Inorganic Nitrate Supplementation Blunts Vasoconstrictor Responsiveness During Exercise in Patients with Type 2 Diabetes

Abstract

Patients with type 2 diabetes (T2D) have exaggerated α1‐ and α2‐vasoconstrictor responsiveness during exercise indicating reduced functional sympatholysis. Nitric oxide (NO) is purported to offset α‐mediated vasoconstriction during exercise (i.e., is sympatholytic). Given T2D have attenuated NO bioavailability, supplementation with inorganic nitrate (an exogenous source of NO) may reduce α1‐ and/or α2‐vasoconstrictor responsiveness during exercise in T2D. Thus, we examined if 8wks of inorganic nitrate supplementation (250mg daily, NO3 group) reduced vasoconstrictor responsiveness to intra‐arterial infusions of phenylephrine (PE, α1‐agonist) and/or dexmedetomidine (DEX, α2‐agonist) during handgrip exercise in T2D relative to a placebo (PL group). Handgrip exercise trials lasted for 6min at 20% maximum grip strength. Steady‐state (SS) blood flow was achieved during the first 3min with either PE or DEX infused during the latter 3min. Forearm blood flow (FBF, ml/min) was calculated using brachial artery diameter and blood velocity measured via Doppler ultrasound. Forearm vascular conductance (FVC, ml/min/100mmHg), a surrogate of vasodilation, was calculated using FBF and mean arterial pressure (MAP). Both FBF and FVC were calculated from data averaged over the final 30sec of rest and SS exercise. Vasoconstrictor responsiveness for all trials was quantified as: ((SS FVCwith drug − SS FVCpre‐drug)/SS FVCpre‐drug)x100%. The magnitude of sympatholysis was calculated as the difference in %vasoconstriction at rest and exercise for both α‐agonists. After baseline assessments, T2D were randomly assigned to the NO3 (n=17, 13M/4F, 58±9yrs, 31.8±5.2kg/m2) or PL (n=17, 12M/5F, 58±9yrs, 32.3±5.3kg/m2) supplementation groups. Following supplementation, there were no differences in resting α1‐ or α2‐vasoconstrictor responsiveness observed between groups (group‐by‐time p=0.86 and 0.15, respectively). The NO3 group had greater increases in FBF (164±68 to 185±70ml/min, p<0.05) and FVC (136±53 to 164±61ml/min/100mmHg, p<0.05) responses to exercise (Δ from rest) relative to the PL group (149±66 to 149±65ml/min and 129±64 to 133±60ml/min/100mmHg, p=0.93 and 0.59, respectively). No between‐group differences were observed for α1‐mediated vasoconstrictor responsiveness during exercise or the corresponding magnitude of sympatholysis (group‐by‐time p=0.41 and 0.90, respectively). However, the NO3 group had reduced α2‐mediated vasoconstrictor responsiveness during exercise (−23.4±6.9 to −20.2±5.6% vs. −24.0±7.9 to −26.5±10.5%) with concomitant improvement in the magnitude of sympatholysis (−26.1±12.9 to −38.1±19.4 vs. −25.1±15.9 to −24.7±15.6) compared to the PL cohort, respectively (p<0.05 for both). Principally, we found 8wks of inorganic nitrate supplementation augments the hyperemic (FBF) and vasodilatory (FVC) responses to exercise in T2D. Additionally, these beneficial effects could be attributable to decreased α2‐mediated vasoconstrictor responsiveness in contracting skeletal muscle (i.e., improved functional sympatholysis).Support or Funding InformationAmerican Diabetes Association 1‐16‐1CTA‐015.