Biomedical subjects

M Endoh

Publications and source records attributed to M Endoh.

At least 19 recordsLinked to original sources

PubMed1995

Angiotensin II activation of a chloride current in rabbit cardiac myocytes.

1. The effects of angiotensin II (Ang II) on membrane currents were investigated in single ventricular myocytes from the rabbit heart by the whole-cell voltage-clamp method. 2. In the presence of an inhibitor of Ca2+ currents (nifedipine at 3 microM or CdCl2 at 0.3 mM) and a beta-adrenoceptor blocker (bupranolol at 1 microM), 1 microM Ang II significantly increased the membrane conductance. 3. After elimination of K+ from external and internal solutions and its replacement by Cs+, Ang II at 0.1 microM increased an outwardly rectifying current that reached a maximum after about 40 min. The effect was concentration dependent (10(-9)-10(-6) M) and was inhibited by saralasin, an antagonist of Ang II receptors. 4. The reversal potential of the Ang II-induced current in the absence of K+ was compatible with the Cl- equilibrium potential at various external concentrations of Cl-. 5. A Cl- channel blocker, 4,4'-dinitrostilbene-2,2'-disulphonic acid (DNDS, at 5 mM), reversibly decreased the Ang II-induced current. 6. The Ang II-induced current developed when the internal solution contained Ca2+ (pCa 7.2 or 7.0) but not when it contained 10 mM EGTA without Ca2+. 7. Besides developing a Cl- current, Ang II at 1 microM increased the inwardly rectifying K+ current (IK1) and this effect reached maximum within 3 min. 8. The effect of Ang II on the action potential was biphasic: the duration of the action potential was initially reduced and then it was increased. 9. These results suggest that Ang II induces a Cl- current that appears likely to modulate the action potential in rabbit ventricular myocytes.

Action Potentials↗

PubMed1995

Acetylcholine and adenosine activate the G protein-gated muscarinic K+ channel in ferret ventricular myocytes.

The properties of the K+ channel activated by acetylcholine (ACh) and adenosine (Ado) were examined in single ferret ventricular myocytes using patch-clamp techniques. In the whole-cell configuration, ACh and Ado induced an inwardly rectifying K+ current and shortened the action potential duration. The effect of ACh was blocked by atropine, while the Ado effect was interrupted by 8-cyclopentyl,1,2-dipropyl xanthine, a specific Ado A1 receptor antagonist. In cell-attached recordings, ACh and Ado added to the pipette solution activated a single population of inwardly rectifying K+ channels, distinct from the iK1 channel. The channel had a slope conductance of approximately 40 pS in symmetrical 150 mM K+ solutions and a mean open time of 0.8 ms. Excision of the patch into the inside-out patch configuration in guanosine triphosphate (GTP)-free solution abolished the channel activity. The channel was reversibly reactivated by adding GTP to the intracellular side of the patch. GTP gamma S activated the channel irreversibly. When the inside-out patch was treated with the A protomer of pertussis toxin (PTX), intracellular GTP no longer activated the K+ channel. The results show that ferret ventricular myocytes possess a K+ channel activated by both muscarinic and Ado A1 receptors. Its electrophysiological properties and the gating by a PTX-sensitive G protein in a membrane-delimited fashion are identical with those of the muscarinic K+ channels in nodal and atrial tissues of other species. In conclusion, the G protein-gated muscarinic K+ channel is expressed in ferret ventricular myocardium and may underlie the direct negative inotropism of ACh and Ado in this tissue.

Acetylcholine↗

PubMed1995

The effects of various drugs on the myocardial inotropic response.

1. The signal transduction process mediated by cyclic AMP that leads to the characteristic positive inotropic effect (PIE) in association with a positive lusitropic effect (acceleration of rate of twitch relaxation) has been well established. Relationships between accumulation of cyclic AMP, changes in intracellular Ca2+ transients and the PIE differ, however, depending on the mechanism of particular drugs that affect different steps in the metabolism of cyclic AMP. Selective partial agonists of beta 1-adrenoceptors and inhibitors of phosphodiesterase (PDE) III cause the accumulation of less cyclic AMP for a given PIE than does isoproterenol. In addition, in aequorin-microinjected canine ventricular muscle, selective inhibitors of PDE III, OPC 18790 and Org 9731, produced smaller decreases in the responsiveness of myofilaments to Ca2+ ions than isoproterenol, while a partial agonist of beta 1-adrenoceptors, denopamine, elicits a decrease in Ca2+ responsiveness of the same extent as does isoproterenol. 2. Activation of myocardial alpha 1-adrenoceptors, as well as stimulation of receptors for endothelin and angiotensin II, which accelerates hydrolysis of phosphoinositide (PI) to result in production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) are associated with very similar inotropic regulation: (1) the dependence on the species of animals of induction of the PIE; (2) an excellent correlation between the extent of acceleration of hydrolysis of PI and the PIE; (3) isometric contraction curves associated with a negative lusitropic effect; (4) the PIE associated with increases in myofibrillar responsiveness to Ca2+ ions; and (5) the selective inhibition of the PIE by an activator of protein kinase C (PKC), phorbol 12,13-dibutyrate (PDBu), with little effect on the PIE of isoproterenol and Bay k 8644. 3. A novel class of cardiotonic agents, namely, Ca2+ sensitizers such as EMD 53998 and Org 30029, act on the Ca(2+)-binding site of troponin C, increasing the affinity of these sites for Ca2+ ions, or at the actin-myosin interface to facilitate the cycling of cross-bridges. These agents produce a PIE with little change or decrease in Ca2+ transients and may bring about a significant breakthrough in the development of drugs for reversal of myocardial failure in the treatment of congestive heart failure.

