Effects of prostaglandin E(1) on the efficacy of xenogeneic extracorporeal pig liver perfusion in a canine model of acute liver failure. (1/42)

Xenogeneic extracorporeal liver perfusion (ECLP) has the potential to become an important tool in the management of patients with severe liver failure. We previously showed that xenogeneic pig liver perfusion may be prolonged for up to 9 hours by the administration of prostaglandin E(1) (PGE(1)). In this study, we used a canine model of acute liver failure to evaluate the effects of PGE(1) on the efficacy of ECLP as a liver-assist device. Liver failure was surgically induced in 12 beagle dogs, with a control group (group 1, n = 4) not connected to the ECLP circuit. Direct cross-circulation between the dogs and the ECLP circuit using a pig liver was performed without (group 2, n = 4) or with (group 3, n = 4) continuous administration of PGE(1) through the portal vein of the pig liver. The duration of cross-circulation in group 3 (9.4 +/- 1.2 hours) was significantly longer than in group 2 (4.3 +/- 1.0 hours). In addition, elevation of blood ammonia, total bile acid, and hyaluronic acid levels was less marked in group 3 compared with the other 2 groups. The ratio of branched-chain amino acids to aromatic amino acids was also improved in group 3. The mean survival time in group 3 (26.6 +/- 0.4 hours) was significantly longer than in group 1 (15.5 +/- 1.3 hours) or group 2 (17.1 +/- 2.9 hours). Continuous administration of PGE(1) to xenogeneic ECLP resulted in a significant improvement in both liver function and survival time of dogs with surgically induced liver failure.  (+info)

Influence of extracorporeal porcine liver perfusion on nonhuman primates: minimizing hemolysis improves subsequent survival. (2/42)

The aim of this study is to detect and analyze risk factors of direct cross-circulation between porcine liver and nonhuman primates before a clinical application of extracorporeal liver perfusion (ECLP) as a liver-assist method. Porcine livers were perfused with baboon blood in an ECLP system. Six healthy baboons were directly connected to the ECLP system with continuous prostaglandin E(1) administration. Cross-circulation was terminated in the following circumstances: (1) hepatic arterial or portal perfusion pressures elevated to 200 or 60 mm Hg, respectively; (2) massive exudative bleeding from the graft surface; or (3) bile output decreased to less than 5 microL/h/g of liver weight. In case 1, cross-circulation was continued for 10 hours. Severe macroscopic hemolysis occurred, and serum hemoglobin (s-Hb) concentration reached a peak of 47 mg/dL. The baboon died of acute renal failure 2 days later. Histological study of the perfused porcine liver showed marked microthrombi formation. In 3 of the later 5 cases, cross-circulation was discontinued when mild macroscopic hemolysis was observed. The duration of the 5 cross-circulations was maximally 6 hours (mean, 4.4 +/- 1.2 [SD] hours). Mean s-Hb concentration in the 5 cases was elevated to 14.8 +/- 5.8 mg/dL at the end of cross-circulation and decreased to the baseline level within 24 hours. These 5 baboons survived without organ dysfunction or immunologic disturbance. When severe hemolysis is avoided, direct cross-circulation using the ECLP system can be achieved without serious complications in nonhuman primates.  (+info)

Pulmonary vasoconstriction during regional nitric oxide inhalation: evidence of a blood-borne regulator of nitric oxide synthase activity. (3/42)

