Activation of protein kinase C and nicotinamide adenine dinucleotide phosphate oxidase in leukocytes of spontaneously hypertensive rats.

The involvement of oxidative stress in polymorphonuclear leukocytes (PMN) in the pathogenesis of hypertension remains to be elucidated. We analyzed the generation of reactive oxygen species (ROS) by the circulating and peritoneally infiltrating PMN from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flow cytometric analysis revealed that ROS generation by PMN from SHR was higher than that from WKY before (at 6 weeks of age) and after (at 16 weeks of age) the onset of hypertension. In vivo, ROS generation by PMN from SHR, but not that by PMN from WKY, was significantly suppressed by 10-week treatment with 50 mg/kg/day carvedilol, and this treatment did not affect blood pressure. Western blotting analysis revealed that protein kinase C alpha (PKCalpha), but not PKCbetaI or betaII, was activated more strongly in PMN from SHR than in PMN from WKY. Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY. These results suggest that ROS generation by PMN is principally enhanced in SHR through activation of PKCalpha and p47phox.     

Sustained ventricular tachycardia responsive to verapamil in patients with hypertrophic cardiomyopathy. Clinical and electrophysiological assessment of drug efficacy

Recently, we examined 2 cases of hypertrophic cardiomyopathy (HCM) presenting with sustained ventricular tachycardia (VT). One case was a 62 year old male with midventricular hypertrophy and monomorphic sustained VT. After admission, the efficacies of procainamide, disopyramide, aprindin, flecainide, mexiletine and verapamil were evaluated by means of continuous electrocardiographic monitoring. Verapamil prevented the recurrence of sustained VT and markedly reduced the frequency and number of runs of nonsustained VT. In the electrophysiologic study, rapid VT was induced by double extrastimuli at the right ventricular apex. Intravenous verapamil at a dose of 10 mg prevented the induction of VT. The patient was discharged on verapamil and remains asymptomatic after 3 months of follow up. The other case was a 34 year old female who was a survivor of cardiac arrest. Monomorphic VT was observed on emergency admission and was converted to sinus rhythm by direct current cardioversion after resuscitation. In the electrophysiologic study, rapid VT was induced by double extrastimuli at the right ventricular outflow tract. Verapamil at a dose of 10 mg prevented the induction of VT. These 2 cases of HCM are rare in that they presented with sustained VT. It is also of interest that verapamil, which has been used conventionally in HCM, prevented VT.     

Met-RANTES ameliorates fibrous airway obliteration and decreases ERK expression in a murine model of bronchiolitis obliterans.

OBJECTIVES: Bronchiolitis obliterans (BO) is the main cause of late mortality among long-term survivors of lung transplantation. Chemokine-chemokine receptor (CCR) interaction and subsequent recruitment of infiltrating cells to the graft are early events in the development of chronic rejection of transplanted lungs. The present study investigated whether blockade of chemokine receptors CCR1 and CCR5 with Met-regulated-on-activation, normal T cells expressed and secreted (RANTES), an amino-terminal modified derivative of RANTES/CCL5, affects the development of BO in murine model and we sought to determine the expression of RANTES/CCL5 and their relationship with extracellular signal-regulated kinase (ERK). Materials and Methods: BALB/c mouse tracheas were heterotopically transplanted into C57Black6 recipients and treated for 21 days with either Met-RANTES at 20 microg/day or vehicle. Animals were killed at 21 days after transplantation for histologic examination of ERK expression. RESULTS: RANTES/CCL5 was highly expressed in allografts compare to isografts. Met-RANTES treatment ameliorated fibrous airway obliteration in a mouse model of BO and decreased ERK expression. CONCLUSION: Blockade of chemokine receptors by Met-RANTES ameliorated airway obliteration and decreased ERK expression. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and ERK may be a new molecular target for chronic rejection.     

Effect of systemic zinc administration on delayed neuronal death in the gerbil hippocampus

The divalent cation zinc has been reported to possess several physiological properties such as blocking apoptotic cell death through an inhibitory effect on Ca²⁺-Mg²⁺ endonuclease activity, or modulating the neurotoxicity via glutamate receptor subtypes. In the present study, we investigated the effect of peripherally injected zinc on delayed neuronal death seen in the hippocampus after transient global ischemia, in order to elucidate a possible beneficial role on zinc in ischemic neuronal cell death. Forty-five adult Mongolian gerbils of both sexes underwent transient bilateral clipping of the common carotid arteries for 3 min. In the pretreated animals, ZnCl₂ (20 mg/kg) was injected subcutaneously once, 1 h before ischemia (superacute group; n=6) or twice at 24 and 48 h before ischemia (subacute group; n=14). Histological survey was carried out 3 days later by in situ DNA fragmentation method and 4 days later by hematoxylin-eosin staining by semiquantatively counting dead neurons in the CA1 sector. Subacute zinc pre-administration significantly reduced the nuclear damage and subsequent neuronal death; however, superacutely pre-administered zinc did not protect hippocampal neurons against ischemia but it did not aggravate the effect of ischemia, either. The present study suggested that transfer of exogenous zinc into the intracellular space is required for neuroprotection, presumably via the anti-endonuclease activity.     

Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration

A 52-year-old woman had a newly recognized disorder of familial hypoceruloplasminemia, blepharospasm, retinal degeneration, and high-density areas in CT of the basal ganglia and liver scan. Immunofixation electrophoresis disclosed apoceruloplasmin deficiency. Kinetic, x-ray analysis, and histochemical study showed accumulation of iron in liver and brain, but not of copper. Intestinal copper absorption was reduced, but liver uptake was increased. Ceruloplasmin is involved in iron metabolism, and the findings suggest that hypoceruloplasminemia due to lack of apoceruloplasmin was causally linked to the iron deposition in basal ganglia and other organs, leading to blepharospasm and retinal degeneration.     

Effects of AETT-Induced Neuronal Ceroid Lipofuscinosis on Learning Ability in Rats

Abstract: The behavioral effects of ceroid-lipofuscin accumulation, induced by intraperitoneal administration of acetyl-ethyl-tetramethyl-tetralin (AETT) in Wistar rats for 3 months, were examined in the present studies. A significant increase in neuronal ceroid-lipofuscin was demonstrated neuropathologically as well as morphometrically. Although the AETT-intoxicated rats showed neither alteration of locomotor activity nor shock sensitivity, a significant impairment of learning ability, especially an acquisition trial in passive avoidance tests, was observed. Results of the present studies indicate the possibility that a diffuse lipofuscin accumulation causes a learning impairment in rats. The results also imply the possibility of a significant role of age-related lipofuscin accumulation in the dementing processes of human especially in the elderly.     

Effects of arginine derivatives on soluble guanylate cyclase from neuroblastoma N1E 115 cells

The effects of L-arginine (Arg) derivatives on soluble guanylate cyclase from neuroblastoma N1E 115 cells were examined. The Arg derivatives were modified at the -NH2, -COOH, C alpha-proton or guanidino group of Arg. Among the synthesized derivatives, eight compounds, i.e. the 5-(dimethylamino)-1-naphthalenesulfonyl (DNS) ones, especially N-cyclohexyl-2-(N-DNSamino)-5-guanidino-2-methylvaleramide and 1-[2-(N-DNSamino)-2-(2-imino-1,2,3,4,5,6-hexahydropyrimidin- 4-yl)acetyl]- piperidine, were found to inhibit the activity of crude guanylate cyclase in the 105,000 g supernatant fraction of the cell homogenate. The enzyme, partially purified by a column of Chelex 100 Na+, was also inhibited by these eight compounds. The mode of the inhibition was competitive. The Ki values were in the range of 2-8 microM for the enzyme in the 105,000 g supernatant fraction and 3-16 microM for the partially purified enzyme, in the presence of Mg2+ as a metal cofactor. In contrast, a new derivative, methyl 2-amino-5-guanidinovalerate (M Arg ME), as well as the Arg methyl ester (Arg ME) and Arg; were found to enhance the activity of the partially purified guanylate cyclase; KA values of M Arg ME, Arg ME and Arg were approximately 9, 4 and 3 microM respectively. From these results, the free guanidino group including 2-imino-1,2,3,4,5,6-hexahydropyrimidin-4-yl or 2-imino-1,2,3,4,5,6-hexahydropyrimidin-5-yl and modification of the --NH2 residue with a hydrophobic group such as DNS seemed to be essential for inhibition of the guanylate cyclase; however, the guanidino and --NH2 residue of Arg should be free for activation by these Arg derivatives.     

Evaluation of therapeutic interventions of sustained monomorphic ventricular tachycardia guided by an electrophysiologic study: a case report

Therapeutic evaluation of sustained monomorphic ventricular tachycardia (VT) using electrophysiologic study (EPS) is presented in a case of refractory VT. A 54-year-old man with a history of recurring syncope underwent coronary angiography which revealed total occlusion of the posterior descending branch of the right coronary artery. Left ventriculography showed a left ventricular aneurysm at the cardiac apex. Ejection fraction of the left ventricle was 36%. He had four VTs of different QRS morphologies in 12 lead electrocardiograms. According to our programmed ventricular stimulations, single or double, and rarely triple, extra stimuli were administered after eight basic stimuli at two basic cycle lengths. Rapid ventricular pacing, up to 210 bpm, was then added. The stimuli were delivered to two different sites in the right ventricle and to at least one site in the left ventricle. When the entire protocol could not induce VT, isoproterenol was given intravenously, and the same protocol was repeated. No drug could prevent VT attacks, even after the surgical resection of two VT foci, VT was still inducible. Postoperative drug therapy could not prevent VT induction in EPS. However, changes in the mode required for VT induction were observed. Among 47 patients with sustained monomorphic VT treated in our hospital, 24 had EPS to evaluate the efficacies of therapeutic interventions, such as drugs and surgery. In 14 patients, no VT was induced by the entire VT induction protocol. Among the remaining 10 patients, four showed changes in the VT induction mode, but VT recurred in their clinical courses even after their treatments.(ABSTRACT TRUNCATED AT 250 WORDS)