SUMMARY 1. It is reported that α 1 ‐receptors and adenosine A1‐receptors are involved in the ischaemic preconditioning (PC) effect on infarct size (IS). However, it is still unclear to what extent α 1 ‐receptors and adenosine A1‐receptors contribute to the mechanism of PC. Therefore, we investigated the extent of the contribution of α 1 ‐receptors and adenosine A1 receptors to the PC effect on IS and examined the relationship between these receptors and protein kinase C. 2. Infarct size was measured in rabbits subjected to 30 min ischaemia and 48 h reperfusion. Tyramine (Tyr) was intravenously administered before 30 min ischaemia in the absence or presence of bunazosin (BN, α 1 ‐receptor blocker) and staurosporine (ST), a protein kinase C inhibitor, respectively. R(‐)N6‐(2‐phenylisapropyl)‐adenosine (PIA), a selective adenosine A1 agonist, was intravenously administered before 30 min ischaemia in the absence or presence of 8‐p‐sulphophenyltheophylline (8SPT), an adenosine blocker and ST, respectively. In the PC groups, BN, BN + PIA, 8SPT, 8SPT + Tyr or placebo saline was injected before or during PC. 3. Both Tyr and PIA reduced the IS, which was blocked by BN and 8SPT, respectively. The IS‐reducing effect of Tyr or PIA was blocked by ST. The IS‐reducing effect of PC was completely blocked by BN and 8SPT, respectively. The blocking effect of BN on the IS‐reducing effect of PC was abolished by adding PIA during PC ischaemia. The blocking effect of 8SPT on the IS‐reducing effect of PC was abolished by adding Tyr before PC ischaemia. 4. These data suggest that an α 1 ‐receptor dependent pathway exists and an adenosine A1‐receptor dependent pathway, stimulation of both of which activates protein kinase C, then reduces the IS. However, exclusive stimulation of a single α 1 ‐receptor dependent pathway or a single adenosine A1‐receptor dependent pathway alone is not sufficient but the summation of these pathways is required to achieve a PC effect on IS in rabbits.
Objective To evaluate the efficacy of combined therapy—hyperbaric oxygenation with nicardipine administration—for neurologic recovery after complete cerebral ischemia. Design Randomized, prospective, controlled, unblinded study, with 14-day postischemic observation. Setting Laboratory of the Department of Anesthesiology, Tohoku University School of Medicine. Subjects Nineteen healthy mongrel dogs (mean weight 10.4 kg) divided randomly into two groups—ten dogs in the untreated group and nine dogs in the treated group. Interventions Fifteen minutes of complete global cerebral ischemia was achieved by occlusion of the ascending aorta and the caval veins. Dogs in the treated group each received a 0.01-mg/kg bolus injection of nicardipine immediately after the reestablishment of circulation, followed by a 0.03-μg/kg/min continuous infusion of nicardipine for 3 days and hyperbaric oxygen therapy with 3 atmospheres absolute pressures in an FIO2 of 1.0 for 1 hr at 3, 24, and 29 hrs after ischemia. Neurologic recovery was evaluated based on the survival time and rate, the Electroencephalogram (EEG) Score (1 = normal, 5 = isoelectric), and the Neurologic Recovery Score (100 = normal, 0 = brain dead) over a 14-day postischemic period. Measurements and Main Results Neurologic Recovery Scores of the treated group were always higher than those scores of the untreated group throughout the 14-day period. The best Neurologic Recovery Score was 83.1 ± 5.3 in the treated group and 46.9 ± 5.2 in the untreated group (p < .01). The numbers of dogs that recovered to a Neurologic Recovery Score of >85 (assessed as almost normal) was five of nine in the treated group and none of ten in the untreated group (p < .01). Recovery of EEG over 14-day period was better in the treated group. The survival rate and the predicted survival rate were 78% and 13.6 days in the treated group and 30% and 9.0 days in the untreated group, respectively (p < .04 for the survival rate and p < .05 for the survival time). Conclusion: Combined therapy, using hyperbaric oxygenation with nicardipine administration, given after 15 mins of complete global cerebral ischemia, accelerates neurologic recovery in dogs. (Crit Care Med 1994; 22:858–863)
A 55-year-old man with idiopathic Parkinson9s disease developed myasthenia gravis shortly after taking trihexyphenidyl. The myasthenic weakness waxed and waned with rise and fall in serum levels of trihexyphenidyl, without marked change of anti-acetylcholine receptor antibody titer.
