Adenosine‐5′‐triphosphate opens potassium channels in the forearm vascular bed

Abstract

In vitro, adenosine-5′-triphosphate (ATP) is an endogenous endothelium-dependent vasodilator. Nitric oxide (NO), prostacyclin and endothelium derived hyperpolarizing factor (EDHF) are the proposed EDRFs in ATP-induced vasodilation. EDHF acts by opening potassium channels or activating Na-K-ATPase. In humans, intrabrachial infusion of ATP induces a powerful forearm vasodilation, of which the mechanism is not known yet. The forearm vasodilator response to ATP could not be inhibited by NG-monomethyl-L-arginine (L, NO-synthase inhibitor), indomethacin (I, inhibitor of COX1 and COX2), or tetra-ethylammonium (T, blocker of KCa channels), when these antagonists were used separately. We hypothesized that other EDRFs compensate for inhibition of formation or function of a single EDRF. Therefore, we studied the effect of a combined infusion of T, I and L on ATP induced vasodilation. In six healthy volunteers, the brachial artery of the left forearm was cannulated for drug infusion. Forearm blood flow (FBF) was measured bilaterally with strain gauge plethysmography. After baseline measurements, ATP (0.1, 0.3, 3 and 10 µg min−1100 ml−1) was infused. Thirty minutes later, the effect of T (0.1 mg min−1100 ml−1), I (5 µg min−1100 ml−1) and L (0.2 mg min−1100 ml−1) was studied on FBF. Subsequently, the ATP infusions were repeated in the presence of the three antagonists. Since this combination of antagonists reduced FBF significantly (Table 1), a similar protocol was used in a separate group of six healthy volunteers but now ATP was replaced by nitroprusside (SNP; 0.02, 0.1, 0.2 and 0.6 µg min−1100 ml−1), a direct smooth muscle cell relaxant. Table 1 FBF and % response from recontrol during subsequent combination of antagonists (mean±s.e. mean). Recontrol values did not significantly differ from baseline or between groups. ATP increased FBF by 94 ± 17, 216 ± 30, 852 ± 185 and 1848 ± 606% in the absence and 51 ± 11, 197 ± 46, 961 ± 194 and 1701 ± 369% in the presence of antagonists (P>0.1 antagonist effect). Likewise, SNP increased FBF by 59 ± 9, 190 ± 20, 294 ± 47 and 544 ± 44% in the absence and 24 ± 7, 147 ± 23, 288 ± 36 and 655 ± 155% in the presence of antagonists. Forearm blood flow in the control arm was not significantly affected by any of the infusions. In conclusion, the carry-over effect of the previous ATP infusions on the subsequent response to T indicates that ATP opened KCa channels. The mechanisms of ATP-induced vasodilation in the forearm vascular bed remain to be elucidated.