Thyroid status and endothelium-dependent vasodilation in skeletal muscle.

Cardiovascular dysfunction is characteristic of both hypo- and hyperthyroidism. Endothelium-dependent dilation of conductance vessels is impaired in hypothyroidism but augmented in hyperthyroidism. We hypothesized that these alterations in dilation extend into the resistance vasculature of skeletal muscle. To test this hypothesis, rats were made hypothyroid with propylthiouracil (Hypo; n = 13) or hyperthyroid with triiodothyronine (Hyper; n = 9) over 3-4 mo. Compared with euthyroid controls (Eut; n = 14), Hypo rats were characterized by reduced skeletal muscle oxidative capacity and blunted growth; Hyper rats exhibited increased muscle oxidative capacity and left ventricular hypertrophy (P < 0.05 for all effects). Vasodilation to the endothelium-dependent agent acetylcholine ( approximately 2 x 10(-4) M) in skeletal muscle was determined in situ. Conductance in certain muscles increased from control [e.g., soleus: 0.98 +/- 0.15 (Eut), 0.79 +/- 0.14 (Hypo), and 1.06 +/- 0.24 ml.min(-1).100 g(-1).mmHg(-1) (Hyper); not significant among groups] to acetylcholine [1.91 +/- 0.21 (Eut), 2.28 +/- 0.26 (Hypo), and 2.15 +/- 0.33 ml.min(-1).100 g(-1).mmHg(-1) (Hyper); P < 0.05 vs. control values for all groups] but did not differ among groups. Expression of mRNA for the endothelial isoform of nitric oxide synthase in resistance vessels isolated from various muscles was similarly unchanged with alterations in thyroid status [e.g., soleus 1A arterioles: 33.15 +/- 0.58 (Eut), 32.73 +/- 0.27 (Hypo), and 32.80 +/- 0.54 (Hyper) cycles at threshold; not significant]. These data suggest that endothelium-dependent dilation of resistance vasculature in skeletal muscle is unchanged in both hypo- and hyperthyroidism. These data also emphasize the importance of examining resistance vasculature to improve understanding of effects of chronic disease on integrated cardiovascular function.

Nonuniform effects of endurance exercise training on vasodilation in rat skeletal muscle.

Endurance exercise training (Ex) has been shown to increase maximal skeletal muscle blood flow. The purpose of this study was to test the hypothesis that increased endothelium-dependent vasodilation is associated with the Ex-induced increase in muscle blood flow. Furthermore, we hypothesized that enhanced endothelium-dependent dilation is confined to vessels in high-oxidative muscles that are recruited during Ex. To test these hypotheses, sedentary (Sed) and rats that underwent Ex (30 m/min x 10% grade, 60 min/day, 5 days/wk, 8-12 wk) were studied using three experimental approaches. Training effectiveness was evidenced by increased citrate synthase activity in soleus and vastus lateralis (red section) muscles (P < 0.05). Vasodilatory responses to the endothelium-dependent agent acetylcholine (ACh) in situ tended to be augmented by training in the red section of gastrocnemius muscle (RG; Sed: control, 0.69 +/- 0.12; ACh, 1.25 +/- 0.15; Ex: control, 0.86 +/- 0.17; ACh, 1.76 +/- 0.27 ml x min(-1) x 100 g(-1) x mmHg(-1); 0.05 < P < 0.10 for Ex vs. Sed during ACh). Responses to ACh in situ did not differ between Sed and Ex for either the soleus muscle or white section of gastrocnemius muscle (WG). Dilatory responses of second-order arterioles from the RG in vitro to flow (4-8 microl/min) and sodium nitroprusside (SNP; 10(-7) through 10(-4) M), but not ACh, were augmented in Ex (vs. Sed; P < 0.05). Dilatory responses to ACh, flow, and SNP of arterioles from soleus and WG muscles did not differ between Sed and Ex. Content of the endothelial isoform of nitric oxide synthase (eNOS) was increased in second-order, fourth-order, and fifth-order arterioles from the RG of Ex; eNOS content was similar between Sed and Ex in vessels from the soleus and WG muscles. These findings indicate that Ex induces endothelial adaptations in fast-twitch, oxidative, glycolytic skeletal muscle. These adaptations may contribute to enhanced skeletal muscle blood flow in endurance-trained individuals.

Hindlimb unweighting decreases ecNOS gene expression and endothelium-dependent dilation in rat soleus feed arteries.

