Jon Egelund

Effects of high-intensity training on cardiovascular risk factors in premenopausal and postmenopausal women

BACKGROUND: Menopause is associated with increased risk of cardiovascular disease and the causal factors have been proposed to be the loss of estrogen and the subsequent alterations of the hormonal milieu. However, which factors contribute to the deterioration of cardiometabolic health in postmenopausal women is debated as the menopausal transition is also associated with increased age and fat mass. Furthermore, indications of reduced cardiometabolic adaptations to exercise in postmenopausal women add to the adverse health profile. OBJECTIVE: We sought to evaluate risk factors for type 2 diabetes and cardiovascular disease in late premenopausal and early postmenopausal women, matched by age and body composition, and investigate the effect of high‐intensity training. STUDY DESIGN: A 3‐month high‐intensity aerobic training intervention, involving healthy, nonobese, late premenopausal (n = 40) and early postmenopausal (n = 39) women was conducted and anthropometrics, body composition, blood pressure, lipid profile, glucose tolerance, and maximal oxygen consumption were determined at baseline and after the intervention. RESULTS: At baseline, the groups matched in anthropometrics and body composition, and only differed by 4.2 years in age (mean [95% confidence limits] 49.2 [48.5‐49.9] vs 53.4 [52.4‐54.4] years). Time since last menstrual period for the postmenopausal women was (mean [95% confidence limits] 3.1 [2.6‐3.7] years). Hormonal levels (estrogen, follicle stimulation hormone, luteinizing hormone) confirmed menopausal status. At baseline the postmenopausal women had higher total cholesterol (P < .001), low‐density lipoprotein‐cholesterol (P < .05), and high‐density lipoprotein‐cholesterol (P < .001) than the premenopausal women. The training intervention reduced body weight (P < .01), waist circumference (P < .01), and improved body composition by increasing lean body mass (P < .001) and decreasing fat mass (P < .001) similarly in both groups. Moreover, training resulted in lower diastolic blood pressure (P < .05), resting heart rate (P < .001), total cholesterol (P < .01), low‐density lipoprotein‐cholesterol (P < .01), total cholesterol/high‐density lipoprotein‐cholesterol index (P < .01), and improved plasma insulin concentration during the oral glucose tolerance test (P < .05) in both groups. CONCLUSION: Cardiovascular risk factors are similar in late premenopausal and early postmenopausal women, matched by age and body composition, with the exception that postmenopausal women have higher high‐ and low‐density lipoprotein‐cholesterol levels. A 3‐month intervention of high‐intensity aerobic training reduces risk factors for type 2 diabetes and cardiovascular disease to a similar extent in late premenopausal and early postmenopausal women.

Potentiation of cGMP signaling increases oxygen delivery and oxidative metabolism in contracting skeletal muscle of older but not young humans

Aging is associated with progressive loss of cardiovascular and skeletal muscle function. The impairment in physical capacity with advancing age could be related to an insufficient peripheral O2 delivery to the exercising muscles. Furthermore, the mechanisms underlying an impaired blood flow regulation remain unresolved. Cyclic guanosine monophosphate (cGMP) is one of the main second messengers that mediate smooth muscle vasodilation and alterations in cGMP signaling could, therefore, be one mechanism by which skeletal muscle perfusion is impaired with advancing age. The current study aimed to evaluate the effect of inhibiting the main enzyme involved in cGMP degradation, phosphodiesterase 5 (PDE5), on blood flow and O2 delivery in contracting skeletal muscle of young and older humans. A group of young (23 ± 1 years) and a group of older (72 ± 2 years) male human subjects performed submaximal knee‐extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. Sildenafil increased leg O2 delivery (6–9%) and leg O2 uptake (10–12%) at all three exercise intensities in older but not young subjects. The increase in leg O2 delivery with sildenafil in the older subjects correlated with the increase in leg O2 uptake (r2 = 0.843). These findings suggest an insufficient O2 delivery to the contracting skeletal muscle of aged individuals and that reduced cGMP availability is a novel mechanism underlying impaired skeletal muscle perfusion with advancing age.

