Synthetic atrial natriuretic peptide improves systemic and splanchnic circulation and has a lung-protective effect during endotoxemia in pigs.

BACKGROUND: Pharmacological blockade of the renin-angiotensin system is thought to maintain gut perfusion during circulatory stress and thereby avoid later failure of distant organs. In this controlled experimental study, we investigated the effects of carperitide, a synthetic atrial natriuretic peptide that inhibits the renin-angiotensin system, on the systemic and splanchnic circulation during fluid-resuscitated endotoxemia in pigs. METHODS: Sixteen domestic pigs of both sexes were randomly divided into 2 groups. The pigs were anesthetized and their lungs ventilated before receiving either saline (Group A: n = 8) or carperitide (Group B: n = 8). After a baseline measurement was taken, the pigs from both groups received a continuous infusion (1.7 microg x kg(-1) x h(-1)) of endotoxin for 240 min. Group B received a continuous infusion of carperitide (0.05 microg x kg(-1) x min(-1)) starting 30 min before the endotoxin infusion and lasting until the end of the study, whereas Group A received the same volume of saline. Fluid resuscitation was titrated to maintain pulmonary artery wedge pressure between 10 and 12 mm Hg. Systemic and regional hemodynamics, oxygenation variables, and the arterial-to-intestinal PCO(2) gap were measured at baseline and after endotoxin infusion for 240 min. The primary end points were cardiac index, superior mesenteric artery flow index, and PCO(2) gap at the end of this study (T240). RESULTS: Cardiac index and superior mesenteric artery flow index in Group B were significantly higher than those in Group A at T240 (83 +/- 15 vs 135 +/- 23 mL x kg(-1) x min(-1), P < 0.001; 2.6 +/- 1.4 vs 7.9 +/- 4.8, P = 0.01), respectively. Carperitide administration resulted in a significantly better maintenance of intestinal mucosal perfusion assessed by the PCO(2) gap at T240 (33.0 +/- 14.5 vs 11.6 +/- 10.0 mm Hg, P = 0.004). The PaO(2)/FIO(2) ratio in Group B was significantly greater than that in Group A from T60 to T240. CONCLUSIONS: In this porcine fluid-resuscitated endotoxemia model, a low dose of carperitide administered before endotoxemia maintained systemic and splanchnic circulation, and prevented the deterioration of oxygenation. Atrial natriuretic peptide infusion is a potentially beneficial therapy with respect to systemic and splanchnic circulation as well as the respiratory system during sepsis.

Pharmacological preconditioning in type 2 diabetic rat hearts: the roles of mitochondrial ATP-sensitive potassium channels and the phosphatidylinositol 3-kinase-Akt pathway.

PURPOSE: The authors examined whether olprinone, a phosphodiesterase type 3 inhibitor, or isoflurane, a volatile anesthetic, could protect the heart against myocardial infarction in type 2 diabetic rats and whether the underlying mechanisms involve protein kinase C (PKC), mitochondrial ATP-sensitive potassium (m-K(ATP)) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. METHODS: All rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wistar rats received isoflurane or olprinone before ischemia with or without the PKC inhibitor chelerythrine (CHE), the m-K(ATP) channel blocker 5-hydroxydecanoic acid (5HD), or the PI3K-Akt inhibitor LY294002 (LY). Goto-Kakizaki (GK) rats were randomly assigned to receive isoflurane or olprinone. In another group, GK rats received LY before the olprinone. RESULTS: In the Wistar rats, both isoflurane (38 +/- 11%) and olprinone (40 +/- 11%) reduced infarct size as compared to the control group (59 +/- 8%). In the GK rats, olprinone (41 +/- 9%) but not isoflurane (53 +/- 11%) reduced infarct size as compared to the GK control group (58 +/- 14%). The beneficial effects of olprinone were blocked by LY (58 +/- 14%). In the Wistar rats, CHE, 5HD, and LY prevented isoflurane-induced reductions of infarct size. On the other hand, LY but not CHE or 5HD prevented olprinone-induced reductions of infarct size. CONCLUSIONS: Olprinone but not isoflurane protects the heart against myocardial infarction in type 2 diabetic rats. The olprinone-induced cardioprotective effect is mediated by the PI3K-Akt pathway but not PKC or m-K(ATP) channels.

Protective Effect of Nitric Oxide on Liver Circulation from Ischemia Reperfusion Injury.

