of a thermostatically controlled hot plate/stirrer.

Flow capacity. Hindquarters flow and venous pressure were adjusted to achieve the isogravimetric state indicative of no net fluid filtration or reabsorption. Isogravimentric capillary pressure was determined according to the method of Papenhiemer and Soto-Rivera [18]. Flow was reduced a small increment (|10%) causing arterial pressure and hindquarters weight to fall, and venous pressure was then increased to re-establish the isogravimetric state. This procedure was repeated to obtain four to five isogravimetric points. Isogravimetric capillary pressure was calculated as the zero flow intercept of the linear relationship between venous pressure and flow [18].

Total vascular resistance ([R.sub.T]), precapillary vascular resistance ([R.sub.a]), and postcapillary vascular resistance ([R.sub.v]) were calculated according to the following relationships: [R.sub.T] = ([P.sub.a] – [P.sub.v])/F, [R.sub.a] = ([P.sub.a] – [P.sub.c])/F, and [R.sub.v] = ([P.sub.c] – [P.sub.v])/F, where [P.sub.a], [P.sub.v], [P.sub.c] and F are arterial pressure, venous pressure, capillary pressure, and flow under isogravimetric conditions, respectively [4,5,17,19].

Total hindquarters flow capacity for control and diabetic rats was determined from the pressure-flow relationship in the maximally vasodilated state [4,5]. Flow was increased in a stepwise manner, and the perfusion pressure was recorded while venous pressure was maintained equal to 0 mmHg.

Capillary exchange capacity. The capillary exchange capacity of the hindquarters microcirculation was determined from measurements of the capillary filtration coefficient (CFC) for fluids and permeability-surface area product (PS) for [.sup.51]Cr-EDTA. CFC was measured according to the method of Pappenhiemer and Soto-Rivera [18]. From the isogravimetric state, venous pressure was increased 8-15 mmHg resulting in an increase in capillary pressure and net fluid filtration as evidenced by an increase in hindquarters weight. The temporal pattern of hindquarters weight gain consists of an initial, fast component attributed to changes in vascular capacitance followed by a slow component caused by net fluid filtration from capillaries into the interstitium. The rate of fluid filtration between 2 and 4 min was determined at three to six different increments in venous pressure for each hindquarter. CFC was calculated as the slope of the linear relationship between the rate of fluid filtration and the increment in capillary pressure [19], which was assumed to be 85% of increment in venous pressure [17,19].

PS for [.sup.51]Cr-EDTA was measured using the single-injection, multiple indicator-dilution method [3,16,20,21]. A bolus injection of perfusate (100 [micro]l) containing a reference tracer that remains intravascular ([.sup.125]I-labeled albumin) and a diffusible solute [.sup.51]Cr-EDTA) was injected into the arterial inflow while continuous sequential samples (1/s) of venous effluent were collected. Samples of venous effluent (200 [micro]l) were placed into counting vials, and the activity of the tracers was measured on a [gamma]-counter (model 1185, Tracor Analytic, Elle Grove Village, IL) interfaced with a computer and multichannel pluse-height analyzer. The relative concentrations of the reference ([C.sub.r]) and diffusible ([C.sub.d]) tracers were determined and the instantaneous extraction at each sample time ([E.sub.t]) was calculated according to the relationship [E.sub.t] = ([C.sub.r] – [C.sub.d])/[C.sub.r] (Fig. 1). PS for [.sup.51]Cr-EDTA was calculated using the mean value for [E.sub.t] from the plateau of the [E.sub.t] vs. time plot according to the relationship PS = -flow. In (1 – [E.sub.t]).

Experimental protocol. After completion of surgical procedures, the hindquarters were flushed with 80-100 ml of perfusate to remove the blood cells from the vasculature before recirculation of perfusate. About 45 min was allowed for the preparation to stabilize, during which time flow and venous pressure were adjusted to achieve the maximally vasodilated, isogravimetric state. The following measurements were made in order: three to five determinations of CFC, isogravimetric capillary pressure, pressure-flow relationship, and three to five determinations of PS at different flows.

Statistical analysis. The data are presented as means [+ or -] SE. Data for control and diabetic groups were compared using a Student’s t test. The statistical significance of differences between control and diabetic groups was based on P [less than or equal to] 0.05.

