TY - JOUR

T1 - Effect of PDE5 inhibition on the modulation of sympathetic α-adrenergic vasoconstriction in contracting skeletal muscle of young and older recreationally active humans

AU - Nyberg, Michael Permin

AU - Piil, Peter Bergmann

AU - Egelund, Jon

AU - Sprague, Randy S

AU - Mortensen, Stefan Peter

AU - Hellsten, Ylva

N1 - CURIS 2015 NEXS 408

PY - 2015

Y1 - 2015

N2 - 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 years) and a group of older (72±1 years) 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 noradrenaline 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.

AB - 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 years) and a group of older (72±1 years) 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 noradrenaline 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.

U2 - 10.1152/ajpheart.00653.2015

DO - 10.1152/ajpheart.00653.2015

M3 - Journal article

C2 - 26432842

VL - 309

SP - H1867-H1875

JO - American Journal of Physiology: Heart and Circulatory Physiology

JF - American Journal of Physiology: Heart and Circulatory Physiology

SN - 0363-6135

IS - 11

ER -