We tested the hypothesis that hindlimb unweighting (HLU) and the associated reduction in soleus muscle blood flow causes decreased expression of endothelial cell nitric oxide synthase (ecNOS) mRNA and protein and attenuated endothelium-dependent vasodilator responses in rat soleus feed arteries (SFA). Male Sprague-Dawley rats were exposed to HLU (n = 12) or cage control (Con; n = 12) conditions for 14 days. At the end of this period, SFA were isolated, removed, and cannulated with two glass micropipettes for examination of vasodilator responses or frozen for analysis of ecNOS mRNA and protein expression. RT-PCR of RNA from single SFA was used to measure ecNOS mRNA, and immunoblots on single SFAs were used to measure ecNOS protein content. Results revealed that both ecNOS mRNA and ecNOS protein expression were lower in SFA from HLU rats. Dilation to increased intraluminal flow was attenuated in SFA from HLU rats (Con: 88 +/- 8% vs. HLU: 53 +/- 8%) as was maximal vasodilation to acetylcholine (10(-9)-10(-4) M; Con: 88 +/- 5% vs. HLU: 73 +/- 5%). Sensitivity to the endothelium-independent vasodilator sodium nitroprusside (10(-10)-10(-4) M) was enhanced by HLU (EC(50): Con: 4.46 x 10(-7) M vs. HLU: 5.00 x 10(-8) M). Collectively, these data indicate that the chronic reduction in soleus blood flow associated with the reduced physical activity during HLU results in reduced expression of ecNOS mRNA and protein in SFA and attenuated endothelium-dependent vasodilation.

Vasomotor responses of soleus feed arteries from sedentary and exercise-trained rats.

Our goals were to determine the nature of endothelium-dependent and -independent vascular responses in isolated soleus feed arteries (SFA) and to test the hypothesis that these responses would be altered by exercise training. Exercise-trained rats ran 30 m/min, up a 15% grade, 1 h/day, 5 days/wk for 10-12 wk, while sedentary control rats were confined to normal cage activity. SFA were isolated, cannulated, and pressurized at 90 cmH2O. After a 1-h equilibration period, the dose-response relationships to constrictors, endothelium-dependent dilators, and endothelium-independent dilators were examined. SFA developed spontaneous tone, demonstrated myogenic reactivity by maintaining vessel diameter in the face of large changes in intraluminal pressure, and constricted in a dose-dependent manner to norepinephrine and potassium chloride. SFA dilated in a dose-dependent manner to the endothelium-dependent dilators acetylcholine and increased flow and to the endothelium-independent dilator sodium nitroprusside. SFA did not dilate to the putative endothelium-dependent dilators bradykinin, substance P, and clonidine or to adenosine. Dilation to acetylcholine was attenuated markedly by arginine analogs and less by 20 mM KCl, but it was unaltered by indomethacin. These results indicate that SFA respond to a number of vasoactive substances, consistent with the hypothesis that SFA participate in the control of vascular resistance. However, exercise training does not appear to elicit a stimulus adequate to alter vasomotor responses in SFA.

Acetylcholine is a vasodilator of porcine skeletal muscle arteries.

The purpose of this study was to test the hypothesis that porcine skeletal muscle arteries exhibit concentration-dependent vasodilation in response to acetylcholine (ACH) as observed in other mammals. We conducted three experiments. First, vasorelaxation responses to ACH were examined in isolated segments of femoral and brachial arteries, mounted on myographs and studied in vitro. Second, we determined whether resistance arteries from porcine skeletal muscle exhibit vasodilation in response to ACH by isolating second order arterioles (2-A) from the medial (MHT), deep-long (LOH) and lateral (LAT) heads of the triceps brachii muscles of four pigs. The rationale for selection of arterioles from these muscles was that these muscles represent muscles composed primarily of slow-oxidative, fast-oxidative-glycolytic, and fast-glycolytic muscle fiber types, respectively. 2-As were isolated and cannulated with micropipettes and intraluminal pressure set at 60 cm H2O. In both sets of in vitro experiments, we determined responses to an endothelium-independent dilator, sodium nitroprusside (10(-10)-10(-4) M), and to endothelium-dependent agents ACH (10(-10)-10(-4) M), and bradykinin (BK; 10(-11)-10(-6) M). Third, we used transcutaneous ultrasound imaging to measure changes in artery diameters and Doppler-principle measurements of blood flow velocities to estimate changes in total blood flow in the femoral vascular bed. Results reveal that ACH and BK produced similar vasorelaxation responses in femoral and brachial arteries and vasodilation of skeletal muscle 2-As. Also, ACH produced increases in blood flow and decreases in vascular resistance in the femoral vascular bed. These results indicate that the arterial tree of porcine skeletal muscle exhibits ACH-induced, endothelium-dependent vasodilation.

Flow-induced dilation of rat soleus feed arteries.

