Sex and nitric oxide bioavailability interact to modulate interstitial Po2 in healthy rat skeletal muscle

Abstract

Premenopausal women express reduced blood pressure and risk of cardiovascular disease relative to age-matched men. This purportedly relates to elevated estrogen levels increasing nitric oxide synthase (NOS) activity and NO-mediated vasorelaxation. We tested the hypotheses that female rat skeletal muscle would: 1) evince a higher O₂ delivery-to-utilization ratio (Q̇o₂/V̇o₂) during contractions; and 2) express greater modulation of Q̇o₂/V̇o₂ with changes to NO bioavailability compared with male rats. The spinotrapezius muscle of Sprague-Dawley rats (females = 8, males = 8) was surgically exposed and electrically-stimulated (180 s, 1 Hz, 6 V). OxyphorG4 was injected into the muscle and phosphorescence quenching employed to determine the temporal profile of interstitial Po₂ (Po_2is, determined by Q̇o₂/V̇o₂). This was performed under three conditions: control (CON), 300 µM sodium nitroprusside (SNP; NO donor), and 1.5 mM N^ω-nitro-l-arginine methyl ester (l-NAME; NOS blockade) superfusion. No sex differences were found for the Po_2is kinetics parameters in CON or l-NAME ( P > 0.05), but females elicited a lower baseline following SNP (males 42 ± 3 vs. females 36 ± 2 mmHg, P < 0.05). Females had a lower ΔPo_2is during contractions following SNP (males 22 ± 3 vs. females 17 ± 2 mmHg, P < 0.05), but there were no sex differences for the temporal response to contractions ( P > 0.05). The total NO effect (SNP minus l-NAME) on Po_2is was not different between sexes. However, the spread across both conditions was shifted to a lower absolute range for females (reduced SNP baseline and greater reduction following l-NAME). These data support that females have a greater reliance on basal NO bioavailability and males have a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO. NEW & NOTEWORTHY Interstitial Po₂ (Po_2is; determined by O₂ delivery-to-utilization matching) plays an important role for O₂ flux into skeletal muscle. We show that both sexes regulate Po_2is at similar levels at rest and during skeletal muscle contractions. However, modulating NO bioavailability exposes sex differences in this regulation with females potentially having a greater reliance on basal NO bioavailability and males having a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.

Keywords: oxygen delivery; sex; vascular control.