Continuous inhibition of poly(ADP-ribose) polymerase does not reduce reperfusion injury in isolated rat heart.

Poly(ADP-ribose) polymerase (PARP), an enzyme that is important to the regulation of nuclear function, is activated by DNA strand breakage. In massive DNA damage, PARP is overactivated, exhausting nicotinamide adenine dinucleotide and leading to cell death. Recent studies have succeeded in reducing cellular damage in ischemia/reperfusion by inhibiting PARP. However, PARP plays an important part in the DNA repair system, and its inhibition may be hazardous in certain situations. We compared the short-time inhibition of PARP against continuous inhibition during ischemia/reperfusion using isolated rat hearts. The hearts were reperfused after 21 minutes of ischemia with a bolus injection of 3-aminobenzamide (3-AB) (10 mg/kg) followed by continuous 3-AB infusion (50 µM) for the whole reperfusion period or for the first 6 minutes or without 3-AB. At the end of reperfusion, contractile function, high-energy phosphate content, nicotinamide adenine dinucleotide content, and infarcted area were significantly preserved in the 3-AB 6-minute group. In the 3-AB continuous group, these advantages were not apparent. At the end of reperfusion, PARP cleavage had significantly proceeded in the 3-AB continuous group, indicating initiation of the apoptotic cascade. Thus, continuous PARP inhibition by 3-AB does not reduce reperfusion injury in the isolated rat heart, which may be because of acceleration of apoptosis.

Relationship between oligomer and functional serum mannose-binding lectin in chronic renal failure.

INTRODUCTION: Mannose-binding lectin (MBL) plays an important role in first-line host defence against pathogens via the lectin pathway. The binding affinity for ligands is greatly increased by oligomerization, although the basic triplet does not bind solid phase mannan and cannot activate complement. Besides, MBL is a positive acute-phase protein. In this study, we examined the relationship between oligomer and functional serum MBL in chronic renal failure patients who were either uraemic [Pre-haemodialysis (pre-HD) patients], or who were receiving maintenance haemodialysis treatment (HD patients). MATERIALS AND METHODS: This study included a total of 20 Pre-HD patients, 130 HD patients and 28 healthy subjects. The oligomer and functional serum MBL levels were measured using enzyme-linked immunosorbent assays established previously. RESULTS: The median serum functional MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). Furthermore, the median functional MBL level in Pre-HD patients was significantly lower than that in HD patients (P<0·05). The median serum oligomer MBL levels in both Pre-HD and HD patients were significantly higher compared with healthy subjects (P<0·05 for both). Furthermore, the median oligomer MBL level in HD patients was significantly (P<0·05) higher than that in Pre-HD patients. The ratios of median serum functional MBL levels to oligomer MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). CONCLUSIONS: We found significant reductions in the ratios of serum functional MBL levels to oligomer MBL levels in HD and Pre-HD patients compared with healthy subjects.

Aortic Aneurysm as a Complication of Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis (MPO-AAV) does not usually involve large vessels, such as the aorta. However, we experienced three cases having an aortic aneurysm as a complication of MPO-AAV with renal insufficiency. In one patient it involved the onset of descending aortic dissection during treatment for MPO-AAV; another two patients had an abdominal aortic aneurysm at the time of our diagnosis of MPO-AAV. Although we found no pathological evidence in our patients, MPO-AAV might result in large vessel inflammation. Therefore, we suggest that patients with MPO-AAV should be examined by computed tomography scan to check for the presence of an aortic aneurysm.

Pathological Renal Findings of Chronic Renal Failure in a Patient with the E66Q Mutation in the α-galactosidase A Gene.

A 66-year-old Japanese man was diagnosed with interstitial nephritis on a renal biopsy at 45 years of age and began to receive hemodialysis at 65 years of age. He was suspected of having Fabry disease as a result of a screening study for Fabry disease performed in hemodialysis patients. He had an E66Q mutation in the α-galactosidase A gene. We conducted an electron microscopic examination of a renal biopsy specimen obtained when the patient was diagnosed with chronic renal failure at 45 years of age in order to elucidate the pathogenicity of the E66Q mutation. Interestingly, an electron microscopic examination of the renal biopsy specimen indicated no characteristic findings of Fabry disease.

Early reperfusion levels of Na(+) and Ca(2+) are strongly associated with postischemic functional recovery but are disassociated from K(ATP) channel-induced cardioprotection.

We previously demonstrated that pinacidil does not affect Na(+)(i) accumulation, cellular energy depletion, or acidosis during myocardial ischemia, but dramatically improves the cationic/energetic status during reperfusion. We investigated the role of this latter effect in K(ATP) channel-induced cardioprotection. Employing (23)Na and (31)P nuclear magnetic resonance spectroscopy with perfused rat hearts, reperfusion Na(+)(i) was altered with brief infusions of ouabain and/or RbCl to transiently decrease or increase Na(+)/K(+) ATPase activity. The increases and decreases in functional recovery (%LVDP-R) with pinacidil or ouabain, respectively, were largely unaltered by each other's presence. Early reperfusion Na(+)(i) and cellular energy were greatly altered by ouabain and indicated linear relationships with %LVDP-R. Pinacidil shifted these relationships to higher %LVDP-R. Increasing early reperfusion Na(+)(i) decreased %LVDP-R but did not diminish pinacidil's capacity to improve %LVDP-R. Approximately 75% and 45% of the pinacidil-induced improvements in %LVDP-R, could be disassociated from early reperfusion Na(+)(i) and cellular energy, respectively. Both pinacidil and RbCl infusion blunted ouabain's elevation of reperfusion Na(+)(i), but RbCl did not improve %LVDP-R. Atomic absorption tissue Ca(2+) measurements indicated that pinacidil reduced late reperfusion Ca(2+) uptake, but did not reduce early reperfusion Ca(2+), and its beneficial effects were resistant to ouabain-induced early reperfusion Ca(2+) increases. In conclusion, K(ATP) channel-induced cardioprotection does not require moderation of Na(+)(i) accumulation, cellular energy depletion, or acidosis during ischemia. K(ATP) channel-induced cardioprotection is largely independent of the accelerated reperfusion Na(+)(i) recovery it induces and does not require early reperfusion reductions of tissue Ca(2+). A larger role for early reperfusion cellular energy cannot be excluded.