Adenosine↗

PubMed1995

The G-protein G(o) in mammalian cardiac muscle: localization and coupling to A1 adenosine receptors.

To investigate the functional relevance of the G-protein G(o) to adenosine-induced effects in the heart, we studied the localization of G(o) and its interaction with A1 adenosine receptors. Concentrations of G(o) in various mammalian hearts differed markedly between the atrial and the ventricular muscle, as well as among species. In most species examined, the concentration of G(o) was much higher in the atrium than in the ventricle. The highest levels of G(o) in atria and ventricles were found in the ferret heart. An immunohistochemical study of the ferret heart with G(o) alpha-specific antibodies showed that G(o) was localized throughout the membranes of cardiac myocytes, including the intercalated disks. In addition, G(o) was densely distributed in the nerve fibers and Purkinje fibers. Analyses of G(o) alpha subtypes showed that bovine atrium mainly contained G(o)A alpha, while bovine ventricle contained only G(o)B alpha. By contrast, ferret ventricle contained both subtypes of G(o) alpha. To study the coupling of G(o) to A1 adenosine receptors, receptors in ventricular membranes of ferrets, which had been pretreated with pertussis toxin, or purified receptors were reconstituted with purified G(o)A and G(o)B. The reconstitution experiments indicated that both subtypes of G(o) coupled with A1 adenosine receptors. These results suggest that the effect of adenosine is mediated by both G(o)A and G(o)B in membranes of ferret cardiac myocytes.

Animals↗

PubMed1995

Species-related differences in inotropic effects of angiotensin II in mammalian ventricular muscle: receptors, subtypes and phosphoinositide hydrolysis.

1. Experiments were carried out to clarify the mechanisms responsible for variations in the positive inotropic effect (PIE) of angiotensin II (AII) on ventricular muscles from various mammals. We examined the density of AII receptors, the relative proportions of receptor subtypes and the acceleration of the hydrolysis of phosphoinositide that was induced by AII, as well as the PIE of AII in ventricular muscles from the rabbit, dog, rat and ferret. 2. In the rabbit, AII (1 microM) in the presence of bupranolol (0.3 microM) and prazosin (0.1 microM) elicited a concentration-dependent PIE, which was antagonized by a selective AT1 subtype antagonist, losartan, but not by an AT2 antagonist, PD123319. AII did not have any inotropic effects in ventricular muscles from the dog, rat and ferret. 3. Specific high-affinity binding of [125I]-AII, with a similar Kd value in each case (1-2 nM), was observed with membrane fractions derived from ventricular muscle of all four species tested. 4. In the rabbit, losartan and PD123319 each displaced approximately 50% of [125I]-AII specific binding having high affinity for the receptors, and indicating that AT1 and AT2 subtypes were present in equal numbers. In the other species the AT1 subtype of receptors was predominant. 5. In all four species AII caused a concentration-dependent acceleration of the hydrolysis of phosphoinositide in ventricular slices that had been prelabelled with myo-[3H]-inositol. 6. The results indicate that the signal-transduction process distal to acceleration of the hydrolysis of phosphoinositide may be responsible for the wide range of species variations in the inotropic action of AII on mammalian ventricular myocardium.

Angiotensin I↗

PubMed1995

In situ hybridization of interleukin 6 in diabetic nephropathy.