Flow-induced dilation is thought to contribute to dilation of skeletal muscle arteries and arterioles during exercise hyperemia. We sought to determine whether rat soleus feed arteries (SFA) exhibit flow-induced dilation and to evaluate the potential contribution of flow-induced dilation of SFA to exercise hyperemia. Rat SFA were isolated and cannulated to allow pressure and intraluminal flow to be independently controlled. Intraluminal pressure was maintained at 90 cmH2O throughout the experiment. All SFA (n = 13) developed spontaneous tone and dilated in response to flow. Flow of 10 and 14 microliters/min produced a 34 +/- 14 and 56 +/- 17 microns increase above basal diameter (135 +/- 12 microns), respectively. Flows > 14 microliters/min produced little further dilation. Maximum flow-induced dilation was 86 +/- 3% of passive diameter determined in calcium-free physiological saline solution. Calculated shear stress was maintained at 4-6 dyn/cm2 at flows of 10-20 microliters/min but increased at greater flows because SFA did not dilate further. To determine whether dilation in response to flows in this range may contribute to exercise hyperemia, we estimated in vivo SFA blood flows from previously published soleus blood flow data. Anesthetized rats are estimated to have flows of 10 microliters/min per SFA, and conscious rats are estimated to have flows of 95 (nonexercising), 153 (walking), and 225 (running) microliters/min per SFA. Corresponding shear stresses were estimated to be 26 (anesthetized), 47 (conscious, nonexercising), 75 (walking), and 111 (running) dyn/cm2. Because estimated in vivo values for both flow and wall shear stress are far greater than the flow and/or shear stresses at which maximal flow-induced dilation occurs in vitro, we conclude that flow-induced dilation contributes little to dilation of SFA during locomotory exercise.

Endothelium-medicated control of the coronary circulation. Exercise training-induced vascular adaptations.

This review discusses the role of the endothelium in the regulation of coronary vascular function. The role of endothelium-mediated mechanisms at rest, during exercise, in exercise training-induced adaptations of coronary function and in the presence of coronary heart disease (CHD) are examined. Mechanisms of control of coronary blood flow are briefly discussed with emphasis on endothelium-mediated control of vascular resistance. The concept that the relative importance of vascular control mechanisms differs as a function of position along the coronary arterial tree is developed and discussed. Metabolic, myogenic and endothelium-mediated control systems contribute in parallel to regulating coronary blood flow. The relative importance of these mechanisms varies throughout the coronary arterial tree. Endothelium-dependent vasodilation contributes to maintenance of resting coronary blood flow but the endothelium's role in dilation of small resistance arteries, thereby increasing coronary blood flow during exercise, remains in question. In contrast, the endothelium plays an essential role in dilation of the conduit coronary arteries during exercise. Atherosclerosis and CHD convert this exercise-induced dilation to a vasoconstriction, apparently due to endothelium dysfunction. Long term increases in physical activity and exercise training alter the control of coronary blood flow. Adaptations in endothelium-mediated control play a role in these changes. However, the effects of the mode, frequency, and intensity of exercise training bouts and duration of training on adaptive changes in endothelial function have not been established. The role of the endothelium in control of the permeability characteristics of the exchange vessels in the coronary circulation is discussed. Current evidence indicates that vascular permeability is a dynamic characteristic of the vessel wall that is controlled, at least in part, by endothelium-dependent phenomena. Also, preliminary results indicate that exercise training alters microvessel permeability and the control of permeability in the coronary circulation. Further research is needed to provide clarification of the effects of exercise training on coronary endothelial control of vascular resistance and vascular permeability in atherosclerosis and CHD.

Active forearm blood flow adjustments to handgrip exercise in young and older healthy men.

1. Our purpose was to test the hypothesis that ageing impairs the active muscle hyperaemia consequent to dynamic exercise in humans. 2. Eleven young (19-29 years) and eleven older (60-74 years) healthy, non-obese men with similar chronic physical activity levels and forearm size performed two protocols of dynamic handgrip exercise: (a) brief (1 min), incremental loads to exhaustion, and (b) sustained (8 min), submaximal loads. Active forearm blood flow (FBF) was measured at rest and during a brief period of relaxation at the end of each minute of exercise. Arterial blood pressure was recorded to calculate active forearm vascular conductance (FVC). Sustained forearm ischaemia plus handgrip was used to elicit a peak forearm vasodilatatory response. 3. There were no differences in pre-exercise levels of any variable between the young and older men. During exercise, ratings of perceived effort, the peak workload attained, and the ability to sustain submaximal workloads were all similar for the two groups. 4. During brief exercise, both submaximal and peak levels of FBF were similar in the two groups; however, the peak increases in FVC were greater in the older men. During sustained exercise, FBF and FVC were not different in the two groups at the lowest loads, but the increases became relatively greater in the older men with increasing workloads. 5. Peak levels of FBF and FVC in response to the peak vasodilatatory stimulus were similar in the young and older men. 6. These findings fail to support the postulate that ageing results in impaired active muscle hyperaemia and vasodilatation during small-muscle dynamic exercise.(ABSTRACT TRUNCATED AT 250 WORDS)