RESULTS

Data for control (n = 7) and diabetic (n = 6) rats are presented in Table 1. Data for one control and two diabetic rats were incomplete as a result of technical problems during the experiments, and these data were omitted from analysis. No diabetic rats died during the experimental period despite a profoundly diabetic state. FPG concentration was elevated in diabetic rats compared with control rats (Table 1). Diabetic rats weighed 26% less than their age-matched controls. Hindquarters of diabetic rats weighted 42% less than control rats and constituted a smaller fraction of total body weight as evidenced by the lower hindquarters-to-body weight ratio. Because of marked differences in hindquarters weight between control and diabetic rats, which is largely the result of muscle atrophy, the data are presented both in absolute terms (i.e., per hindquarters) and normalized per 100 g of tissue. This approach makes it possible to distinguish between diabetes-induced vascular adaptations and the influence of muscle atrophy when normalizing data.

[TABULAR DATA OMITTED]

Flow capacity. In the isogravimetric state, arterial, venous, perfusion (arterial minus venous), and capillary pressures were similar in hindquarters of control and diabetic rats (Table 2). Absolute isogravimetric flow (ml/min) was not different in hindquarters of control and diabetic rats. Absolute total, precapillary, and postcapillary vascular resistances were unchanged in diabetic rats (Table 2). However, because of marked hindlimb muscle atrophy in diabetic rats, isogravimetric flow normalized per 100 g was 70% greater than in control rats. Therefore, total, precapillary, and postcapillary vascular resistances expressed per 100 g were less in diabetic rats. The precapillary-to-postcapillary resistance ratio was similar in control and diabetic rats.

Pressure-flow relationships revealed that absolute flow at a given perfusion pressure was unchanged in hindquarters of control and diabetic rats (Fig. 2A). However, flow per 100 g of perfused tissue was greater in diabetic rats compared with control rats reflecting an increased flow capacity per tissue mass in diabetics (Fig. 2B).

Capillary exchange capacity. Absolute CFC was 30% lower in diabetic rats (0.0251 [+ or -] 0.0014 ml [multiplied by] [min.sup.-1] [multiplied by] [mmHg.sup.-1]) compared with control rats (0.0355 [+ or -] 0.0016 ml [multiplied by] [min.sup.-1] [multiplied by] [mmHg.sup.-1]) (Fig. 3A). However, because hindquarters of diabetic rats were smaller than control rats, CFC expressed per 100 g was not significantly different between diabetic (0.0297 [+ or -] 0.0024 ml [multiplied by] [min.sup.-1] [multiplied by] [mmHg.sup.-1] [multiplied by] 100 [g.sup.-1]) and control (0.0243 [+ or -] 0.0010 ml [multiplied by] [min.sup.-1] [multiplied by] [mmHg.sup.-1] [multiplied by] 100 [g.sup.-1]) rats (Fig. 3B).

PS measured in the isogravimetric state was 32% lower in hindquarters of diabetic rats (3.71 [+ or -] 0.34 ml/min) compared with control rats (5.64 [+ or -] 0.42 ml/min). When expressed per 100 g, PS for diabetic (4.39 [+ or -] 0.46 ml [multiplied by] [min.sup.-1] [multiplied by] 100 [g.sup.-1]) and control (3.91 [+ or -] 0.31 ml [multiplied by] [min.sup.-1] [multiplied by] 100 [g.sup.-1]) rats were not different. Measurements of PS over a wide range of flows revealed that absolute PS in hindquarters of diabetic rats was less than control rats at all comparable flows (Fig. 4A). However, the relationship between flow per 100 g and PS per 100 g for hindquarters of control and diabetic rats was not different (Fig. 4B).

DISCUSSION

The results of this study indicate that vascular transport capacity is well maintained in hindlimb skeletal muscle of STZ-induced diabetic rats. Absolute flow capacity is not altered in hindlimbs of diabetic rats, but because of muscular atrophy, flow capacity per muscle mass is greater in diabetic rats relative to control rats. In contrast, reductions in absolute capacity for microvascular exchange of water (CFC) and small solutes (PS) are offset by proportional reductions in hindlimb skeletal muscle mass, such that microvascular exchange capacity per muscle mass in diabetic rats is equivalent to control rats. These results also indicate that the effects of STZ-induced diabetes are not uniform at all levels of the skeletal muscle microcirculation. The constancy of absolute flow capacity in diabetic rat hindquarters suggests that the arteriolar tree is relatively spared, whereas the reduction in absolute microvascular exchange capacity (decreased CFC and PS) in diabetic rats suggests that a loss of microvascular surface area available for exchange occurs.

