Ivabradine increases the high frequency gain ratio in the vagal heart rate transfer function via an interaction with muscarinic potassium channels.

Muscarinic potassium channels (I ) are thought to contribute to the high frequency (HF) dynamic heart rate (HR) response to vagal nerve stimulation (VNS) because they act faster than the pathway mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. However, the interactions between the two pathways have not yet been fully elucidated. We previously demonstrated that HCN channel blockade by ivabradine (IVA) increased the HF gain ratio of the transfer function from VNS to HR.

Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study.

Beta-blockers are well known to reduce myocardial oxygen consumption (MVO) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe β-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated β-blocker administration system.

Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under β-blockade.

Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e.

GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor-suppressor gene TGFβR2 in colorectal cancer.

Chromosome 7q (Ch.7q) is clonally amplified in colorectal cancer (CRC). We aimed to identify oncogenes on Ch.

Wave reflection correlates with pulmonary vascular wall thickening in rats with pulmonary arterial hypertension.

Background: Wave reflection is enhanced in patients with pulmonary arterial hypertension (PAH), which may be derived from a mismatch of pulmonary artery (PA) impedance between proximal and distal sites of arteries. Whether enhanced wave reflection correlates with histological remodeling remains unknown, partly because lung biopsy is not clinically recommended for PAH patients due to substantial risks of mortality and morbidity.

Methods: Pulmonary hypertension was induced by SU5416 injection and 3-week hypoxic exposure (SuHx-PH) in rats, and hemodynamic and histological examinations were performed at 4weeks (SuHx-PH) and 8weeks (SuHx-PH) after SU5416 injection (n=7 each).

Sodium ion transport participates in non-neuronal acetylcholine release in the renal cortex of anesthetized rabbits.

This study examined the mechanism of release of endogenous acetylcholine (ACh) in rabbit renal cortex by applying a microdialysis technique. In anesthetized rabbits, a microdialysis probe was implanted into the renal cortex and perfused with Ringer's solution containing high potassium concentration, high sodium concentration, a Na/K-ATPase inhibitor (ouabain), or an epithelial Na channel blocker (benzamil). Dialysate samples were collected at baseline and during exposure to each agent, and ACh concentrations in the samples were measured by high-performance liquid chromatography.

Relevance of cardiomyocyte mechano-electric coupling to stretch-induced arrhythmias: optical voltage/calcium measurement in mechanically stimulated cells, tissues and organs.

Stretch-induced arrhythmias are multi-scale phenomena in which alterations in channel activities and/or calcium handling lead to the organ level derangement of the heart rhythm. To understand how cellular mechano-electric coupling (MEC) leads to stretch-induced arrhythmias at the organ level, we developed stretching devices and optical voltage/calcium measurement techniques optimized to each cardiac level. This review introduces these experimental techniques of (1) optical voltage measurement coupled with a carbon-fiber technique for single isolated cardiomyocytes, (2) optical voltage mapping combined with motion tracking technique for myocardial tissue/whole heart preparations and (3) real-time calcium imaging coupled with a laser optical trap technique for cardiomyocytes.

Prognostic markers for immunochemotherapy using tegafur -uracil (UFT) and protein-bound polysaccharide K (PSK).

Aim/background: We previously reported that PSK-induced lymphocyte blastogenesis reaction (PSK-stimulation index; PSK-SI) may be a prognostic marker for immunochemotherapy using PSK in gastrointestinal cancer patients. In this study we evaluated the usefulness of PSK-SI as a prognostic marker for PSK therapy at higher and lower serum immunosuppressive acidic protein (IAP) levels.

Patients And Methods: 98 gastric and 135 colorectal cancer patients were analyzed.

H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs.

Purpose: Inhalation of hydrogen (H(2)) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H(2) gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mK(ATP)) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H(2) gas in canine hearts.

Large conductance Ca2+-activated K+ channels inhibit vagal acetylcholine release at the rabbit sinoatrial node.

