L-arginine improves endothelial and myocardial function after brain death.

BACKGROUND: Recently, we showed that brain death (BD) leads to a severe impairment of endothelial function. METHODS: To test the hypothesis, that nitric oxide supply improves endothelial function, we infused L-arginine (40 mg/kg) in 6 dogs after BD induction (subdural balloon). Six vehicle-treated BD animals served as controls. Coronary blood flow (CBF), preload recruitable stroke work (PRSW), and plasma L-arginine and nitrite/nitrate levels were measured before and 6 hr after BD induction. In addition, endothelium-dependent vasodilatation after intracoronary application of acetylcholine (ACH) and endothelium-independent vasodilation after sodium nitroprusside (SNP) were assessed. RESULTS: Six hours after BD, CBF decreased significantly in the control group (38.2+/-3.5 vs. 26.8+/-3.1 ml/min, P<0.05), whereas the decrease was less pronounced in the L-arginine group (41.8+/-6.9 vs. 36.0+/-1.2 ml/min, P<0.05 vs. control). Before BD, ACH led to a similar vasodilative response in both groups (81+/-6 vs. 75+/-7%). After BD, a paradox vasoconstriction occurred after ACH in the control group, while the vasodilative response did not change in the L-Arginine group (36+/-6 vs. 69+/-7%, P<0.05). The response to SNP did not differ between the groups and over the time. After BD PRSW decreased in both groups, however, it was still significantly higher in the L-arginine group (56+/-7 vs. 71+/-7 kerg, P<0.05). L-arginine (711+/-144 vs. 234+/-54 microM P<0.05) and nitrite/nitrate (39+/-3 vs. 27+/-3 microM P<0.05) levels were significantly higher in the L-arginine group. CONCLUSION: L-arginine treatment prevents endothelial dysfunction and improves myocardial performance after BD via enhancement of endogenous nitric oxide synthesis.

Brain death impairs coronary endothelial function.

BACKGROUND: To characterize the impact of brain death (BD) on endothelial dysfunction after cardiac transplantation we investigated coronary circulation and vasomotor function in a canine model. METHODS: Left ventricular pressure-volume data (conductance catheter) and coronary blood flow (CBF) were monitored continuously. Endothelium-dependent vasodilatation after acetylcholine and endothelium-independent vasodilation after sodium nitroprusside were assessed before and 3 hr after BD induction (inflation of a subdural balloon). RESULTS: BD led to an initial hyperdynamic reaction with significant (P<0.05) increase of CBF. After 3 hr, CBF decreased significantly (P<0.05). Although before BD, application of acetylcholine led to a monophasic vasodilatative response, after BD a short mild vasodilatation was followed by a longer vasoconstriction. Endothelium-independent vasodilatation remained unchanged. CONCLUSIONS: BD affects coronary circulation by two means: (1) impairment of CBF to decrease in parallel in afterload with consecutive hemodynamic deterioration and (2) severe endothelial dysfunction that may be a contributing factor to posttransplant outcome.

Ventricular energetics after the Fontan operation: contractility-afterload mismatch.

OBJECTIVE: Fontan-type operations offer the opportunity to create pulmonary and systemic circulation in series with a single pumping chamber. The effectiveness of such a circulatory pattern determines resting and exercise hemodynamics in these patients. The present study investigated cardiac performance after the Fontan operation by using ventricular-vascular coupling framework analysis. METHODS: In 12 anesthetized open-chest dogs, Fontan circulation was established by using a cavopulmonary anastomosis. Left ventricular hemodynamic variables were measured by using a combined pressure-volume-conductance catheter. Additionally, aortic flow and pressure were recorded continuously. Ventricular contractility was quantified by using the load-independent slope of the end-systolic pressure-volume relationship. Arterial system properties were quantified by using the end-systolic pressure/stroke volume ratio. The coupling between the left ventricle and arterial system was expressed by using the ratio of end-systolic pressure/stroke volume to slope of the end-systolic pressure-volume relationship. Additionally, external stroke work, total mechanical energy and mechanical efficiency (Mechanical efficiency = Stroke work/Total mechanical energy) were calculated. Impedance spectra were determined by means of Fourier analysis. RESULTS: During Fontan circulation, the slope of the end-systolic pressure-volume relationship (5.3 +/- 0.6 vs 7.5 +/- 0.6 mm Hg/mL, P <.05) decreased, and the end-systolic pressure-stroke volume relationship (4.2 +/- 0.7 vs 3.3 +/- 0.5 mm Hg/mL, P =.23) increased with parallel increased characteristic impedance. Furthermore, the end-systolic pressure-stroke volume/slope of the end-systolic pressure-volume relationship ratio increased significantly (0.76 +/- 0.04 vs 0.42 +/- 0.03, P <.005). Simultaneously, stroke work (1846 +/- 146 vs 1389 +/- 60 mm Hg/mL, P <.05) and mechanical efficiency (0.82 +/- 0.09 vs 0.56 +/- 0.05, P <.05) were significantly reduced. CONCLUSIONS: Fontan circulation leads to contractility-afterload mismatch by means of increased impedance caused by additional connection of the pulmonary vascular bed to the systemic vasculature and by means of deterioration of myocardial contractility. The increased ventriculoarterial coupling ratio and reduced mechanical efficiency predict limited cardiac functional reserve after the Fontan operation.