The isolated, perfused rat hindquarters preparation permits assessment of the effects of diabetes on an intact, continuous vascular bed free of regulatory and rheological influences [9,16]. Rat hindquarters consist of |75% skeletal muscle with the balance being principally skin and bone [16,22]. Because the vascularity of skin and bone are considerably less than maximally vasodilated skeletal muscle, the relative contribution of skin and bone to the overall measurements are small. Thus, measurement of vascular transport capacity in rat hindquarters largely reflects that of the skeletal muscle microcirculation [16].

The muscle fiber-type composition of rat hindlimbs is |75% fast-twitch glycolytic (FG), 19% fast-twitch oxidative-glycolytic (FOG), and 5% slow-twitch oxidative (SO) muscle fibers [22]. Fiber-type composition varies within and among different muscles [22], so that measurements of flow capacity, CFC, and PS reflect the weighted average of the all perfused tissues. Thus, it is expected that, in rat hindquarters, these measurements are most sensitive to vascular changes in FG muscles. In fact, Armstrong et al.[1] found a 25% decrease in FG muscle fiber cross-sectional area in diabetic rats, whereas SO and FOG fiber areas were unaffected. In addition, large vessel disease, which might obscure evaluation of microvascular functional capacity, has not been observed in diabetic rats [23]. Thus, the rat hindquarters preparation is a good model in which to assess the effects of diabetes on vascular transport capacity in an intact and continuous skeletal muscle vascular bed.

The increase in flow capacity per hindquarters mass in diabetic rats in this study is in accord with previous reports by Mueller et al. [9,10]. They found significant reduction in vascular resistance of maximally vasodilated, perfused rat hindquarters after 5 weeks of alloxan-induced diabetes [9], although the difference was not statistically significant after 14 weeks of diabetes [10]. The decrease in total vascular resistance was attributed to structural alterations in the hindquarters vasculature [9]. However, close examination of their data reveals that absolute flows were similar in control and diabetic rats, and the decrease in resistance can be accounted for by and [greater than]50% reduction in hindquarters mass in the diabetic rats. Bohlen and Niggl [2] reported that the number of arterioles in the cremaster muscle of diabetic mice was unchanged from control mice. They also noted that passive arteriolar diameters were slightly less in diabetic mice, which would be expected to increase the resistance to flow [2]. However, because of the reduction in cremaster muscle mass in the diabetic mice, the number of arterioles (2A and 3A arterioles) per muscle mass in diabetic mice was increased 67% [2]. Thus, these data combined with those from this study indicate that absolute flow is unaltered in skeletal muscle of diabetic rats and suggest that muscle atrophy diabetic rats is not associated with significant alterations in total arteriolar cross-sectional area.

The effect of diabetes on muscle blood flow capacity in humans is less clear. Reports indicate that peak muscle blood flow after ischemic exercise in diabetic patients is either unchanged [11,13] or reduced [7,8] relative to control flows. Because humans do not show the marked muscle atrophy observed in diabetic rats, the maintenance of flow capacity in diabetic individuals may reflect the similar absolute flow capacity observed in hindquarters of control and diabetic rats. Alternatively, differences in flow between results in humans and rats may be because the rat hindquarters were pharmacologically vasodilated with papaverine and independent of normal regulatory mechanisms. In addition, perfusion of the hindquarters with a cell-free media eliminates the potential influence of diabetes-induced changes in rheological properties of the blood that may obscure assessment of vascular flow capacity [14].

Isogravimetric capillary pressure was identical in maximally vasodilated hindquarters of control and diabetic rats. Possibly, the microvascular permeability to plasma proteins is increased in diabetes [15]. However, an increase in protein permeability would result in a lower capillary pressure under isogravimetric conditions [18, 24,25]. Thus, these data suggest that microvascular permeability to plasma proteins is not significantly altered in STZ-induced diabetes. Protein extravasation can increase with elevation of capillary pressure by solvent drag even if microvascular permeability is unchanged [17,21,24]. Increases in capillary pressure in vivo associated with reduced autoregulatory capacity and altered vascular sensitivity to constrictor agents may be an important initiating event in the development of microvascular disease in diabetes [12,14,15]. The pre-to-post-capillary vascular resistance ratio under maximally vasodilated conditions was also similar in both groups. If differences exist in capillary pressure between control and diabetic rats in vivo, these differences are probably caused by alterations in pre- and postcapillary vascular tone [21,25].