In Brief Morphine has been an optimal choice for cancer pain management. However, several recent studies suggested that morphine induces apoptosis in human peripheral blood lymphocytes (PBLs), raising a serious concern about the use of opioid-based analgesic strategies. In this study, therefore, we aimed to evaluate whether morphine induced apoptosis in cultured human PBLs. Apoptotic events were assessed by flow-cytometrical detection of surface phosphatidylserine and nuclear fragmentation, as well as Fas, Bcl-2, and Caspase-3 activity in PBLs gated on a light-scatter basis. Peripheral blood mononuclear cells isolated from healthy subjects were cultured with etoposide, morphine, or vehicle (medium) for 48 h. During co-culture with etoposide, apo-ptosis was significantly induced in PBLs, and the cells did not survive for 48 h. In comparison, morphine had no effect on the expression rate of any of the detected molecules, suggesting that no apparent apoptotic processes were induced during the incubation. Furthermore, co-incubation with a Fas-specific antibody did not increase apoptotic cell rates in the morphine cultures. These results do not support the hypothesis that morphine directly modulates PBL apoptosis resulting in immunosuppression. We believe that the choice of opioids for optimal pain relief should not be discouraged until further studies clarify this issue. IMPLICATIONS: Recent reports that morphine potentially induces apoptosis in human lymphocytes in vitro have raised a concern about the use of opioid-based analgesic strategies. Regarding this issue, we present rather contradictory findings that morphine has no effects on the cell expression of various apoptosis-related molecules in cultured human lymphocytes.
We compared the affinities of a new alpha1-adrenoceptor (AR) antagonist, JTH-601 with those of several alpha1-AR antagonists in human prostates and arteries.In the functional study, noradrenaline produced concentration-dependent contractions in human prostates and mesenteric arteries. The pA2/pKB values for the antagonists in the human prostate were 9.78 for tamsulosin, 8.84 for JTH-601, 8.39 for WB4101, 8.23 for prazosin, 8.12 for JTH-601-G1 (a main metabolite of JTH-601 in human) and 6.57 for BMY7378. Compared these affinities with those in the mesenteric artery, only JTH-601 and JTH-601-G1 exhibited unique uroselectivity, showing 10- to 20-fold higher affinity for the human prostate than for mesenteric artery. The affinity profile of these antagonists suggested that the noradrenaline-induced contractions in the human prostate and the mesenteric artery were mediated by the alpha1L-AR and alpha1B-AR, respectively. In the competition binding study, the pharmacological profiles of the antagonists against [3H]-prazosin were examined in the human prostate and aorta. The resulting pKi values for JTH-601 and JTH-601-G1 were also approximately 10- to 20-fold higher for the human prostate than for the human aorta.These results have suggested that JTH-601 and JTH-601-G1 are unique uroselective alpha1-AR antagonists that show higher affinity for the human prostate than for the human arteries.
The mouse XX gonadal primordium develops seminiferous-like tubules after transplantation into the renal subcapsular site of the adult male or female mouse. We examined the ontogeny of Sertoli cell differentiation in XX gonadal grafts by immunocytochemical staining and organ culture bioassay for Müllerian Inhibiting Substance (MIS). During normal in situ development of the XY gonad, MIS staining was first detected in fetal Sertoli cells at 12 days of gestation (d.g.) and remained intense until 4 days postpartum (d.pp.), after which it gradually diminished with progressive testicular development. In the normal in situ XX gonad, MIS was detected in granulosa cells of growing follicles at 7 d.pp. and thereafter. When the XX gonad at 12 d.g. was grafted beneath the renal capsule, a few testicular cords composed of MIS-positive cells appeared on Day 7 post-transplantation (equivalent to 19 d.g.), much earlier than the normal appearance of MIS production in the intact XX ovary. The ovarian region containing germ cells at the meiotic prophase was unstained for MIS in the same sections. The incidence of XX gonadal grafts containing MIS-positive testicular cords and the number of such cords per gonadal graft steadily increased from Day 7 to Day 14 post-transplantation. Germ cells were absent or scarce inside the MIS-positive testicular cords. The MIS bioactivity in both control gonads and gonadal grafts coincided with the immunocytochemical staining for MIS. These results support the hypothesis that XX cells differentiate into Sertoli cells as a consequence of oocyte loss in the gonadal graft.
