Richard M. McAllister

Adaptations in control of blood flow with training: splanchnic and renal blood flows.

Acute exercise is associated with large increases in cardiac and active skeletal muscle blood flows and reduced blood flows to inactive muscle, skin, kidneys, and organs served by the splanchnic circulation. Splanchnic and renal blood flows are reduced in proportion to relative exercise intensity. Increased sympathetic nervous system outflow to splanchnic and renal vasculature appears to be the primary mediator of reduced blood flows in these circulations, but the vasoconstrictors angiotensin II and vasopressin also make important contributions. Human and animal studies have shown that splanchnic and renal blood flows are reduced less from resting levels during acute exercise after a period of endurance exercise training. Investigations of mechanisms involved in these adaptations suggest that reductions in sympathetic nervous system outflow, and plasma angiotensin II and vasopressin concentrations, are involved in lesser splanchnic and renal vasoconstriction exhibited by trained individuals. In addition, a reduced response to the sympathetic neurotransmitter norepinephrine in renal vasculature may contribute to greater blood flow to the kidney during acute exercise after training. Greater splanchnic and renal blood flows during acute exercise following training are potentially beneficial in that disturbance from homeostasis would be less in the trained state. Additionally, increased splanchnic blood flow in the trained state may confer benefits for glucose metabolism during prolonged exercise.

Vascular nitric oxide: effects of exercise training in animals

Exercise training is known to induce several adaptations in the cardiovascular system, one of which is increased skeletal muscle blood flow at maximal exercise. Improved muscle blood flow, in turn, could in part be accounted for by augmented endothelium-dependent, nitric oxide (NO)-mediated vasodilation. Studies have indeed demonstrated that endothelium-dependent, NO-mediated dilation of conductance-type vessels is augmented after endurance exercise training; recently, this adaptation has been extended into resistance-type vessels within rodent skeletal muscle. With the latter, however, it appears that only resistance vessels supplying muscle active during training sessions exhibit this adaptation. These findings in rats are in contrast to those from human studies, in which increased endothelium-dependent dilation has been observed in vasculatures not associated with elevated blood flow during exercise. Increased expression of endothelial NO synthase (eNOS) appears to underlie enhanced endothelium-dependent, NO-mediated dilation of both conductance and resistance vessels. Greater eNOS expression may also underlie the preventive and (or) rehabilitative effect(s) of exercise training on atherosclerosis, given that NO inhibits several steps of the atherosclerotic disease process. Thus, exercise training may induce adaptations that benefit both vasodilation and vascular health.

Contribution of endothelium-derived nitric oxide (EDNO) to the skeletal muscle blood flow response to exercise

Blood flow (BF) to active muscle increases dramatically during exercise. This increase in BF is permitted by relaxation of smooth muscle (and ensuing vasodilation) in the vasculature of muscle tissue. Recently, attention has focused on the possible role of the endothelium-derived relaxing factor nitric oxide (EDNO) in the vasodilation of muscle vasculature during exercise. A variety of experimental approaches have been used in elucidating the role of EDNO. These include isolated vessel, isolated muscle or muscle group, and conscious exercising animal preparations. Studies utilizing isolated vessels have shown that arterioles from muscle dilate, in an endothelium-dependent manner, to stimuli present during exercise (e.g., increased flow rates). A limitation of such studies, however, is that only the potential for EDNO-induced vasodilation is indicated. The isolated muscle/muscle group approach has consistently demonstrated a role for EDNO in determining resting BF. Findings for muscle BF during contractions are equivocal. A limitation of this approach is that exercise is simulated by stimulating the motor neuron of the muscle of interest. Since this type of muscle activity elicits a relatively small active hyperemia, it may be that a role for EDNO in exercise-induced hyperemia is masked. Findings from exercising animals are equivocal. Some studies demonstrate a role for EDNO in permitting increased muscle blood flow during exercise, while others show no impact of inhibition of EDNO synthesis. Some studies suggest that the importance of EDNO may vary with the muscle (and its fiber type composition) studied. Additional research is needed to clarify the role of EDNO in mediating increased BF to skeletal muscle during exercise.