CFC and PS are products of the microvascular surface area available for exchange and the microvascular permeability to water and [.sup.51]Cr-EDTA, respectively [18,21, 24,25]. Therefore, the lower CFC and PS in hindquarters of diabetic rats could be caused by reductions in microvascular surface are or microvascular permeability or both. Even under maximally vasodilated conditions, microvascular perfusion may not be uniform, and some capillaries may be poorly perfused or not perfused at all as a result of heterogeneity of microvascular perfusion [20,21]. CFC is considered to be a better indicator of total effective microvascular surface area than PS because increases in venous pressure during measurement of CFC can cause net fluid filtration even in poorly perfused or nonperfused vessels, thereby minimizing the effects of perfusion heterogeneity [20,26]. In contrast, PS is more sensitive to microvascular perfusion heterogeneity, and measurements of PS reflect only the perfused surface area [20,21,26]. In this study, the increase in PS with increasing flow probably reflects reduced perfusion heterogeneity and the recruitment of effective exchange surface area [20,21]. The plateau seen in the PS versus flow relationship in both control and diabetic hindquarters suggests that maximal PS values were obtained [25]. If microvascular permeability is increased in diabetes as has been suggested [15], then both CFC and PS would be expected to be greater in hindquarters of diabetic rats. The fact that absolute CFC and PS were reduced to similar extent in hindquarters of diabetic rats (-30 and -32%, respectively) supports the notion that a marked reduction occurs in the maximal available microvascular surface area in skeletal muscle of diabetic rats.

In addition to marked FG muscle fiber atrophy, Armstrong et al. [1] noted a tendency for lower capillary-to-fiber ratios in FG muscle of diabetic rats. Because rat hindquarters are predominantly FG muscle, even a small decrease in capillary-to-fiber ratio would profoundly reduce the measured CFC and PS. Bohlen and Niggl [2] reported that the 23% decrease in cremaster muscle mass observed in diabetic mice was accompanied by a 25% decrease in capillary number such that the capillary number per muscle mass remained constant. In this study, CFC per 100 g and PS per 100 g of perfused tissue were similar in hindquarters of control and diabetic rats, which suggests that the reduction in absolute CFC and PS in muscle of diabetic rats may be attributed to proportional reductions in both microvascular surface area and muscle mass. The causes of muscle atrophy and capillary loss in skeletal muscle of diabetic rats and mice are not known. Possibly, diabetes somehow reduces microvascular growth or causes involution and loss of existing microvessels [2].

The effects of diabetes on microvascular exchange in skeletal muscle of human diabetic individuals are less clear. Katz and Janjan [6] reported that CFC was lower in the hyperemic forearm muscle of diabetic patients, which they attributed to a decrease in microvascular surface area. However, Alpert et al. [7] found that CFC in the hyperemic calf muscle of diabetic patients was unchanged from control subjects but noted that capillary diffusing capacity (i.e., PS) was increased. They reasoned that, because CFC was unchanged and diffusing capacity was increased, permeability to small solutes must be increased, in the diabetic individuals [7]. Leinonen et al. [8] also observed increased capillary diffusing capacity in the muscle of diabetic patients but found no difference in capillary density (number of capillaries per square millimeter) in muscle samples from control and diabetic subjects. They concluded that the increase in diffusing capacity was caused by an increased microvascular permeability to small solutes. However, they provided no data for muscle fiber area or capillary-to-fiber ratio, so it is not possible to ascertain whether these changes were caused by structural alterations in the muscle vasculature or to changes in microvascular permeability.

Despite marked muscular atrophy in hindlimbs of rats with 17-20 weeks of STZ-induced diabetes, absolute hindquarters flow capacity is unchanged from control rats. Consequently, flow capacity normalized per muscle mass is greater in diabetic rats. Absolute values for capillary exchange capacity for water (CFC) and small solutes (PS for [.sup.51]Cr-EDTA) are reduced in hindquarters of diabetic rats. However, the reduction in CFC and PS is proportional to the degree of muscle atrophy, such that both CFC/100 g and PS/100 g of tissue are similar in hindquarters of control and diabetic rats. These results suggest that muscle atrophy in STZ-induced diabetic rats is accompanied by a proportional reduction in the maximal microvascular surface area available for water and solute exchange. The maintenance of normal exchange capacity with an increased flow capacity indicates that vascular transport capacity is greater in hindquarters of rats with long-standing STZ-induced diabetes.

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