Nitric oxide-mediated vasodilation becomes independent of β-adrenergic receptor activation with increased intensity of hypoxic exercise

Abstract

Casey DP, Curry TB, Wilkins BW, Joyner MJ. Nitric oxidemediated vasodilation becomes independent of ␤-adrenergic receptor activation with increased intensity of hypoxic exercise. J Appl Physiol 110: 687-694, 2011. First published December 30, 2010 doi:10.1152/japplphysiol.00787.2010.-Hypoxic vasodilation in skeletal muscle at rest is known to include ␤-adrenergic receptorstimulated nitric oxide (NO) release. We previously reported that the augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes ␤-adrenergic mechanisms. However, it is unclear whether a ␤-adrenergic receptor-stimulated NO component exists during hypoxic exercise. We hypothesized that NO-mediated vasodilation becomes independent of ␤-adrenergic receptor activation with increased exercise intensity during hypoxic exercise. Ten subjects (7 men, 3 women; 23 Ϯ 1 yr) breathed hypoxic gas to titrate arterial O2 saturation to 80% while remaining normocapnic. Subjects performed two consecutive bouts of incremental rhythmic forearm exercise (10% and 20% of maximum) with local administration (via a brachial artery catheter) of propranolol (␤-adrenergic receptor inhibition) alone and with the combination of propranolol and nitric oxide synthase inhi-] under normoxic and hypoxic conditions. Forearm blood flow (FBF, ml/min; Doppler ultrasound) and blood pressure [mean arterial pressure (MAP), mmHg; brachial artery catheter] were assessed, and forearm vascular conductance (FVC, ml·min Ϫ1 ·100 mmHg Ϫ1 ) was calculated (FBF/ MAP). During propranolol alone, the rise in FVC (⌬ from normoxic baseline) due to hypoxic exercise was 217 Ϯ 29 and 415 Ϯ 41 ml·min Ϫ1 ·100 mmHg Ϫ1 (10% and 20% of maximum, respectively). Combined propranolol-L-NMMA infusion during hypoxic exercise attenuated ⌬FVC at 20% (352 Ϯ 44 ml·min Ϫ1 ·100 mmHg Ϫ1 ; P Ͻ 0.001) but not at 10% (202 Ϯ 28 ml·min Ϫ1 ·100 mmHg Ϫ1 ; P ϭ 0.08) of maximum compared with propranolol alone. These data, when integrated with earlier findings, demonstrate that NO contributes to the compensatory vasodilation during mild and moderate hypoxic exercise; a ␤-adrenergic receptor-stimulated NO component exists during low-intensity hypoxic exercise. However, the source of the NO becomes less dependent on ␤-adrenergic mechanisms as exercise intensity increases.hypoxia; skeletal muscle blood flow UNDER CONDITIONS of systemic hypoxia (decreased oxygen availability) and during exercise (increased demand) there is a need for an increase in blood flow. The combination of these conditions produces a compensatory vasodilation relative to the same level of exercise under normoxic conditions and greater than that predicted by a simple summation of the individual responses (3,5,6,21,23,31,32). The compensatory vasodilation during hypoxic exercise occurs to ensure an adequate oxygen delivery to the active muscles.The factors responsible for the compensatory vasodilation, as well as their interactions, remain unclear. Previous studies have demonstrated that ␤-adrenergic receptor activation is responsible for a...

Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase

“…Second, it is possible that the doses of L-NMMA and KETO selected to inhibit NOS and COX were not adequate to achieve complete inhibition of these mechanisms. However, our dose of L-NMMA is common in the literature (Casey et al 2010, 2011) and our dose of KETO was greater than those who have used similar experimental design (Schrage et al 2004; Crecelius et al 2011) or similar to previous studies using forearm exercise model (Markwald et al 2011; Crecelius et al 2011). Furthermore, in order to test active vascular control mechanisms during steady-state exercise, we only evaluated NOS and COX at one exercise intensity.…”

“…This seems an unlikely explanation for observations in the current study as the exercise intensity selected does not increase muscle sympathetic nervous activity (Limberg et al 2014), and similar vascular responses to arterial infusion of α-adrenergic agonists using an identical forearm exercise model have been observed (Limberg et al 2010). Additionally, arterial epinephrine does not appear to change with exercise and with propranolol (Wilkins et al 2008; Casey et al 2011). Inhibition of EDHF or cytochrome P450 2C9 has been found to not affect blood flow during exercise; however, these mechanisms have only been tested in small studies in young men (Hillig et al 2002; Mortensen et al 2007), and only in knee-extensor exercise models.…”

Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

“…Adenosine appears to contribute only during hypoperfusion (75,83). ␤-Adrenergic receptor mechanisms appear to contribute during lower intensity hypoxic exercise (509), but much of this contribution is likely due to ␤-adrenergic-mediated NO release (73,117). This response again highlights the general observation that many dilator substances involved in exercise hyperemia have effects both on vascular smooth muscle and the vascular endothelium.…”

S-nitrosylation: integrator of cardiovascular performance and oxygen delivery

“…Accordingly, skeletal muscle has evolved efficient mechanisms to rapidly adapt to large shifts in oxygen demand. Just as β 2 -AR activation increases cardiac contractility during hypoxia (44), β 2 -AR-coupled increases in bioactive NO are also critical for compensatory vasodilation during mild to moderate hypoxic exercise (52,53). In a manner that parallels myocardial β 2 -AR signaling, SNO-based signals inhibit β 2 -AR receptor desensitization in the periphery to facilitate adrenergic responses (45).…”