Bradykinin B2 receptor is involved in the late phase of preconditioning in rabbit heart.

Activation of bradykinin B2 receptor has been shown to confer short-term cardioprotection against a prolonged ischemic insult. The present study was designed to delineate the role of B2 receptor in the late phase of ischemic preconditioning. Anesthetized, open chest, male rabbits were assigned to 1 of 6 groups (n=8/group). Ischemic preconditioning was elicited by four 5-min occlusion periods interspersed with 10 min of reperfusion. To test the role of B2 receptors, rabbits were pretreated with specific receptor antagonist, HOE-140 (1 microgm/kg IV bolus), 15 min prior to ischemic preconditioning. Additionally, two separate groups of animals were treated by intra-atrial infusion with either bradykinin (0.05 microg/kg/min for 15 min) or saline. Twenty-four hours later, the animals were subjected to 30 min of ischemia and 3 h of reperfusion. Infarct size was determined by tetrazolium staining. Ischemic preconditioning reduced infarct size from 43.09+/-4.66 to 20.65+/-1.87 (% risk area, P<0.05), which was blocked by HOE-140 as indicated by increase in infarct size (36.72+/-4.04%, P<0.05). HOE-140 treatment had no significant effect on infarct size in the sham group. Similarly, intra-atrial infusion of bradykinin caused decrease in the infarct size from 52.36+/-2.17% in the saline control group to 22.83+/-1.71% (P<0.05). The degree of infarct limitation with bradykinin was comparable to ischemic preconditioning (20.65+/-1.87%v 22.83+/-1.71%, P>0.05). For the first time, these results provide evidence for the involvement of B2 receptor in the genesis of late phase of ischemic preconditioning.

Calpain-mediated proteolytic cleavage of troponin I induced by hypoxia or metabolic inhibition in cultured neonatal cardiomyocytes.

While ischemic damage to myofibrillar proteins is thought to be responsible in part for depressed cardiac function, the relation between myofilament protein breakdown and chronic hypoxia has not been defined. We previously characterized a chemical hypoxia model of neonatal cardiomyocytes mediated by 1 mM azide that exhibits features of calpain activation (Mol Cell Biochem 178:141-149, 1998). We here show that both hypoxia and azide-mediated metabolic inhibition induced heme oxygenase-1 expression, and caused cell death associated with lipid peroxidation. While blocking calcium influx or inhibiting calpain activity efficiently attenuated hypoxia-induced cell injury, it failed to prevent cell injury caused by adenoviral overexpression of the tumor suppressor protein p53. Inhibitors of caspases, on the other hand, suppressed cell injury caused by p53 overexpression. Hypoxia caused selective cleavage of troponin I (TnI), which could be suppressed by either nifedipine or calpeptin. Other myofilament proteins such as troponin T, myosin heavy chain, and actin appeared to remain largely intact. p53-mediated cell injury exhibited proteolysis of the caspase protein substrate lamin B without appreciable breakdown of TnI. We suggest that calpain-induced TnI breakdown may constitute a unique biochemical marker associated with chronically hypoxic cardiomyocytes.

Problems with rabies postexposure management: a survey of 499 public hospitals in Thailand.

Rabies is still a major public health problem in Asia. The incidence of known annual human cases in India alone has recently been revised from 20,000 to 30,000, and over 500,000 patients are given some form of postexposure rabies treatment. Only China, Peninsular Malaysia, Singapore, and Thailand are reporting a significant decrease in the prevalence of this disease in humans. Over 150,000 courses of postexposure treatment (PET) are given in Thailand every year. To determine remaining barriers to further reduction of the number of human rabies deaths, we carried out a questionnaire study of government hospitals throughout the Kingdom.

An immunogenicity and efficacy study of purified chick embryo cell culture rabies vaccine manufactured in Japan.

Purified chick embryo cell rabies vaccine manufactured by the Chemo-Sero-Therapeutic Institute(Kaketsuken) at Kumamoto, Japan (Kaketsuken) was submitted to an immunogenicity and efficacy study. 52 severely rabies exposed patients were treated with the conventional five doses intramuscular WHO approved ('Essen') postexposure schedule. This included the administration of 40 IU kg-1 of equine rabies immune globulin on Day 0. A control group of equally severely exposed subjects were treated with human diploid cell rabies vaccine manufactured by the Swiss Serum and Vaccine Institute as well as human rabies immune globulin. There were no deaths in either group in the more than 2 years follow-up period. Subjects treated with the chick embryo vaccine showed greater suppression of the neutralizing antibody response by the equine rabies immune globulin than those given the human diploid cell vaccine and human rabies immune globulin. A group of 20 less severely rabies exposed patients who received only the chick embryo vaccine without immune globulin all had antibody titers greater than the WHO minimal acceptable level on Day 14, 30, 90 and 180. Fourteen subjects among the severely exposed vaccine and immune globulin study group were given vaccine boosters on Day 180 because of low antibody titers. It is concluded that chick embryo rabies vaccine manufactured by Kaketsuken is an immunogenic and effective rabies vaccine, but that the potency of future batches must be increased to provide a greater safety margin.

Immune response to simulated postexposure rabies booster vaccinations in volunteers who received preexposure vaccinations.

Several studies of the efficacy of intradermal postexposure rabies vaccination have shown that this procedure is safe, effective, and cost saving. Less is known about the reliability of the present World Health Organization (WHO)-approved intradermal preexposure regimen, which consists of three 0.1-mL doses that are generally given on days 0, 7, and 28. Previous studies have shown that neutralizing antibody responses are lower and of shorter duration in subjects given the reduced-dose intradermal regimen. Thus, it is still uncertain whether the WHO-recommended single intramuscular or intradermal booster injections given on days 0 and 3 would prevent death in all cases. In this preliminary study, we evaluated titers of neutralizing antibody in Thai student volunteers given two simulated postexposure boosters, as recommended by WHO, and we compared these volunteers to a group given vaccine intramuscularly. We observed a lower, although adequate, accelerated immune response in those given the preexposure series and postexposure boosters intradermally.