Effects of hyperthyroidism on vascular contractile and relaxation responses

Previous research has shown that skeletal muscle blood flow, at rest and during muscular contractions, is elevated in the hyperthyroid state. We hypothesized that reduced vascular contractile and enhanced endothelium-dependent relaxation responses contribute to these observations. To test these hypotheses, male rats were administered triiodothyronine (Hyper, n = 27; 300 micrograms/kg) for 6-12 wk. Compared with euthyroid control rats (Eut, n = 27), Hyper exhibited left ventricular hypertrophy (Eut, 2.01 +/- 0.04 mg/g body wt; Hyper, 2.70 +/- 0.06; P < 0.0005) and greater oxidative enzyme activity in several skeletal muscles (all P < 0.0005). Vascular rings, 2-3 mm in axial length, were prepared from abdominal aortas, and responses to vasoactive agents were determined in vitro. Compared with Eut, vascular rings with intact endothelium from Hyper exhibited reductions in contractile responses to norepinephrine (NE) across a range of NE concentrations (P < 0.05). Maximal tension developed in response to NE was reduced approximately 30% in hyperthyroidism (Eut, 3.8 +/- 0.2 g; Hyper, 2.6 +/- 0.4; P < 0.01). Contractile responses to NE were not different between Eut and Hyper in rings denuded of endothelium. Maximal vasorelaxation responses to acetylcholine (ACh), after precontraction with NE (10(-7) M), were enhanced in the hyperthyroid state (Eut, 65.1 +/- 4.8%; Hyper, 84.0 +/- 7.1; P < 0.05). Enhanced vasorelaxation to ACh was also observed when precontraction was induced by prostaglandin F2 alpha. These findings indicate that vascular contractile and relaxation responses are altered in male hyperthyroid rats.Previous research has shown that skeletal muscle blood flow, at rest and during muscular contractions, is elevated in the hyperthyroid state. We hypothesized that reduced vascular contractile and enhanced endothelium-dependent relaxation responses contribute to these observations. To test these hypotheses, male rats were administered triiodothyronine (Hyper, n = 27; 300 μg/kg) for 6-12 wk. Compared with euthyroid control rats (Eut, n = 27), Hyper exhibited left ventricular hypertrophy (Eut, 2.01 ± 0.04 mg/g body wt; Hyper, 2.70 ± 0.06; P < 0.0005) and greater oxidative enzyme activity in several skeletal muscles (all P < 0.0005). Vascular rings, 2-3 mm in axial length, were prepared from abdominal aortas, and responses to vasoactive agents were determined in vitro. Compared with Eut, vascular rings with intact endothelium from Hyper exhibited reductions in contractile responses to norepinephrine (NE) across a range of NE concentrations ( P < 0.05). Maximal tension developed in response to NE was reduced ∼30% in hyperthyroidism (Eut, 3.8 ± 0.2 g; Hyper, 2.6 ± 0.4; P < 0.01). Contractile responses to NE were not different between Eut and Hyper in rings denuded of endothelium. Maximal vasorelaxation responses to acetylcholine (ACh), after precontraction with NE (10-7 M), were enhanced in the hyperthyroid state (Eut, 65.1 ± 4.8%; Hyper, 84.0 ± 7.1; P < 0.05). Enhanced vasorelaxation to ACh was also observed when precontraction was induced by prostaglandin F2α. These findings indicate that vascular contractile and relaxation responses are altered in male hyperthyroid rats.

Influence of peak VO2 and muscle fiber type on the efficiency of moderate exercise.

PURPOSE The purpose of this study was to determine if %Type I fibers and/or aerobic fitness (as peak .VO(2)) would predict Delta efficiency (DeltaEff) and Delta.VO(2)/Deltawork rate (WR) for moderate (below lactate threshold <LT) constant work rate exercise in subjects with diverse level of fitness and fiber type. METHODS Twenty-two subjects (15 male, 23 +/- 6 yr) heterogenous for fitness (peak .VO(2): 43.9 +/- 7.1 mL.kg(-1).min(-1)) were tested. On 3 different days, each subject performed constant load exercise for 6 min at work rates corresponding to 30, 50, 70, and 90% LT, separated by 6 min of 10% LT pedaling. After a short rest, each subject then completed 8 min of exercise at a WR corresponding to 50% of the difference between LT and peak .VO(2) (Delta50%). The mean .VO(2) determined for the last 3 min of each <LT WR was regressed against the absolute WR for each subject and trial. RESULTS The group mean Delta.VO(2)/DeltaWR was 10.1 mL.min(-1).W(-1) (range 8.6-11.2 mL.min(-1).W(-1)), whereas the mean DeltaEff was 28.0% (range 24.5-32.0%); both were significantly inversely correlated with each other (r = 0.972, P < 0.0001). DeltaEff was significantly negatively, and Delta.VO(2)/DeltaWR positively, correlated with peak .VO(2)(r = -0.51 and 0.57, respectively; both P < 0.01), but not to % Type I fibers (r = 0.01 and 0.11, P > 0.05). CONCLUSION These results suggest that aerobic fitness affects the energetic response to changes in power output during moderate exercise, such that the more aerobically fit a subject, the greater the increase in oxygen cost (.VO(2)) (reduced efficiency) as work rate increases. Further, Delta.VO(2)/DeltaWR reflects the inverse of DeltaEff for moderate-intensity exercise in healthy fed subjects.

Thyroid status and exercise tolerance. Cardiovascular and metabolic considerations.

SummaryBoth hypo- and hyperthyroidism are characterised by exercise intolerance. In hypothyroidism, inadequate cardiovascular support appears to be the principal factor involved. Insufficient skeletal muscle blood flow compromises exercise capacity via reduced oxygen delivery, and endurance through decreased delivery of blood-borne substrates. The latter effect results in increased dependence on intramuscular glycogen. Additionally, decreased mobilisation of free fatty acids from adipose tissue and, consequently, lower plasma free fatty acid levels compound the problem of reduced lipid delivery to active skeletal muscle in the hypothyroid state. In contrast, cardiovascular support is enhanced in hyperthyroidism, implicating other factors in exercise intolerance. Greater reliance on muscle glycogen appears to be the primary reason for decreased endurance. Biochemical changes with hyperthyroidism that would favour enhanced flux through glycolysis may account for this dependence on glycogen. Deviations from normal thyroid function, and the ensuing exercise intolerance, require appropriate medical therapy to attain euthyroid status.