Although large conductance Ca(2+)-activated K(+) (BK) channels play an important role in determining vascular tone, their role in the efferent cardiac vagal system remains to be elucidated. In anesthetized rabbits (n=9), acetylcholine (ACh) was measured at the right atrium near the sinoatrial node by a cardiac microdialysis technique, and the ACh release in response to electrical stimulation of the cervical preganglionic vagal nerves was examined. Local administration of a BK channel blocker iberiotoxin (2 microM) through a dialysis fiber increased the stimulation-induced ACh release from 7.

Role of Ca2+-activated K+ channels in catecholamine release from in vivo rat adrenal medulla.

To elucidate the role of Ca(2+)-activated K(+) (K(Ca)) channels in the presynaptic acetylcholine (ACh) release from splanchnic nerve endings and the postsynaptic catecholamine release from chromaffin cells, we applied microdialysis technique to the left adrenal medulla of anesthetized rats and investigated the effects of local administration of K(Ca) channel antagonists through dialysis probes on the release of ACh and/or catecholamine, induced by electrical stimulation of splanchnic nerves or local administration of ACh through the dialysis probes. Nerve stimulation-induced release: in the presence of a cholinesterase inhibitor, neostigmine, large-conductance K(Ca) (BK) channel antagonists, iberiotoxin and paxilline enhanced the presynaptic ACh release and postsynaptic norepinephrine (NE) and epinephrine (Epi) release. Small-conductance K(Ca) (SK) channel antagonists, apamin and scyllatoxin enhanced the Epi release without any changes in ACh or NE release.

Accentuated antagonism in vagal heart rate control mediated through muscarinic potassium channels.

Although muscarinic K(+) (K(ACh)) channels contribute to a rapid heart rate (HR) response to vagal stimulation, whether background sympathetic tone affects the HR control via the K(ACh)channels remains to be elucidated. In seven anesthetized rabbits with sinoaortic denervation and vagotomy, we estimated the dynamic transfer function of the HR response by using random binary vagal stimulation (0-10 Hz). Tertiapin, a selective K(ACh) channel blocker, decreased the dynamic gain (to 2.

Development of an algorithm for detection of fatal cardiac arrhythmia for implantable cardioverter-defibrillator using a self-organizing map.

In this study, we have introduced the pattern classifier using the self-organizing map (SOM) for detecting fatal cardiac arrhythmia in implantable cardioverter-defibrillators (ICDs). The SOM has learned patterns of sinus rhythm, ventricular fibrillation and ventricular tachycardia with the feature vectors extracted from electrocardiogram and right ventricular volume measured during an arrhythmia induction experiment of a dog. After learning, neurons of the SOM were labeled by using the k-Nearest Neighbor method.

Muscarinic potassium channels augment dynamic and static heart rate responses to vagal stimulation.

Vagal control of heart rate (HR) is mediated by direct and indirect actions of ACh. Direct action of ACh activates the muscarinic K(+) (K(ACh)) channels, whereas indirect action inhibits adenylyl cyclase. The role of the K(ACh) channels in the overall picture of vagal HR control remains to be elucidated.

Automated drug delivery system to control systemic arterial pressure, cardiac output, and left heart filling pressure in acute decompensated heart failure.

Pharmacological support with inotropes and vasodilators to control decompensated hemodynamics requires strict monitoring of patient condition and frequent adjustments of drug infusion rates, which is difficult and time-consuming, especially in hemodynamically unstable patients. To overcome this difficulty, we have developed a novel automated drug delivery system for simultaneous control of systemic arterial pressure (AP), cardiac output (CO), and left atrial pressure (Pla). Previous systems attempted to directly control AP and CO by estimating their responses to drug infusions.

Myocardial interstitial choline and glutamate levels during acute myocardial ischaemia and local ouabain administration.

Aim: Noradrenaline (NA) uptake transporters are known to reverse their action during acute myocardial ischaemia and to contribute to ischaemia-induced myocardial interstitial NA release. By contrast, functional roles of choline and glutamate transporters during acute myocardial ischaemia remain to be investigated. Because both transporters are driven by the normal Na+ gradient across the plasma membrane in a similar manner to NA transporters, the loss of Na+ gradient would affect the transporter function, which would in turn alter myocardial interstitial choline and glutamate levels.

Effects of partial left ventriculectomy on left ventricular pump function studied by theoretical analyses.