BACKGROUND: Inhaled nitric oxide (INO) is thought to cause selective pulmonary vasodilation of ventilated areas. The authors previously showed that INO to a hyperoxic lung increases the perfusion to this lung by redistribution of blood flow, but only if the opposite lung is hypoxic, indicating a more complex mechanism of action for NO. The authors hypothesized that regional hypoxia increases NO production and that INO to hyperoxic lung regions (HL) can inhibit this production by distant effect. METHODS: Nitric oxide concentration was measured in exhaled air (NO(E)), NO synthase (NOS) activity in lung tissue, and regional pulmonary blood flow in anesthetized pigs with regional left lower lobar (LLL) hypoxia (fraction of inspired oxygen [FIO2] = 0.05), with and without INO to HL (FIO2 = 0.8), and during cross-circulation of blood from pigs with and without INO. RESULTS: Left lower lobar hypoxia increased exhaled NO from the LLL (NO(E)LLL) from a mean (SD) of 1.3 (0.6) to 2.2 (0.9) parts per billion (ppb) (P < 0.001), and Ca2+-dependent NOS activity was higher in hypoxic than in hyperoxic lung tissue (197 [86] vs. 162 [96] pmol x g(-1) x min(-1), P < 0.05). INO to HL decreased the Ca2+-dependent NOS activity in hypoxic tissue to 49 [56] pmol x g(-1) x min(-1) (P < 0.01), and NO(E)LLL to 2.0 [0.8] ppb (P < 0.05). When open-chest pigs with LLL hypoxia received blood from closed-chest pigs with INO, NO(E)LLL decreased from 2.0 (0.6) to 1.5 (0.4) ppb (P < 0.001), and the Ca2+-dependent NOS activity in hypoxic tissue decreased from 152 (55) to 98 (34) pmol x g(-1) x min(-1) (P = 0.07). Pulmonary vascular resistance increased by 32 (21)% (P < 0.05), but more so in hypoxic (P < 0.01) than in hyperoxic (P < 0.05) lung regions, resulting in a further redistribution (P < 0.05) of pulmonary blood flow away from hypoxic to hyperoxic lung regions. CONCLUSIONS: Inhaled nitric oxide downregulates endogenous NO production in other, predominantly hypoxic, lung regions. This distant effect is blood-mediated and causes vasoconstriction in lung regions that do not receive INO.  (+info)

Cardiac effects of clinically available Kampo medicine assessed with canine isolated, blood-perfused heart preparations. (4/42)

Cardiac effects of 10 kinds of clinically available Kampo medicines were investigated: Kakkon-to (TJ-1), Dai-saiko-to (TJ-8), Boi-ogi-to (TJ-20), Chorei-to (TJ-40), Rokumi-gan (TJ-87), Tsu-do-san (TJ-105), Gosha-jinki-gan (TJ-107), San'o-shashin-to (TJ-113), Sairei-to (TJ-114) and Inchin-gorei-san (TJ-117). Chronotropic and inotropic effects were studied using canine isolated, blood-perfused heart preparations, while subcellular mechanisms were analyzed by measuring the drug-induced changes of the adenylate cyclase activity in the canine ventricular membrane preparation. Intracoronary injections of TJ-1, TJ-20, TJ-105 and TJ-113 increased the sinoatrial rate and developed tension of papillary muscle in a dose-related manner, which was significantly attenuated by the pretreatment of the preparations with beta-blocker propranolol. Meanwhile, the other extracts hardly affected these parameters. TJ-1, TJ-20 and TJ-113 increased the adenylate cyclase activity in a dose-related manner, but their potency was significantly less compared with that by an equivalent concentration of isoproterenol. Moreover, TJ-105 did not increase the adenylate cyclase activity. These results suggest that the positive chronotropic and inotropic effects of TJ-1, TJ-20, TJ- 105 and TJ-113 may be exerted through the direct stimulation of the beta-adrenoceptor and/or the norepinephrine release from the postganglionic nerve terminals in the heart.  (+info)

Cardiac effects of a selective rho-associated kinase inhibitor, Y-27632, assessed in canine isolated, blood-perfused heart preparations. (5/42)

Chronotropic, inotropic and coronary effects of Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate), a specific inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK), were assessed using canine isolated, blood-perfused heart preparations. Y-27632 slightly enhanced sinoatrial automaticity and significantly increased coronary blood flow, while it decreased ventricular contraction. The concentrations of Y-27632 needed to cause the currently observed changes were similar to those inhibiting ROCK in a previous in vitro study. These results suggest that the constitutional ROCK in the heart mainly regulates the ventricular contractility and coronary vascular tone rather than the sinoatrial automaticity.  (+info)

Standardization of an isolated pig heart preparation with parabiotic circulation: methodological considerations. (6/42)