Endothelium-Mediated Control of the Coronary Circulation

SummaryThis 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 dilatation 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.

Skeletal muscle oxidative capacity and exercise tolerance in rats with heart failure.

PURPOSE Past research has shown the development of exercise intolerance after myocardial infarction (MI). The purpose of this study was to test the hypothesis that reductions in oxidative enzyme activity, in a variety of skeletal muscles, coincide with the development of exercise intolerance in a rat model of chronic heart failure (CHF) induced by MI. METHODS The animals were initially divided into two groups: sham-operated controls (Sham) and animals in which a MI was surgically induced. MI rats were then subdivided into two groups according to left ventricular end-diastolic pressure (LVEDP): <20 mm Hg [small MI (SMI)] and > 20 mm Hg [large MI (LMI)]. Exercise tolerance was measured by performing a progressive run to fatigue test (RTF). Citrate synthase (CS), 3-hydroxyacyl CoA dehydrogenase (HADH), and malate dehydrogenase (MDH) activities were measured in six hindlimb muscles. RESULTS After approximately 6 wk of recovery, LVEDP differed among groups (P < 0.05): Sham (1 +/- 1 mm Hg, N = 7), SMI (7 +/- 2 mm Hg, N = 7), and LMI (30 +/- 2 mm Hg, N = 6). RTF was 20 +/- 1 min for Sham, 25 +/- 3 min for SMI, and 11 +/- 2 min for LMI (P < 0.05 for LMI vs Sham, SMI). Significant reductions in enzyme activity were found for all three enzymes in the red portion of the gastrocnemius muscles of LMI. However, no significant correlation was found between RTF and CS, HADH, or MDH in any muscle of the three groups of animals. DISCUSSION The results of the present study demonstrate that severe left ventricular dysfunction is associated with reductions in exercise tolerance and modest decreases in oxidative enzyme activities in selected muscles. It does not appear, however, that the development of exercise intolerance in CHF and oxidative enzyme activities are mechanistically related to one another.

Chronic inhibition of nitric oxide synthase augments the ACTH response to exercise

Exercise can activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and regular exercise training can impact how the HPA axis responds to stress. The mechanism by which acute exercise induces HPA activity is unclear. Therefore, the purpose of this study was to test the hypothesis that nitric oxide modulates the neuroendocrine component of the HPA axis during exercise. Female Yucatan miniature swine were treated with N-nitro-l-arginine methyl ester (l-NAME) to test the effect of chronic nitric oxide synthase (NOS) inhibition on the ACTH response to exercise. In addition, we tested the effect of NOS inhibition on blood flow to tissues of the HPA axis and report the effects of handling and treadmill exercise on the plasma concentrations of ACTH and cortisol. Chronic NOS inhibition decreased plasma NO(x) levels by 44%, increased mean arterial blood pressure by 46%, and increased expression of neuronal NOS in carotid arteries. Vascular conductance was decreased in the frontal cortex, the hypothalamus, and the adrenal gland. Chronic NOS inhibition exaggerated the ACTH response to exercise. In contrast, chronic NOS inhibition decreased the ACTH response to restraint, suggesting that the role of NO in modulating HPA activity is stressor dependent. These results demonstrate that NOS activity modulates the response of the neuroendocrine component of the HPA axis during exercise stress.

Effects of Chronic Nitric Oxide Synthase Inhibition on Endothelium-Dependent and -Independent Relaxation in Arteries that Perfuse Skeletal Muscle of Swine

The purpose of this investigation was to test the hypothesis that chronic N(G)-nitro-l-arginine methyl ester (l-NAME) treatment produces differential effects on conduit artery and resistance arteriole relaxation responses to endothelium-dependent and -independent vasodilators in arteries that perfuse skeletal muscle of swine. To test this hypothesis, conduit skeletal muscle arteries and second-order skeletal muscle (2A) arterioles were harvested from 14 Yucatan swine that were chronically administered l-NAME and from 16 controls. In vitro assessments of vasorelaxation to increasing doses of acetylcholine (ACH), bradykinin (BK), and sodium nitroprusside (SNP) were performed in both conduit and 2A arterioles. l-NAME treatment produced a significant reduction in both BK and ACH relaxation responses in the conduit arteries. In contrast, the relaxation response and/or sensitivity to SNP were significantly greater in the intact, but not denuded, conduit arterial rings from chronically l-NAME-treated swine. There were no significant effects of chronic l-NAME treatment on vasodilation of skeletal muscle arterioles. These findings suggest (1) that unlike arterioles, skeletal muscle conduit arteries do not functionally compensate for a lack of NO through the upregulation of alternative vasodilator pathways; (2) that the greater relaxation response in conduit arteries of chronically l-NAME-treated swine to SNP can be explained by alterations to the endothelium.