Although partial left ventriculectomy (PLV) was devised to reduce myocardial wall stress in patients with severe heart failure, whether the operation acutely improves cardiac pump function has not been determined either clinically or experimentally. Because precise control of preload, afterload, and heart rate is virtually impossible in animal experiments as well as clinically before and after surgery, we took advantage of the theoretical analysis to study quantitatively the changes in pump function by PLV. We reconstructed the endsystolic and end-diastolic pressure-volume relationships based on two different geometric conditions (i.

Analysis of the genetic alterations in a case of juvenile multiple colon carcinoma with hypogammaglobulinemia.

Background: We have previously reported the clinical characterization of a case of juvenile multiple colorectal carcinoma with hypogammaglobulinemia. Several recent studies have determined that agammaglobulinemia was caused by the loss of Bruton's tyrosine kinase (Btk) function. However, any genetic alterations associated with carcinoma formation in individuals with this immunodeficient disease have not been reported.

Single-beat estimation of ventricular end-systolic elastance-effective arterial elastance as an index of ventricular mechanoenergetic performance.

Background: The ratio of ventricular end-systolic elastance (Ees) to effective arterial elastance (Ea) is known to reflect not only ventricular mechanical performance but also energetic performance. Despite these useful features, technical difficulties associated with estimating Ees make the clinical application of Ees/Ea impractical. We developed a framework to estimate Ees/Ea without measuring ventricular volume or altering the loading condition.

Mechanism of contraction induced by bradykinin in the rabbit saphenous vein.

1. By using fura-PE3 fluorometry and receptor-coupled permeabilization by alpha-toxin, the mechanism of the bradykinin (BK)-induced contraction was determined in the rabbit saphenous vein (RSV). The receptor subtype responsible for the BK-induced contraction of RSV was determined by means of a pharmacological blocker study and reverse transcription polymerase chain reaction (RT-PCR).

Dose intensity of uracil and tegafur in postoperative chemotherapy for patients with poorly differentiated gastric cancer.

A retrospective analysis of postoperative chemotherapy had shown the continuous administration of UFT, an oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 1:4, to be effective for poorly differentiated gastric cancer. We therefore sought to determine prospectively the effective dose of postoperative chemotherapy with UFT for patients with poorly differentiated gastric cancer following a curative resection. We determined the effect of the combined intravenous administration of mitomycin C (MMC) and oral treatment with protein-bound polysaccharide Kreha (PSK), extracted from the basidiomycete Coriolus versicolor, and UFT at a dose of either 8 mg/kg or 12 mg/kg daily for 1 year.

K-ras and p53 mutations are an independent unfavourable prognostic indicator in patients with non-small-cell lung cancer.

We examined 159 consecutive cases of non-small-cell lung cancer (NSCLC) for a mutation at codon 12 of the K-ras gene and for a mutation of the p53 gene occurring in exons 5-8. Eleven (6.9%) had mutations of the K-ras (ras+) and 57 (35.

Postoperative adjuvant randomised trial comparing chemoendocrine therapy, chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year results from the Nishinihon Cooperative Study Group of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) of Japan.

Between 1985 and 1988, the effect of using ftorafur (FT) or PSK (an immunotherapy agent) in combination with the conventional postoperative adjuvant therapy using mitomycin (MMC) plus tamoxifen (TAM) was assessed in stage II, oestrogen receptor-positive (ER+) breast cancer patients. Furthermore, in ER- breast cancer stage II patients, the effects of postoperative adjuvant therapy using MMC plus FT were compared with the effects of postoperative adjuvant therapy using MMC plus PSK. Patients had primary stage II breast cancer and had undergone total mastectomy plus axillary dissection or more radical surgery.

In vitro reactivity to a protein-bound polysaccharide PSK of peripheral blood lymphocytes from patients with gastrointestinal cancer.

The effect of PSK, a protein-bound polysaccharide and an immunomodulator, on lymphocytes was examined in vitro for 36 patients with gastric cancer and 26 with colorectal cancer. Cultured lymphocytes with PSK at 100 micrograms/ml increased the level of DNA synthesis, as determined by the 3H-thymidine uptake, from 0.9 to 3.