Adenosine instead of supranormal potassium in cardioplegic solution preserves endothelium-derived hyperpolarization factor-dependent vasodilation.

OBJECTIVE: We have recently shown that adenosine instead of supranormal potassium in cold crystalloid cardioplegia improves cardioprotection. Studies indicate that hyperkalemia has unfavorable effects on vascular endothelial function. Three pathways have been identified as major vasodilatory pathways: the nitric oxide (NO) pathway, the cyclooxygenase (COX) pathway, and the endothelium-derived hyperpolarization (EDHF) pathway, where the EDHF pathway, in particular, seems susceptible to hyperkalemia. We hypothesized that adenosine cardioplegia improves postcardioplegic endothelial function. METHODS: Sixteen pigs were randomized to receive either cold (6 degrees C) hyperkalemic cardioplegia (n=8) or cardioplegia where hyperkalemia was substituted with 1.2 mM adenosine (n=8). After 1h of cold ischemic arrest, coronary blood flow was monitored for the following 2h. The LAD artery was then explanted, and cylindrical rings were mounted for isometric tension recordings in organ chambers. Vessels were preconstricted with U46610 (Thromboxane A(2) analog) and then bradykinin-mediated relaxation was investigated. To differentiate between the vasodilatory pathways the relaxation was assessed in the absence and presence of inhibitors of the COX (indomethacin), NO (L-NAME+carboxy-PTIO), and EDHF (apamin+charybdotoxin) pathways. RESULTS: Invivo: The adenosine group had, as distinct from the hyperkalemic group, a significantly increased coronary blood flow index 1h after cross-clamp release (from (ml/min/100 g, mean+/-SD) 50.9+/-13.9 to 72.8+/-21.9, p=0.010). The difference was, however, not statistically significant between groups. Invitro: Maximal relaxation without blockers was 27.4+/-10.1% of maximal tension in the adenosine group and 22.2+/-7.5% in the hyperkalemic group. To investigate EDHF-dependent vasodilation the vessel rings were simultaneously treated with indomethacin, L-NAME, and carboxy-PTIO. Maximal relaxation in the hyperkalemic group was then reduced to 47.4+/-17.4% of maximal tension, which was a significant reduction compared to the adenosine group with a maximal relaxation of 20.6+/-8.7% (p=0.028). CONCLUSION: Adenosine instead of supranormal potassium in cold crystalloid cardioplegia increases postcardioplegic myocardial blood flow and preserves EDHF-dependent vasodilation.

Endothelium-derived hyperpolarization factor (EDHF) is up-regulated in a pig model of acute liver failure.

BACKGROUND: Acute liver failure (ALF) is hemodynamically characterized by hyperdynamic circulation, but the pathophysiologic mechanisms underlying these disturbances are not known. The purposes of the present experiments were: to study systemic and peripheral hemodynamics in vivo, to measure changes in vascular reactivity in vitro, and to determine the role of endothelium-dependent vasodilator pathways in a well-validated porcine model of ALF. METHODS: Landrace pigs (24-29 kg) were allocated to sham operation (n=8) or ALF induced by hepatic devascularization (n=9). Systemic and regional hemodynamics were monitored. Femoral artery rings were prepared for isometric tension recordings 8 h after ALF induction. Contractile responses to phenylephrine were assessed in ring segments of endothelium-intact femoral arteries in the absence or presence of inhibitors of endothelium-derived hyperpolarizing factor, nitric oxide synthase, cyclooxygenase and heme oxygenase pathways. RESULTS: Pigs with ALF developed a hyperdynamic circulation. Cardiac index increased (PGT<0.001), while mean arterial pressure (PGT=0.012) and systemic vascular resistance decreased (PGT<0.001) in this group. Femoral artery blood flow decreased in controls, while it remained unchanged in ALF (PGT=0.010). Accordingly, vascular resistance across the hind leg was significantly decreased (PGT<0.001) in ALF. The combination of Ca2+-activated potassium channel inhibitors charybdotoxin and apamin, which block the release of endothelium-derived hyperpolarizing factor, increased the contraction force (ANOVA, PGT=0.05) and Emax (P=0.01) to phenylephrine in ALF. In contrast, inhibitors of nitric oxide synthase, cyclooxygenase and heme oxygenase pathways did not increase isometric contraction force. CONCLUSIONS: Endothelium dependent hyperpolarization of vascular smooth muscle contributes to the development of hyperdynamic circulation in ALF.