Yasutaka Hirata

Nitric oxide-mediated effects of interleukin-6 on [Ca2+]i and cell contraction in cultured chick ventricular myocytes.

Cytokines have significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In the present study, we examined both the early and delayed effects of interleukin-6 (IL-6) on cultured chick embryo ventricular myocytes. Exposure of these cells to human recombinant IL-6 significantly decreased peak systolic [Ca2+]i (71.0 +/- 0.6% of the control value) and the amplitude of cell contraction (66.0 +/- 7.4% of the control value) within a few minutes. Pretreatment with NG-monomethyl-L-arginine (L-NMMA) or methylene blue completely inhibited the IL-6-induced early changes. Subsequent addition of L-arginine reversed the effects of L-NMMA. The levels of cGMP were significantly increased after 30 minutes of exposure to IL-6 (134.4 +/- 9.1% of the control value). Pretreatment with L-NMMA or EGTA significantly inhibited the IL-6-induced early elevation of cGMP. These results suggest that IL-6 acutely decreases intracellular Ca2+ transients and depresses cell contraction by nitric oxide (NO)-cGMP-mediated pathway. Therefore, IL-6 may enhance the Ca(2+)-dependent constitutive NO synthase activity in cardiac myocytes. On the other hand, 24-hour exposure to IL-6 also increased the levels of cGMP (159.0 +/- 22.8% of the control value) regardless of pretreatment with EGTA. These delayed increases in cGMP were also shown to be coupled with decreases in intracellular Ca2+ transients and the amplitude of cell contraction. Thus, IL-6 may induce Ca(2+)-independent NO synthase in cardiac myocytes. Together with the previous reports that have suggested the possible roles of IL-6 in myocardial stunning or endotoxic shock, this negative inotropic effect of IL-6 may contribute to these clinical settings.

Thoracic and cardiovascular surgery in Japan during 2014

The Japanese Association for Thoracic Surgery has conducted annual surveys of thoracic surgery throughout Japan since 1986 to determine the statistics regarding the number of procedures according to operative category. Here, we have summarized the results from our annual survey of thoracic surgery performed during 2014.

The effects of human atrial 28-amino acid peptide on systemic and renal hemodynamics in anesthetized rats.

The effects of synthetic human atrial 28-amino acid peptide (alpha-human atrial polypeptide) on systemic and renal hemodynamics were examined in two separate groups of Inactin-anesthetized rats. First, mean arterial pressure, heart rate, and cardiac output were measured before and during infusion of the peptide at rates of 0.04-0.67 microgram/kg per min. Cardiac output was determined by the dye-dilution method with a microcuvette inserted into a carotid-femoral arterial shunt. After 10 minutes of infusion, mean arterial pressure, cardiac output, and total peripheral resistance were reduced in a dose-dependent manner by 21% (P less than 0.001), 9% (P less than 0.05), and 11% (P less than 0.05), respectively, with 0.67 microgram/kg per min of alpha-human atrial natriuretic polypeptide. Despite the marked fall in blood pressure, the heart rate did not change. Second, urine volume, urinary sodium excretion, glomerular filtration rate ([3H]inulin clearance) and renal blood flow ([14C]p-aminohippuric acid sodium clearance and hematocrit) were measured. Increases in urine volume, urinary sodium excretion, filtration fraction, and fractional sodium excretion and a decrease in renal vascular resistance were dose dependent: +490% (P less than 0.01), +1340% (P less than 0.01), +19% (P less than 0.05), +1160% (P less than 0.01), and -18% (P less than 0.05), respectively, with 0.67 microgram/kg per min of alpha-human atrial natriuretic polypeptide. The glomerular filtration rate increased with 0.33 and 0.67 microgram/kg per min of alpha-human atrial natriuretic polypeptide (both P less than 0.05), whereas renal blood flow did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term administration of L-arginine improves nitric oxide release from kidney in deoxycorticosterone acetate-salt hypertensive rats.

