Background: Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. Methods: Norwegian Landrace pigs weighing 27.1 ± 0.5 kg (mean ± s x (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10 −13 -10 −5 mol/L) or norepinephrine (10 −13 -10 −3 mol/L). Results: Pigs suffering from ALF developed a hyperdynamic circulation with an increased cardiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 ± 7 versus 56 ± 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 ± 8 versus 93 ± 16 mN, P = 0.55). Conclusions: This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.
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 8C) hyperkalemic cardioplegia (n = 8) or cardioplegia where hyperkalemia was substituted with 1.2 mM adenosine (n = 8). After 1 h of cold ischemic arrest, coronary blood flow was monitored for the following 2 h. 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: In vivo: The adenosine group had, as distinct from the hyperkalemic group, a significantly increased coronary blood flow index 1 h after cross-clamp release (from (ml/min/100 g, mean AE SD) 50.9 AE 13.9 to 72.8 AE 21.9, p = 0.010). The difference was, however, not statistically significant between groups. In vitro: Maximal relaxation without blockers was 27.4 AE 10.1% of maximal tension in the adenosine group and 22.2 AE 7.5% in the hyperkalemic group. To investigate EDHFdependent 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 AE 17.4% of maximal tension, which was a significant reduction compared to the adenosine group with a maximal relaxation of 20.6 AE 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 dependent hyperpolarization of vascular smooth muscle contributes to the development of hyperdynamic circulation in ALF.
Background: Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. Methods: Norwegian Landrace pigs weighing 27.1 ± 0.5 kg (mean ± s x (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10 −13 -10 −5 mol/L) or norepinephrine (10 −13 -10 −3 mol/L). Results: Pigs suffering from ALF developed a hyperdynamic circulation with an increased cardiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 ± 7 versus 56 ± 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 ± 8 versus 93 ± 16 mN, P = 0.55). Conclusions: This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.
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