Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

Abstract

In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5±4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 ,ug/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9+0.3 ml/100 ml forearm per min for placebo and 1.8±0.2, 2.0±0.3, 3.8±0.9, 6.3±1.2, 11.3±2.2, and 19.3±3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6±0.2 ml/100 ml forearm per min for placebo and 2.1±0.3, 3.3±0.6, 5.8±1.1, 6.9±1.4, 14.4±2.9, and 23.5±4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the fore- arm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man. (J. Clin. Invest. 1995. 95:658-668.)

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

“…It is well known from previous studies with these drugs that forearm blood flow measured with strain-gauge plethysmography increases by a factor of 3 to 5 in response to phentolamine 27,28 and by a factor of 10 in response to adenosine. 29 Therefore, our observation with phentolamine indicates that an increase in flow before ischemic exercise to Ϸ10 mL · min Ϫ1 · dL…”

ATP‐induced vasodilation in human skeletal muscle

“…Bilateral forearm blood flow (FBF) was measured by ECGtriggered mercury-in-silastic strain gauge plethysmography, as described before (Rongen et al, 1995), while the hand circulation was occluded using wrist cuffs (Lenders et al, 1991). All experiments started 30 min after intra-arterial cannulation with the measurement of baseline blood flow, obtained during infusion of saline (NaCl 0.9%).…”

Molecular cloning and functional characterization of inhibitor-sensitive (mENT1) and inhibitor-resistant (mENT2) equilibrative nucleoside transporters from mouse brain

“…These include enhancement of the target selectivity and effectiveness of cytotoxic nucleoside analogues used in anti-cancer and anti-viral therapy [1,2], as well as manipulation of the biological activities of adenosine to enhance its neuroprotective [3][4][5][6][7] and cardioprotective [8][9][10][11][12] actions. Many of these protocols involve inhibition of the cellular uptake or release of nucleosides.…”