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Biomedical subjects

N Homma

Publications and source records attributed to N Homma.

At least 37 records · Page 2Linked to original sources
PubMed1990

Anticholinergic action of quinidine sulfate in the rabbit atrioventricular node.

Anticholinergic action of quinidine sulfate was electrophysiologically studied by recording spontaneous action potentials and membrane current of the rabbit atrioventricular node. In the presence of 0.1 mumol/l carbachol, the spontaneous activity of the atrioventricular nodal preparations was markedly inhibited, whereas subsequent addition of 1, 5 and 20 mumol/l quinidine restored automaticity in a concentration-dependent manner. In some preparations, quinidine at concentrations of 5 mumol/l and higher slowed the spontaneous activity by its direct membrane action even in the presence of carbachol. The dose-response curve for acetylcholine action on the spontaneous firing frequency showed that one molecule of acetylcholine bound to one muscarinic receptor of the atrioventricular node cell (Hill coefficient = 1.2). A parallel shift of this curve towards higher acetylcholine concentrations was observed at 0.03, 0.1 and 0.3 mumol/l but not at 1 and 3 mumol/l quinidine, suggesting a noncompetitive antagonism of quinidine against acetylcholine. Voltage clamp experiments revealed that 5 mumol/l quinidine reduced the slow inward current, hyperpolarization-activated inward current, and delayed rectifying K+ current, through its membrane actions. Quinidine at this concentration almost completely suppressed the acetylcholine-activated K+ current, which showed a relaxation phenomenon. Hence, the direct blockage of the acetylcholine-activated K+ current by quinidine was considered responsible for the anticholinergic action of this drug. We conclude that quinidine is a non-specific ionic channel blocker that inhibits all the membrane currents in the atrioventricular node including the acetylcholine-activated K+ current.

Action Potentials↗
PubMed1990

Electrophysiologic actions of aprindine in rabbit atrioventricular node.

Aprindine hydrochloride is a potent antiarrhythmic agent against various atrial and ventricular tachyarrhythmias. To elucidate its pharmacological actions in the atrioventricular node, electrophysiologic experiments were conducted by applying microelectrode and voltage clamp methods to small preparations of the rabbit atrioventricular node. At a concentration 1 mumol/l, aprindine decreased the spontaneous firing frequency, maximal rate of depolarization, action potential amplitude, and take-off potential (P less than 0.05, n = 7). The spontaneous and rate-controlled action potential durations at 50 and 100% repolarization were prolonged by aprindine. Voltage-clamp experiments using the double microelectrode method revealed that aprindine blocked the slow inward current (Isi) in a voltage-dependent manner with a dissociation constant of 10 mumol/l and Hill coefficient of 0.8. The steady-state inactivation curve for Isi was shifted toward more negative potentials by 2.5 +/- 0.9 mV (P less than 0.05, n = 5) without a significant change in the slope factor. This finding suggests that aprindine has a higher affinity for inactivated slow inward (or Ca2+) channels than for resting channels. Aprindine caused use-dependent block of Isi, a result consistent with the drug's slow dissociation from inactivated Ca2+ channels. The delayed rectifying K+ current (IK) tail obtained on repolarization from +10 mV to -60 mV was significantly decreased from 15.4 +/- 2.4 to 6.8 +/- 1.4 nA (P less than 0.01, n = 6) and the deactivation time constant significantly increased by 20.7% (P less than 0.01, n = 6). The steady-state activation curve for IK was shifted in the hyperpolarized direction by 6.9 +/- 2.9 mV, suggesting a potent voltage-dependent block of this current by aprindine. The hyperpolarization-activated inward current (Ih) was decreased from 14.4 +/- 5.4 to 12.0 +/- 5.5 nA (P less than 0.05, n = 5). The transient outward and inward currents induced by 1 mumol/l acetylstrophanthidin were almost completely suppressed after the addition of 1 mumol/l aprindine. These results suggest that aprindine exerts a negative chronotropic action both by slowing deactivation of IK and by reducing Isi and Ih, and delays atrioventricular nodal conduction by reducing Isi and IK. These blocking actions of aprindine together with its inhibition of the transient outward and inward currents may explain its antiarrhythmic effects on the atrioventricular node.