Poly-ADP-ribose polymerase inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest.

OBJECTIVE: Free radical production and related cytotoxicity during ischemia and reperfusion might lead to DNA strand breakage, which activates the nuclear enzyme poly-ADP-ribose synthetase and initiates an energy-consuming and inefficient cellular metabolic cycle with transfer of the adenosine diphosphate-ribosyl moiety of nicotinamide adenine dinucleotide (NAD(+)) to protein acceptors. We investigated the effects of poly-ADP-ribose synthetase inhibition on myocardial and endothelial function during reperfusion in an experimental model of cardiopulmonary bypass. METHODS: Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6) or PJ34 (10 mg/kg), a potent poly-ADP-ribose synthetase inhibitor (n = 6). Biventricular hemodynamic variables were measured by means of a combined pressure-volume conductance catheter, and the slope of the end-systolic pressure-volume relationships was calculated at baseline and after 60 minutes of reperfusion. Left anterior descending coronary blood flow, endothelium-dependent vasodilatation to acetylcholine, and endothelium-independent vasodilatation to sodium nitroprusside were also determined. RESULTS: The administration of PJ34 led to a significantly better recovery of left and right ventricular systolic function (P <.05) after 60 minutes of reperfusion. In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved in the PJ34 group. Coronary blood flow was also significantly higher in the PJ34 group (P <.05). Although the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the PJ34 group (P <.05). CONCLUSIONS: Poly-ADP-ribose synthetase inhibition improves the recovery of myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

p53 autoantibodies as tumor marker in head and neck squamous cell cancer.

p53 autoantibodies (AAB) are a new serological parameter with unknown potential in patients with malignancies. The reason why and the mechanism by which they develop is still unclear. So far, only in a limited number of studies has the usefulness of p53 AAB in the follow-up of cancer patients been shown. In this study 32 patients with head and neck cancer, seropositive for p53 AAB in their serum detected with an ELISA, were followed-up for at least 42 months. In 9 out of 32 p53 seropositive AAB head and neck cancer patients a correlation with the clinical course of the disease was seen. The remaining 23 of the p53 AAB-positive patients did not demonstrate any significant AAB titer changes during the follow-up and no significant correlation with the clinical course was observed. In conclusion, the clinical value of p53 AAB as a tumor marker for patients with head and neck cancer seems to be limited.

Myocardial protection after systemic application of L-arginine during reperfusion.

The L-arginine-nitric oxide (NO) pathway plays an important role in ischemia-reperfusion injury. In the present study we investigated the role of NO-precursor L-arginine on cardiac and pulmonary function after reversible hypothermic ischemia. Twelve anesthetized dogs underwent cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started with application of either saline vehicle (control, n = 6) or L-arginine (40 mg/kg i.v. bolus then 3 mg/kg i.v. infusion during the first 20 minutes of reperfusion, n = 6). The vasodilative response to acetylcholine was significantly higher in the L-arginine group (P < 0.05). The preload recruitable stroke work of the left ventricle decreased significantly after reperfusion, however remained unchanged in the L-arginine group. Arterial blood gas analysis did not show any difference between the two groups. Plasma L-arginine concentration reached peak level at 20 minutes of administration (675.0 +/- 66.6 versus 207.7 +/- 14.5 in the L-arginine group, P < 0.05) and returned to baseline at 40 minutes, while in the control group remained unchanged during ischemia and reperfusion (276.2 +/- 71.6 versus 283.8 +/- 38.5, P < 0.05). Plasma nitrite concentration followed L-arginine changes parallel, however nitrate levels increased slower. Supplementation with L-arginine during reperfusion prevents myocardial and endothelial dysfunction, however does not have any overriding effect on pulmonary function. Considerably rapid elimination of plasma L-arginine was demonstrated during early reperfusion.

Mesenteric complications after hypothermic cardiopulmonary bypass with cardiac arrest: underlying mechanisms.

The aim of this study was to determine the pathophysiological mechanisms of postcardiopulmonary bypass (CPB) intestinal dysfunction using an in vivo canine model of extracorporeal circulation. Six dogs underwent a 90 min hypothermic CPB with continuous monitoring of mean arterial blood pressure (MAP) and mesenteric blood flow (MBF). Reactive hyperemia and vasodilator responses of the superior mesenteric artery to acetylcholine and sodium nitroprusside were determined before and after CPB. Mesenteric lactate production, glucose consumption, creatine kinase (CK) release and venous free radicals were determined. CPB induced a significant fall (p < 0.05) in MAP and MBF. After CPB, reactive hyperemia (-26 +/- 15% versus -53 +/- 2%, p < 0.05) and the response to acetylcholine (-42 +/- 9 versus -55 +/- 6%, p < 0.05) were significantly decreased. Reperfusion increased lactate production (0.8 +/- 0.09 mmol/L versus 0.4 +/- 0.18, p < 0.05) and the CK release (446 +/- 98 U/L versus 5 +/- 19 U/L, p < 0.01). Endothelial dysfunction, conversion from aerobic to anaerobic metabolism, and intestinal cell necrosis seem to be responsible for intestinal complications associated with CPB.