INTRODUCTION: The reduction of endogenous nitric oxide (NO) production during hepatic ischemia-reperfusion injury, generally via a reduction in endothelial NO synthase activity, leads to liver injury. We hypothesized that administration of an exogenous NO donor into the portal vein may ameliorate hepatic blood flow reduction after a period of ischemia. MATERIAL AND METHODS: A total of 90 min of ischemia (portal vein and hepatic artery) was applied in 15 anesthetized pigs, using the Pringle method under sevoflurane anesthesia. All animals were administered either saline (control group, n = 8) or sodium nitroprusside (SNP, n = 7) as exogenous NO donor drugs into the portal vein, 30 min before and after ischemia. The portal venous blood flow and hepatic artery blood flow were measured continuously using transonic flow probes attached to each vessel. Endogenous NO (NOx = NO2- + NO3-) production was measured every 10 min using a microdialysis probe placed in the left lobe of the liver. RESULTS: In the SNP group, portal venous flow remained unchanged and hepatic artery flow significantly increased compared to baseline. Although the production of liver tissue NOx transiently decreased to 60% after ischemia, its level in the SNP group remained higher than the control saline group. CONCLUSION: Regional administration of SNP into the portal vein increases hepatic arterial flow during ischemia reperfusion periods without altering mean systemic arterial pressure. We speculate that administration of an exogenous NO donor may be effective in preventing liver injury via preservation of total hepatic blood flow.

Milrinone and levosimendan administered after reperfusion improve myocardial stunning in swine.

OBJECTIVES: We assessed the effect of milrinone application timing after reperfusion against myocardial stunning as compared with levosimendan in swine. Furthermore, we examined the role of p38 mitogen-activated protein kinase (p38 MAPK) in the milrinone-induced cardioprotection. DESIGN: All swine were subjected to 12-minutes ischemia followed by 90-minutes reperfusion to generate stunned myocardium. Milrinone or levosimendan was administered intravenously either for 20 minutes starting just after reperfusion or for 70 minutes starting 20 minutes after reperfusion. In another group, SB203580, a selective p38 MAPK inhibitor, was administered with and without milrinone. Regional myocardial contractility was assessed by percent segment shortening (%SS). RESULTS: Milrinone starting just after reperfusion, but not starting 20 minutes after reperfusion, improved %SS at 30, 60, and 90 minutes after reperfusion compared with that in the control group. SB203580 abolished the beneficial effect of milrinone. On the other hand, levosimendan starting 20 minutes after reperfusion, but not for 20 minutes starting just after reperfusion, improved %SS at 60 and 90 minutes after reperfusion. CONCLUSIONS: Milrinone should be administered just after reperfusion to protect myocardial stunning through p38 MAPK, whereas levosimendan improvement of contractile function could be mainly dependent on its positive inotropic effect.

Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs.

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng · mL(-1) (group LD, n = 9), 10 ng · mL(-1) (group MD, n = 9), or 100 ng · mL(-1) (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system.

Effects of nitric oxide donor on hepatic arterial buffer response in anesthetized pigs.

The effects of systemic administration of exogenous nitric oxide (NO) donor on hepatic arterial buffer response (HABR) have not yet been studied in an anesthetized model. In this study, 28 anesthetized pigs received administration of sodium nitroprusside (SNP) or nitroglycerin (NTG) as exogenous NO donors. Pressure-flow (P-Q) relationships in the hepatic artery defined the pressure at zero flow (P(Qha = 0)) and flow-dependent resistance (R). The magnitude of HABR was evaluated by comparing the change in hepatic arterial blood flow (DeltaQha) divided by the change in portal venous blood flow (DeltaQpv), using the index of change in blood flow (DeltaQha/DeltaQpv). Mean arterial pressure decreased from baseline (95.6 +/- 3.8 mmHg) to SNP condition (68.3 +/- 1.9 mmHg) and decreased from baseline (92.7 +/- 4.4 mmHg) to NTG condition (66.2 +/- 1.7 mmHg). Mean index of change in blood flow (DeltaQha/DeltaQpv) was also significantly increased from baseline (0.19 +/- 0.12) to SNP condition (0.28 +/- 0.17; p = .009) and from baseline (0.18 +/- 0.17) to NTG (0.28 +/- 0.20; p < .05). In conclusion, systemic administration of SNP and NTG increases HABR with reduced hepatic arterial tone under decreased mean arterial pressure, presumably via exogenous NO enhancing another regulatory system and reducing the pressure gradient for sinusoidal washout.

Administration of the Rho-kinase inhibitor fasudil before ischemia or just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium in swine.