To examine the effects of L-arginine (L-Arg) on endothelial function, we administered 0.5 g/L L-Arg in drinking water to deoxycorticosterone acetate (DOCA)-salt rats for 8 weeks and then measured nitric oxide (NO) release from isolated kidneys using a newly developed real-time chemiluminescence method. Renal pathology was also analyzed. Acetylcholine caused much smaller declines in renal perfusion pressure (10(-7) mol/L acetylcholine: -24 +/- 2% [SEM] versus -50 +/- 2%, P < .001) and NO release in DOCA-salt rats (+3 +/- 1 versus +33 +/- 3 fmol/min per gram kidney weight, P < .001) compared with control rats. L-Arg did not influence the time course of systolic blood pressure elevation in DOCA-salt rats (211 +/- 5 versus 208 +/- 6 mmHg, DOCA versus L-Arg/DOCA, P = NS). However, oral administration of L-Arg improved acetylcholine-induced declines in renal perfusion pressure (10(-7) mol/L acetylcholine: L-Arg/DOCA, -39 +/- 3%, P < .01 versus DOCA). This change was associated with an increase in NO release by acetylcholine (10(-7) mol/L acetylcholine: L-Arg/DOCA, +10 +/- 1 fmol/min per gram kidney weight, P < .05 versus DOCA). However, morphological changes in renal vessels and glomeruli were similar between DOCA and L-Arg/DOCA rats. These results suggest that L-Arg administration partially reverses renal endothelial function with respect to vasorelaxation and NO release independent of blood pressure changes, indicating that hypertensive vessels seem to be depleted of L-Arg and/or have defects in the availability of L-Arg for NO synthesis.

Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance.

DNA released from obesity-induced degenerated adipocytes stimulates inflammation in adipose tissue and insulin resistance. Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

Role of endogenous atrial natriuretic peptide in DOCA-salt hypertensive rats. Effects of a novel nonpeptide antagonist for atrial natriuretic peptide receptor.

BackgroundTo explore roles of endogenous atrial natriuretic peptide (ANP) in blood pressure and volume regulation, we examined the effects of a newly developed ANP antagonist, HS-142-1 (HS) in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Methods and ResultsWe examined 1) the effects of HS on ANP- or brain natriuretic peptide (BNP)-induced reductions in renal vascular resistance (RVR) of rat isolated perfused kidneys, 2) the effects of HS on cyclic GMP (cGMP) production in rat cultured vascular smooth muscle cells pretreated with ANP or BNP, and 3) the renal and systemic effects of HS in DOCA-salt-treated rats and control rats. We found that 1) HS dose-dependently reversed ANP- or BNP-induced decreases in RVR; 2) ANP or BNP at 100 nM caused an eightfold increase in cGMP production. These increases in cGMP were inhibited by HS in a dose-dependent fashion, and 300, μg/ml HS decreased cGMP to the control level. HS alone did not influence RVR or cGMP production; and 3) DOCA-salt rats showed higher plasma concentrations of ANP (198 versus 75 pg/ml) and BNP (23.7 versus 2.7 pg/ml, each p<0.01) than the control rats. Bolus administration of 8 mg/kg HS elevated blood pressure by 8% (p<0.01). This rise in blood pressure was attributed to an increase in systemic vascular resistance (+14%, p<0.05). Conversely, urinary excretion of sodium (-41%), glomerular filtration rate (-27%), and plasma (-77%) and urinary cGMP (-69%, each p<0.01) were decreased by administration of 8 mg/kg HS. These effects were dose dependent in DOCA-salt rats but slight or negligible in the control rats. ConclusionThese results suggest that endogenous ANP and BNP may be involved in the regulation of blood pressure and body fluid volume in DOCA-salt rats in which ANP and BNP secretion is augmented.

Role of endogenous atrial natriuretic peptide in regulating sodium excretion in spontaneously hypertensive rats. Effects of neutral endopeptidase inhibition.

To explore whether pathophysiological plasma levels of atrial natriuretic peptide (ANP) actually involve sodium excretion in spontaneously hypertensive rats (SHR), we examined the in vivo and ex vivo effects of ANP and an endopeptidase inhibitor, thiorphan, on urinary sodium excretion and the elimination rate of ANP. We found the following: 1) The basal plasma ANP level was higher in 16-week-old SHR than in Wistar-Kyoto (WKY) rats (109±10 [SEM] versus 63±4 pg/ml, p<0.001). Thiorphan (30 mg/kg i.v.) significantly increased plasma ANP by 60% in both SHR and WKY rats. However, increases in urinary sodium excretion (+290% versus +130%, p<0.05) and cyclic GMP (+160% versus +60%, p+0.05) were greater in SHR than in WKY rats. Urinary excretion of ANP was markedly increased by thiorphan, and its increase was greater in SHR than in WKY rats. 2) The thiorphan-induced natriuresis was substantially attenuated by antiserum for ANP but not by a bradykinin receptor antagonist 3) Isolated SHR kidneys excreted 50% less sodium than WKY rat kidneys at perfusion pressures of 100 and 160 mm Hg (p<0.05). Urinary sodium excretion was increased at the perfusate ANP level of 100 pg/ml, a concentration similar to the SHR plasma ANP (+70% at 160 mm Hg). 4) After bolus administration of ANP to the isolated kidney, the ANP concentration of the recirculating perfusate decreased rapidly in a log-linear fashion. Pretreatment with thiorphan significantly prolonged the elimination half-life of ANP to a greater degree in the SHR kidney than in the WKY rat kidney (+75% versus +36%, p<0.05). Thus, endogenous ANP may keep the pressure-natriuresis curve to the left and consequently facilitate sodium excretion in SHR. Moreover, the enzymatic degradation of ANP seems to be increased in SHR kidneys.