Action Potentials↗
PubMed1989

Ionic mechanisms of the depression of automaticity and conduction in the rabbit atrioventricular node caused by hypoxia or metabolic inhibition and protective action of glucose and valine.

The effects of hypoxia and a metabolic inhibitor, sodium cyanide (NaCN), on the spontaneous action potential and membrane current systems were studied in small preparations (0.2 x 0.2 x 0.1 mm) of rabbit atrioventricular node. When the PO2 of the superfusate was lowered from 500 to less than 20 mm Hg, all the preparations initially showed reductions in the spontaneous firing frequency (due to the decreased rate of diastolic depolarization) and maximal rate of depolarization, which were followed by a cessation of automatic activity with subsequent membrane hyperpolarization to -57 +/- 3 mV (n = 4). Voltage clamp experiments using double microelectrode techniques revealed that hypoxia reduced the slow inward current by 20 to 80% without affecting its inactivation kinetics. The delayed rectifying potassium current tail was also reduced or abolished by severe hypoxia, whereas the background outward current was greatly increased. The hyperpolarization-activated inward current was decreased by hypoxia. Similar changes in the spontaneous action potential and membrane currents were obtained on adding 0.1 to 0.5 mM NaCN to the superfusate under conditions of normal PO2. Hypoxia-induced suppression of automaticity was reversed completely by 5 mM glucose, and partially by 40 mM valine. These results suggest that (1) hypoxia impairs atrioventricular nodal conduction by reducing the slow inward current and the delayed rectifying potassium current; (2) hypoxia depresses automaticity by increasing the background outward current and, to some extent, by reducing the slow inward current; and (3) glucose and valine contribute to the generation of high-energy phosphates in cytoplasm and mitochondria, respectively, and protect the atrioventricular node from hypoxia.

Action Potentials↗
PubMed1989

Subtypes of muscarinic receptors in pancreatic exocrine secretion in anesthetized dog.

Characterization of muscarinic receptor subtypes on the dog pancreas in situ was examined by using specific muscarinic receptor antagonists to study pancreatic exocrine secretion. Bethanechol caused an increase in pancreatic exocrine secretion, with a high concentration of protein and little effect on bicarbonate concentration. Thus bethanechol may mainly affect the muscarinic receptors of the acinar cells. Bethanechol-stimulated secretion was inhibited by pirenzepine (a specific M1 muscarinic antagonist), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP, a specific M3 muscarinic antagonist), and atropine (a mixed muscarinic receptor antagonist). However, [11-[[2-(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11- dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepine-6-one (AF-DX 116, a specific cardioselective M2 antagonist) did not have any effects on bethanechol-stimulated secretion. Increased protein secretion in pancreatic juice stimulated by bethanechol was significantly inhibited by 4-DAMP and atropine and was suppressed by pirenzepine, but was not modified by AF-DX 116. Bicarbonate concentration was not modified by these antagonists. 4-DAMP, atropine, and pirenzepine caused a progressive parallel rightward shift in the dose-response curve of pancreatic secretion for bethanechol. Schild analysis of the data indicated a pA2 value of 8.7 for 4-DAMP, 7.9 for atropine, and 6.2 for pirenzepine, respectively. Thus 4-DAMP has 7.5 times and 440 times greater potency than atropine and pirenzepine to inhibit bethanechol-stimulated secretion. The slope of the Schild regression line was not different from 1. These results suggest that inhibitions of bethanechol-stimulated pancreatic secretion are competitive for 4-DAMP, atropine, and pirenzepine and that bethanechol-stimulated pancreatic secretion is mediated by M3 muscarinic receptors in dogs.

Animals↗
PubMed1989

Augmentation and subsequent attenuation of Ca2+ current due to lipid peroxidation of the membrane caused by t-butyl hydroperoxide in the rabbit sinoatrial node.

Cellular electrophysiological effects of membrane lipid peroxidation by t-butyl hydroperoxide (TBH) were studied in the rabbit sinoatrial (SA) node. Superfusion for 1-5 min with 300 microM TBH caused an initial increase and subsequent decrease in the spontaneous firing frequency of the SA node. Voltage clamp experiments revealed that TBH initially enhanced but later blocked the Ca2+ current. Thus, membrane lipid peroxidation appears to accelerate and then suppress physiological automaticity by causing biphasic changes in the Ca2+ current.

