Urinary trypsin inhibitors afford cardioprotective effects through activation of PI3K-Akt and ERK signal transduction and inhibition of p38 MAPK and JNK.

BACKGROUND: We determined the effect of urinary trypsin inhibitors (UTI) in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases such as phosphatidylinositol-3-OH kinases (PI3K)-Akt and extracellular signal-regulated kinases (ERK 1/2) and apoptotic kinases such as p38 and JNK. METHODS: The rats were anesthetized and subjected to an I/R insult consisting of 30-min left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size was measured after 120 min of reperfusion. UTI was given alone or along with wortmannin (inhibitor of PI3K) or PD098059 (inhibitor of ERK1/2) before LAD occlusion. The phosphorylation of Akt, ERK1/2, p38 and JNK was determined by immunoblotting after 5 min of reperfusion. UTI was administered 10 min before LAD occlusion, and wortmannin and PD098059 were administered 20 min before LAD occlusion. RESULTS: UTI significantly reduced the infarct size compared with the control. Wortmannin or PD098059 alone did not affect the infarct size, but they abolished the UTI-induced cardioprotective effect. UTI significantly reduced the phosphorylation of p38 and JNK, while it enhanced that of Akt and ERK1/2. CONCLUSIONS: UTI has a protective effect against regional myocardial I/R injury through activation of survival kinases PI3K-Akt and ERK1/2 and attenuation of p38 and JNK.

Sevoflurane concentrations required to block autonomic hyperreflexia during transurethral litholapaxy in patients with complete spinal cord injury.

BACKGROUND: Autonomic hyperreflexia (AHR) is a potentially life-threatening hypertensive condition that occurs in patients with high spinal cord injury (SCI). The current study was aimed to determine sevoflurane concentrations that block AHR in SCI patients. METHODS: The study involved 28 patients with chronic, complete SCI scheduled to undergo transurethral litholapaxy during general anesthesia. Nine patients without SCI served as controls post hoc. Anesthesia was induced with thiopental, and sevoflurane concentrations in 50% nitrous oxide were adjusted to maintain a Bispectral Index of 40-50. When a patient developed AHR during bladder distension, the target sevoflurane concentration was maintained for at least 10 min, and then the procedure was resumed. Systolic blood pressure, heart rate, and Bispectral Index as well as plasma concentrations of catecholamines and arginine vasopressin were measured before and during the bladder distension. Each target concentration was determined by the up-and-down method based on changes (15% increase or more) of systolic blood pressure in response to bladder distension. RESULTS: In SCI, systolic pressure increased by 67 +/- 33 mmHg, whereas heart rate decreased by 13 +/- 8 beats/min during the first trial (P < 0.01). The hypertensive event was associated with increases of norepinephrine concentrations, but not of epinephrine or vasopressin concentrations. Systolic pressure, heart rate, and norepinephrine concentrations did not change significantly in the control patients. The end-tidal concentrations of sevoflurane to prevent AHR were EC50 of 3.12% and EC95 of 3.83%. CONCLUSION: The EC95 for sevoflurane in 50% nitrous oxide to block AHR during transurethral litholapaxy in patients with SCI was 3.83%.