Two-staged pancreatoduodenectomy with external drainage of pancreatic juice and omental graft technique

Although operative mortality after pancreatoduodenectomy (PD) has been reduced dramatically by improvements in surgical techniques and perioperative care and the indications for PD have been expanded to more risky cases such as the very aged or emergency patients, 1-3 pancreatic leakage, once it has occurred, may cause severe infection and subsequent fatal bleeding from the stumps of the major vessels, contributing to postoperative mortality. High-risk patients with severe chronic liver diseases such as liver cirrhosis (LC) have been excluded as candidates for PD. Here, we report a successful two-staged PD with external drainage of pancreatic juice and omental graft technique in a patient with LC receiving anticoagulant therapy after cardiac valve replacement. TECHNIQUE

Effects of a nonpeptide vasopressin antagonist (OPC-21268) on cytosolic Ca2+ concentration in vascular and cardiac myocytes.

A selective V, antagonist, l-{l-[4(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinolinone (OPC-21268), which is nonpeptide and orally effective, has been recently synthesized. We studied the effects of vasopressin and OPC-21268 on cell contraction with a video motion detector and cytosolic Ca2+ concentration ([Ca2+]i) by using indo-1 in cultured rat vascular smooth muscle cells and cultured chick embryo ventricular myocytes. Exposure of cultured vascular smooth muscle cells to vasopressin (1–100 nM) dose-dependently produced an initial transient increase (from control level [Ca2+]i of 133.6±10.9 nM to peak [Ca2+], of 842.7±172.8 nM at 100 nM vasopressin, p < 0.01) and then a small sustained increase in [Ca2+]i. After pretreatment of vascular smooth muscle cells with 1 μM OPC-21268, the effects of 100 nM vasopressin on [Ca2+]i were abolished. Exposure of ventricular myocytes to 100 nM vasopressin slightly but significantly decreased peak systolic cell position (−8.7±3.7%, p < 0.05) and also produced reductions in peak systolic [Ca2+]i (from 962.2±76.4 to 751.2±70.5 nM, p < 0.01) within 30 seconds. Pretreatment of ventricular myocytes with OPC-21268 (1 μM) completely suppressed vasopressininduced changes in peak systolic cell position and [Ca2+]i. These results suggest that vasopressin may increase vascular tone and may also cause a direct negative inotropic effect via V1 receptors and that this orally active V1 antagonist (OPC-21268) may have potential clinical usefulness.

The national clinical database as an initiative for quality improvement in Japan.

The JCVSD (Japan Cardiovascular Surgery Database) was organized in 2000 to improve the quality of cardiovascular surgery in Japan. Web-based data harvesting on adult cardiac surgery was started (Japan Adult Cardiovascular Surgery Database, JACVSD) in 2001, and on congenital heart surgery (Japan Congenital Cardiovascular Surgery Database, JCCVSD) in 2008. Both databases grew to become national databases by the end of 2013. This was influenced by the success of the Society for Thoracic Surgeons’ National Database, which contains comparable input items. In 2011, the Japanese Board of Cardiovascular Surgery announced that the JACVSD and JCCVSD data are to be used for board certification, which improved the quality of the first paperless and web-based board certification review undertaken in 2013. These changes led to a further step. In 2011, the National Clinical Database (NCD) was organized to investigate the feasibility of clinical databases in other medical fields, especially surgery. In the NCD, the board certification system of the Japan Surgical Society, the basic association of surgery was set as the first level in the hierarchy of specialties, and nine associations and six board certification systems were set at the second level as subspecialties. The NCD grew rapidly, and now covers 95% of total surgical procedures. The participating associations will release or have released risk models, and studies that use ‘big data’ from these databases have been published. The national databases have contributed to evidence-based medicine, to the accountability of medical professionals, and to quality assessment and quality improvement of surgery in Japan.