OBJECTIVES: We assessed the effect of administration time for fasudil treatment of the stunned myocardium in 40 anesthetized open chest swine. MATERIALS AND METHODS: All swine were subjected to 12 min ischemia followed by reperfusion to generate stunned myocardium. Group A (n = 11) received saline in place of fasudil both before ischemia and after reperfusion. Group B (n = 10) received 30 min intravenous fasudil at a rate of 13 mug/kg/min starting 45 min before ischemia and received saline after reperfusion. Groups C (n = 10) and D (n = 9) received saline before ischemia, and received fasudil at a rate of 13 microg kg(-1) min(-1) starting just before reperfusion in group C and 30 min after reperfusion in group D. In both groups, treatment lasted 30 min. Myocardial contractility was assessed by percent segment shortening (%SS). RESULTS AND DISCUSSION: Three swine in group A, 2 swine in each of groups B and C, and one swine in group D had ventricular fibrillation or tachycardia after reperfusion and were excluded from further analysis. The changes of %SS from baseline at 90 min after reperfusion in groups B and C were 68 +/- 8% and 75 +/- 8%, respectively, which were significantly higher than in group A or D (47 +/- 10% or 43 +/- 8%). CONCLUSION: We conclude that fasudil administered before ischemia or just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium.

Cardioprotection induced by olprinone, a phosphodiesterase III inhibitor, involves phosphatidylinositol-3-OH kinase-Akt and a mitochondrial permeability transition pore during early reperfusion.

PURPOSE: Ischemic preconditioning is mediated by the activation of phosphatidylinositol-3-OH kinase-Akt (PI3K-Akt) and by the inhibition of the opening of a mitochondrial permeability transition pore (mPTP) during early reperfusion. Preischemic administration of the phosphodiesterase type III inhibitor olprinone protects the myocardium against infarction, but its mechanism has not been fully clarified. We hypothesized that this olprinone-induced cardioprotective effect was mediated by the activation of PI3K-Akt and by the inhibition of mPTP during early reperfusion. METHODS: Pentobarbital-anesthetized rats (n = 42) subjected to 30-min coronary occlusion followed by 2-h reperfusion, received olprinone (20 microg.kg(-1)) or saline (control) in the preischemic phase in the presence or absence of the PI3K-Akt inhibitor wortmannin (0.6 mg.kg(-1)) or the mPTP opener atractyloside (5 mg.kg(-1)) before 5 min of reperfusion. The myocardial infarct size was expressed as a percentage of the area at risk. All values were expressed as means +/- SD. Statistical comparisons within groups were made using repeated-measures analysis of variance (ANOVA), followed by a paired t-test, and comparisons among groups were analyzed using a two-way ANOVA, followed by the Tukey-Kramer test. RESULTS: Mean arterial pressure and heart rate showed no significant differences within or among groups. The preischemic administration of olprinone significantly reduced the infarct size (12 +/- 4%) as compared with that in the control group (43 +/- 4%). Wortmannin or atractyloside abolished the protective effect of olprinone (42 +/- 11% or 41 +/- 10%). CONCLUSION: The olprinone-induced cardioprotective effect could be exerted via the activation of PI3K-Akt and the inhibition of mPTP during early reperfusion.

Milrinone administered before ischemia or just after reperfusion, attenuates myocardial stunning in anesthetized swine.

PURPOSE: We assessed the dose or timing effect of milrinone administered against myocardial stunning in 37 anesthetized open-chest swine. METHODS: All swine were subjected to 12-min ischemia followed by reperfusion to produce myocardial stunning. Group A (n = 12) received saline in place of milrinone both before and after ischemia. Group B (n = 9) and C (n = 9) received intravenous milrinone at a rate of 5 microg/kg/min for 10 min followed by 0.5 microg/kg/min for 10 min and 10 microg/kg/min for 10 min followed by 1 microg/kg/min for 10 min, respectively, until 30 min before coronary occlusion. Group D (n = 7) received the same dose of milrinone as group B starting 1 min after reperfusion. Myocardial contractility was assessed by percentage segment shortening (%SS). RESULTS: Five swine in group A and two swine in groups B and C each had ventricular fibrillation or tachycardia after reperfusion, and were thus excluded from further analysis. The percentage changes of %SS from the baseline 90 min after reperfusion in groups B, C, and D were 78 +/- 9%, 82 +/- 13%, and 79 +/- 7%, respectively, which were significantly higher than those in group A (43 +/- 13%). CONCLUSION: We conclude that milrinone administered before ischemia or just after reperfusion attenuates myocardial stunning.

Hemodynamic interactions of propofol and dantrolene in chronically instrumented dogs.

UNLABELLED: The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia. IMPLICATIONS: Our study suggests that dantrolene reverses the hypotensive action produced by propofol and causes an increase in coronary blood flow with a decrease in coronary vascular resistance, but does not significantly change the negative inotropic effects.

The interaction of MCI-154, a calcium sensitizer, and isoflurane on systemic and coronary hemodynamics in chronically instrumented dogs.

UNLABELLED: We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia. IMPLICATIONS: MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.