Action Potentials↗
PubMed1989

Collagen-binding affinity of beta-2-microglobulin, a preprotein of hemodialysis-associated amyloidosis.

beta 2-Microglobulin (B2M) is the amyloid preprotein that accumulates in amyloid osteoarthropathy associated with hemodialysis. To elucidate the mechanism of such amyloidogenesis, we investigated the interaction between B2M and collagen in vitro by solid-phase enzyme immunoassay. Soluble collagens which had been solidified on plastic plates were allowed to react sequentially with B2M, peroxidase-conjugated antibody to B2M, and the substrate. The collagen-binding activity was dependent on the concentration of B2M and collagen, respectively. These results suggest that the collagen-binding affinity of B2M plays an important role in amyloidogenesis.

Amyloidosis↗
PubMed1989

Effects of DN-9693, a synthesized phosphodiesterase inhibitor, on pancreatic exocrine secretion in dogs.

The effects of DN-9693, a synthesized phosphodiesterase inhibitor, on the secretion of pancreatic juice were investigated in preparations of the isolated and blood-perfused dog pancreas. DN-9693 injected intraarterially caused a dose-dependent increase in the secretion of pancreatic juice and decrease in the perfusion pressure. The threshold doses to increase the pancreatic secretion and to decrease the perfusion pressure were about 100 micrograms and 1 microgram, to decrease the perfusion pressure were about 100 micrograms and 1 micrograms, respectively. Thus, the secretory response was less effective than the vascular response. The secretory activity of DN-9693 (0.3 mg) was approximately equal to that of 0.03 mg of 3-isobutyl-1-methylxanthine, 0.5 mg of papaverine, 5 mg of theophylline, 0.08 0.5 mg of papaverine, 5 mg of theophylline, 0.08 units of secretin and 0.2 units of cholecystokinin. The concentration of bicarbonate in the pancreatic juice induced by DN-9693 was increased, but protein concentration was not. DN-9693-induced pancreatic secretion was not modified by pretreatments with phentolamine, propranolol, atropine, sulpiride and cimetidine. Secretin-induced pancreatic secretion was significantly potentiated by infusion of DN-9693 (10 micrograms/min), but cholecystokinin-induced one was not. From these results, it is concluded that DN-9693 may produce an increase in pancreatic secretion by acting directly on the pancreatic exocrine gland of the dog, which might be mediated through an increase of intracellular cyclic AMP concentration by inhibiting phosphodiesterase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Central alpha 2 adrenoceptor-mediated pancreatic exocrine response to yohimbine in anesthetized dog.

Effects of yohimbine on the secretion of pancreatic juice in anesthetized dogs were investigated. Intravenous yohimbine (0.1-1 mg/kg) caused dose-dependent increases in the secretion of pancreatic juice and vasodilation. However, intra-arterial yohimbine (0.3-1 mg) did not cause any secretory responses. The secretory activity of 0.3 mg/kg of yohimbine was approximately equal to that of 0.04 U/kg of secretin and 40 mg/kg of 2-deoxy-D-glucose (2-DG). Secretory responses to yohimbine were inhibited by pretreatment with clonidine or atropine and abolished by vagotomy. The concentration of protein in the pancreatic juice induced by yohimbine was increased, but the bicarbonate concentration was scarcely changed. These results indicate that yohimbine stimulates, at least in part, pancreatic exocrine secretion by acting on the central alpha 2 adrenoceptor in the dog.

Animals↗
PubMed1987

Effects of nicorandil and verapamil, antianginal agents, on plasma digoxin concentrations in rats and dogs.

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg-1) alone, or in combination with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg-1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1). In dogs, a loading dose of digoxin (50 micrograms kg-1) was given orally on day 1, then 25 micrograms kg-1 was administered for the following 6 days. On day 8, digoxin (50 micrograms kg-1) was given with nicorandil (5 mg kg-1) or verapamil (20 mg kg-1). In rats, the AUC0-24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.

Animals↗
PubMed1987

Immunological studies on Kawasaki disease: II. Isolation and characterization of an immunosuppressive factor in acute phase sera.

