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 O(2) 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 O(2) 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 O(2) delivery (6–9%) and leg O(2) uptake (10–12%) at all three exercise intensities in older but not young subjects. The increase in leg O(2) delivery with sildenafil in the older subjects correlated with the increase in leg O(2) uptake (r(2) = 0.843). These findings suggest an insufficient O(2) 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.