Early Postmenopausal Phase Is Associated With Reduced Prostacyclin-Induced Vasodilation That Is Reversed by Exercise Training: The Copenhagen Women Study

The postmenopausal phase is associated with an accelerated rate of rise in the prevalence of vascular dysfunction and hypertension; however, the mechanisms underlying these adverse vascular changes and whether exercise training can reverse the decline in vascular function remains unclear. We examined the function of the vascular prostanoid system in matched pre- and postmenopausal women before and after 12 weeks of exercise training. Twenty premenopausal and 16 early postmenopausal (3.1±0.5 [mean±SE] years after final menstrual period) women only separated by 4 (50±0 versus 54±1) years of age were included. Before the training period, the vasodilator response to intra-arterial infusion of either the prostacyclin analog epoprostenol or acetylcholine was lower (≈13%–41%; P<0.05) in the postmenopausal compared with the premenopausal women. Acetylcholine infusion induced a similar release of prostacyclin (6-keto prostaglandin F1a). To elucidate the role of vasoconstrictor prostanoids, acetylcholine infusion was combined with the cyclooxygenase inhibitor ketorolac and here the vascular response to acetylcholine was reduced to a similar extent in pre- and postmenopausal women. Exercise training increased (P<0.05) the vasodilator response to epoprostenol (≈100%–150%) and acetylcholine (≈100%–120%) infusion in the postmenopausal group. These findings demonstrate that the early postmenopausal phase is associated with a marked reduction in vascular function. Despite of a reduced sensitivity to prostacyclin, the overall balance between vasodilator and vasoconstrictor prostanoids does not seem to be altered. Exercise training can reverse the decline in vascular sensitivity to epoprostenol and acetylcholine, suggesting that beneficial vascular adaptations with exercise training are preserved in recent postmenopausal women.

Leg vascular and skeletal muscle mitochondrial adaptations to aerobic high-intensity exercise training are enhanced in the early postmenopausal phase

Exercise training effectively improves vascular and skeletal muscle function; however, these effects of training may be blunted in postmenopausal women as a result of the loss of oestrogens. Accordingly, the capacity to deliver oxygen to the active muscles may also be impaired in postmenopausal women. In both premenopausal and recent postmenopausal women, exercise training was shown to improve leg vascular and skeletal muscle mitochondrial function. Interestingly, these effects were more pronounced in postmenopausal women. Skeletal muscle oxygen supply and utilization were similar in the two groups of women. These findings suggest that the early postmenopausal phase is associated with an enhanced capacity of the leg vasculature and skeletal muscle mitochondria to adapt to exercise training and that the ability to deliver oxygen to match the demand of the active muscles is preserved in the early phase following the menopausal transition.

Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans

Aging is associated with an altered regulation of blood flow to contracting skeletal muscle; however, the precise mechanisms remain unclear. We recently demonstrated that inhibition of cGMP-binding phosphodiesterase 5 (PDE5) increased blood flow to contracting skeletal muscle of older but not young human subjects. Here we examined whether this effect of PDE5 inhibition was related to an improved ability to blunt α-adrenergic vasoconstriction (functional sympatholysis) and/or improved efficacy of local vasodilator pathways. A group of young (23 ± 1 yr) and a group of older (72 ± 1 yr) male subjects performed knee-extensor exercise in a control setting and following intake of the highly selective PDE5 inhibitor sildenafil. During both conditions, exercise was performed without and with arterial tyramine infusion to evoke endogenous norepinephrine release and consequently stimulation of α1- and α2-adrenergic receptors. The level of the sympatholytic compound ATP was measured in venous plasma by use of the microdialysis technique. Sildenafil increased (P < 0.05) vascular conductance during exercise in the older group, but tyramine infusion reduced (P < 0.05) this effect by 38 ± 9%. Similarly, tyramine reduced (P < 0.05) the vasodilation induced by arterial infusion of a nitric oxide (NO) donor by 54 ± 9% in the older group, and this effect was not altered by sildenafil. Venous plasma [ATP] did not change with PDE5 inhibition in the older subjects during exercise. Collectively, PDE5 inhibition in older humans was not associated with an improved ability for functional sympatholysis. An improved efficacy of the NO system may be one mechanism underlying the effect of PDE5 inhibition on exercise hyperemia in aging.

Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling

Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training-induced adaptations in the regulation of skeletal muscle blood flow and oxidative metabolism during exercise in aging humans. We measured leg hemodynamics and oxidative metabolism during exercise engaging the knee extensor muscles in young [ n = 15, 25 ± 1 (SE) yr] and older ( n = 15, 72 ± 1 yr) subjects before and after a period of aerobic high-intensity exercise training. To determine the role of cGMP signaling, pharmacological inhibition of phosphodiesterase 5 (PDE5) was performed. Before training, inhibition of PDE5 increased ( P < 0.05) skeletal muscle blood flow and O2 uptake during moderate-intensity exercise in the older group; however, these effects of PDE5 inhibition were not detected after training. These findings suggest a role for enhanced cGMP signaling in the training-induced improvement of regulation of blood flow in contracting skeletal muscle of older men. NEW & NOTEWORTHY The present study provides evidence for enhanced cyclic GMP signaling playing an essential role in the improved regulation of blood flow in contracting skeletal muscle of older men with aerobic exercise training.

Probenecid Inhibits α-Adrenergic Receptor–Mediated Vasoconstriction in the Human Leg VasculatureNovelty and Significance

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to &agr;1- and &agr;2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (&agr;1- and &agr;2-adrenergic receptor stimulation) by ≈15%, whereas the response to the &agr;1-agonist phenylephrine was unchanged. Inhibition of &agr;1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via &agr;1-adrenoceptors and in the constrictive effect of noradrenaline via &agr;2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.

Aerobic exercise training lowers platelet reactivity and improves platelet sensitivity to prostacyclin in pre- and postmenopausal women

Essentials It is unknown how regular exercise affects platelet function after menopause. We studied the effect of 3‐months of high‐intensity exercise in pre‐ and postmenopausal women. Platelet sensitivity to the inhibitory effect of arterially infused prostacyclin was increased. Reduced basal platelet reactivity was seen in the premenopausal women only.

Effect of high-intensity exercise training on functional sympatholysis in young and older habitually active men

The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction during exercise, termed functional sympatholysis, can be improved by exercise training. However, to what extent age affects functional sympatholysis is unclear. Thus, this study examined the effect of 8 weeks of high‐intensity exercise training on α‐adrenergic responsiveness at rest and on functional sympatholysis in a group of young (n = 15; 25 ± 1 years) and older (n = 15; 72 ± 1 years) habitually active, healthy male subjects. Before and after the exercise training, all subjects participated in an experimental day in which leg hemodynamics and venous plasma norepinephrine were assessed at rest and during knee‐extensor exercise without and with tyramine infusion. The results of the study show that before exercise training, the young and older subjects had similar α‐adrenergic responsiveness at rest and similar incomplete functional sympatholysis during knee‐extensor exercise. Exercise training resulted in a reduction in α‐adrenergic responsiveness at rest in both groups, whereas functional sympatholysis was improved in the young group only. The improvement in functional sympatholysis in the young but not the older subjects despite a reduced α‐adrenergic responsiveness at rest suggests that improving sympatholytic capacity by training may be a slower process in aged than in young men.

Platelet responses to pharmacological and physiological interventions in middle-aged men with different habitual physical activity levels.

The current guidelines following an acute coronary syndrome recommend dual‐antiplatelet therapy (DAPT) (aspirin plus a P2Y12 antagonist) alongside lifestyle modifications, including more regular physical activity. It is currently unknown whether regular exercise affects the pharmacology of DAPT.