In the present study we standardized an experimental model of parabiotic circulation of isolated pig heart. The isolated heart was perfused with arterial blood from a second animal as support and submitted to regional ischemia for 30 min, followed by total ischemia for 90 min and reperfusion for 90 min. Parameters for measurement of ventricular performance using different indices measured directly or indirectly from intraventricular pressure were defined as: maximum peak pressure, final diastolic pressure, pressure developed, first derivative of maximum pressure (dP/dt max), first derivative of minimum pressure (dP/dt min), systolic stress of the left ventricle (sigmas), and maximum elastance of the left ventricle. Isolated hearts subjected to regional and global ischemia presented significant worsening of all measured parameters. Less discriminative parameters were dP/dt max and dP/dt min. Elastance was the most sensitive parameter during the reperfusion period, demonstrating an early loss of ventricular function during reperfusion. The model proved to be stable and reproducible and permitted the study of several variables in the isolated heart, such as ischemia and reperfusion phenomena, the effects of different drugs, surgical interventions, etc. The model introduces an advantage over the classical models which use crystalloid solutions as perfusate, because parabiotic circulation mimics heart surgery with extracorporeal circulation.  (+info)

Cross-circulation study of natriuretic factors in postobstructive diuresis. (7/42)

To study the role of circulating natriuretic factors in the postobstructive diuresis that occurs after relief of bilateral, but not unilateral ureteral ligation, cross-circulation was carried out between normal recipient rats and donor rats have either 24-h bilateral (BUL) or unilateral (UUL) ureteral ligation. With BUL donors, there was a rapid marked increase in sodium and water excretion in the recipient rats, sustained for 80-140 min, with a peak approximately 10 times control values. With UUL donors, no significant natriuretic response occurred. Changes in glomerular filtration rate, renal plasma flow, blood pressure, hematocrit, or circulating levels of aldosterone or Pitressin did not explain the diuresis-natriuresis produced by cross-circulation with BUL donors. Differences in the intrinsic renal damage produced by bilateral as compared to unilateral ureteral obstruction did not appear to account for this response, since UUL donors given an acute urea load and urine reinfusion caused a similar diuresis-natriuresis. Moreover, normal donor rats given a urea load also caused a diuresis-natriuresis nearly equal to that produced by BUL rats, and the relationship between increased urea excretion and sodium excretion or urine flow in the recipients was not different in the two groups. Total urine reinfusion for 3 h in donor rats produced a significant, although less marked, diuresis-natriuresis in recipient animals, with only a slight elevation of the blood urea nitrogen level, much less increase in urea excretion rate, and no significant relationship between urea excretion and sodium excretion or urine flow. The results indicate that potent natriuretic factors, which act by decreasing the tubular reabsorption of sodium and water, are present in the blood of rats with bilateral, but not unilateral, ureteral ligation. High blood and urine urea levels appear to be the factors responsible for the marked natriuresis-diuresis occurring in normal rats during cross-circulation with BUL donors, although suggestive evidence of other natriuretic factors in urine reinfused intravenously was also obtained. The data suggest that urea osmotic diuresis is an important mechanism for determining the striking difference between the postobstructive diuresis observed after relief of bilateral as compared to unilateral ureteral ligation.  (+info)

Detrimental effects after dobutamine infusion on rat left ventricular function: mechanical work and energetics. (8/42)

We have previously reported that continuous infusion of dobutamine into the coronary artery induces positive inotropic effects but induces no detrimental effects in cross-circulated, excised normal rat hearts and even in Ca2+ overload-induced contractile failing rat hearts. However, we hypothesized that some detrimental effects on left ventricular (LV) function are induced after continuous dobutamine infusion and the following clearance of blood dobutamine, as is the case after beta-adrenergic receptor stimulation. To test this hypothesis, we investigated LV mechanical work and energetics in the same type of preparations that underwent continuous dobutamine infusion and clearance of blood dobutamine. We found that both mean end-systolic pressure and systolic pressure-volume area (PVA; a measure of total mechanical energy per beat) at midrange LV volume were significantly (P < 0.01) decreased. The mean myocardial oxygen consumption per beat intercept, which is composed of for the total Ca2+ handling in excitation-contraction coupling and basal metabolism, of the and PVA linear relation was also significantly (P < 0.05) decreased (n=8). The mean slope of the linear relation was unchanged in such hearts. Post-dobutamine basal metabolism was unchanged (n = 5 of the 8 hearts). The moderate proteolysis of a cytoskeleton protein, alpha-fodrin was identified (n = 7 of the 8 hearts with the decreased intercept), after clearance of blood dobutamine. In agreement with our hypothesis, the detrimental effect of the post-beta-adrenergic receptor stimulation was induced by a moderate concentration of dobutamine; we found systolic dysfunction due to the impairment of Ca2+ handling in excitation-contraction coupling in the rat LV and proteolysis of a cytoskeleton protein, alpha-fodrin.  (+info)

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