Acute phase serum from a patient with Kawasaki disease possessed strong inhibitory activity for the proliferative response of Con A-stimulated peripheral blood mononuclear cells. The inhibitor was fractionated step-wise by means of DEAE-Sephadex A-50 ion exchange chromatography followed by Sephadex G-100 gel filtration and high performance liquid chromatography. A major protein of 140 kD with 2000 times greater inhibitory activity than the original serum was identified in the final fraction. Immunization of mice with this fraction resulted in the production of three hybridoma clones secreting monoclonal antibodies (MoAb) of IgG1 class which blocked the inhibitory activity of the fraction. Two of these MoAb recognized the same epitope of the inhibitory factor, while the remaining MoAb was directed to a different epitope. Western blot analysis of acute phase sera by the MoAb demonstrated the presence of 140 kD molecules in 43 of 55 patients.

Acute-Phase Reaction↗
PubMed1986

Inhibition of lymphocyte DNA synthesis by plasma from patients with Kawasaki disease.

Plasma obtained from patients with Kawasaki disease during the acute phase markedly inhibited DNA synthesis in autologous peripheral blood lymphocytes (PBLs) stimulated by phytohaemagglutinin-P (PHA-P) or concanavalin A (Con A). The inhibition became less marked with the progression of the disease and there was no effect on DNA synthesis in PBLs stimulated by pokeweed mitogen (PWM). The plasma also inhibited DNA synthesis in PBLs obtained from healthy adults. The postulated suppressors markedly inhibited DNA synthesis in PBLs from healthy adults stimulated by PHA-P, Con A, purified protein derivative (PPD) or mixed lymphocyte culture reaction (MLR) but they had little effect on the DNA synthesis stimulated by PWM or protein A. With respect to the mechanism, the suppression was found to be potentiated by an increase in the concentration of the patients' plasma, and not to be associated with cytotoxicity nor with a deficiency of factor(s) indispensable for PBL proliferation. It was also evident that the suppression was not related to the concentration of the stimulant, to the lengths of the culturing period nor to the presence of prostaglandins.

Adult↗
PubMed1986

Effects of three purine-related compounds on pancreatic exocrine secretion in the dog.

The effects of adenosine, adenosine 5'-triphosphate (ATP) and inosine on pancreatic exocrine secretion were investigated in the vascularly isolated and self-haemoperfused dog pancreas. Drugs were injected close-arterially (i.a.) in a single bolus. These three purine-related compounds per se did not affect resting rate of pancreatic secretion and the concentrations of protein and bicarbonate in the resting juice. Graded doses of adenosine (0.1-1.0 mg, i.a.) and ATP (0.1-1.0 mg i.a.) administered 1 min prior to secretin (0.025 clinical units, i.a.) increased a secretin-stimulated secretory volume dose-dependently, and the effects of adenosine and ATP were reversed by pretreatments with theophylline (0.3 mg, i.a.). Inosine (1.0 mg, i.a.) affected neither secretin- nor dopamine-stimulated (3 micrograms, i.a.) pancreatic secretion. Adenosine and ATP did not affect dopamine-stimulated pancreatic secretion. These results suggest that adenosine and ATP (or terminal phosphate hydrolyzed derivatives) enhance secretin-stimulated pancreatic exocrine secretion through 'P1' purine receptors in the exocrine cells, without conversion to inosine.

Adenosine↗
PubMed1986

Effects of diazepam on pancreatic exocrine secretion in the dog.

The effects of diazepam on pancreatic exocrine secretion were investigated in the vascularly isolated and self-hemoperfused dog pancreas under constant perfusion pressure of 100 mmHg. Close-arterial injections (i.a.) of diazepam (0.3-3.0 mg) caused dose-dependent increases in the secretion of pancreatic juice and in the rate of perfusion blood flow. Protein and bicarbonate concentrations of the pancreatic juice stimulated by 3.0 mg of diazepam were significantly higher than those of the resting pancreatic juice. The secretory activity of 1.0 mg (i.a.) of diazepam was comparable to that of 0.05 units (i.a.) of secretin. These secretory and vascular responses to diazepam were not modified by pretreatments with atropine, sulpiride, cimetidine, theophylline and Ro 15-1788. These results suggest that large doses of diazepam act directly on both acinar and ductular cells of the pancreas and induce protein and bicarbonate secretions.

Animals↗