Increased mesangial expansion is one of the most characteristic histological changes in diabetic nephropathy (DN). Although the pathogenesis of DN remains unclear, recent studies associate interleukin (IL) 6 with mesangial proliferative glomerulonephritis. To elucidate the expression and localization of IL-6 mRNA in renal tissues of patients with DN, a high-resolution in situ hybridization using digoxigenin-labeled oligonucleotide was performed. Patients were divided into three groups based on light microscopy findings: mild (group 1), moderate (group 2), and severe (group 3) mesangial expansion. The relationship between the expression of IL-6 mRNA and the degree of glomerular mesangial expansion in DN was examined. Individual cells positive for IL-6 mRNA were observed in glomeruli. These cells were mesangial cells, glomerular epithelial cells, and Bowman's capsule. The signal intensity was strongest in tissues from group 2 but was weak in those from groups 1 and 3. Most cells in the area of mesangial proliferation were strongly stained for IL-6 mRNA, and few positive cells were found in the Kimmelstiel-Wilson nodular lesion. In the interstitium, some tubules, particularly atrophic tubules, and some infiltrating cells were positively stained for IL-6 mRNA. The interstitial expression of IL-6 mRNA correlated significantly with the degree of interstitial injury and was remarkable in tissues from groups 2 and 3. We conclude that IL-6 mRNA is expressed by glomerular resident cells and interstitial cells in the renal tissue of patients with DN and that its expression may be associated with mesangial proliferation and may be involved in the tissue injury of DN.

Adolescent↗

PubMed1995

Possible predictive markers of immunotherapy in esophageal cancer: retrospective analysis of a randomized study. The Cooperative Study Group for Esophageal Cancer in Japan.

The aim of this report is to evaluate retrospectively the data from a prospective randomized study of 158 esophageal cancer patients who actually completed therapy with protein-bound polysaccharide P (PSK) and the 5-year survivals with and without raised alpha 1-antichymotrypsin and sialic acid levels to determine the value of these parameters in predicting effectiveness of immunotherapy. There was a significant difference in survival between the patients with and without PSK therapy. The survival of the radiochemotherapy plus PSK group treated for > 3 months was significantly better than that of the radiochemotherapy group. Among the patients with abnormal levels of alpha 1-antichymotrypsin and sialic acid, those who received PSK may have a significantly better survival than those without PSK. These results indicate that the preoperative serum levels of alpha 1-antichymotrypsin and sialic acid may possibly predict the effectiveness of immunotherapy using PSK.

Adult↗

PubMed1995

[Examination of cardiac myxomas complicated with embolism].

Cardiac myxomas complicated with embolism were examined. Of 51 patients who underwent surgical excision of myxomas during the last 19 years, 10 patients (6 patients originated from left atrium, 4 patients originated from right atrium) had complications by embolisms. The embolism occurred in cerebral arteries (5 cases), a coronary artery (1 case), a retinal artery (1 case), and pulmonary arteries (4 cases). Patients were divided into an embolism group and a non-embolism group to investigate risk factors of embolism. Arrhythmia, diameter, narrow peducle, and tumor friability were thought to be major risk factors. Gelatinous and rough surface type tumor tended to cause embolism. Hypervascular tumors did not cause embolism. Among 10 patients, 2 patients had already had new embolism and another 2 patients had aggravated their symptoms before making diagnosis of myxoma. Myxomas should always be considered as a source of embolization, which need meticulous investigation and prompt indication of surgical resection.

Adolescent↗

PubMed1995

Immunotherapy for esophageal cancer. A randomized trial in combination with radiotherapy and radiochemotherapy. Cooperative Study Group for Esophageal Cancer in Japan.

We investigated the effect of multimodal therapy in 187 patients with esophageal cancer. All patients were followed up over a period of 5 years. Among the 187 patients, 174 (93.1%) eligible patients with biopsy-proved esophageal squamous cell carcinoma underwent esophagectomy and were randomly assigned to receive radiotherapy (RT) with or without protein-bound polysaccharide (PSK), or RT plus chemotherapy (CT) with or without PSK. The 5-year survival rates of patients with RT, RT+PSK, RT+CT and RT+CT+PSK were 40.0%, 42.3%, 29.1% and 37.2%, respectively. There was a tendency for longer survival on PSK, but statistical significance was not reached (RT+CT group versus RT+CT+PSK group: log-rank and generalized Wilcoxon tests, P = .1930, P = .1034). However, Cox multivariate regression analysis indicated that postoperative therapy with or without PSK was the most significant prognostic factor for patients receiving RT+CT and for the eligible patients. These results indicate that PSK may have a beneficial effect on esophageal carcinoma when given in combination with CT+RT.

Adult↗

PubMed1995

[Evaluation of photon-counting X-ray radiography for the detection of pulmonary nodule: a preliminary report on experimental and clinical studies].

To evaluate the utility of photon counting X-ray radiography (quantum radiography: QR) for the detection of pulmonary nodules, experimental and clinical studies were performed in comparison with conventional X-ray (CXR). In the experimental study, spatial resolution was analyzed by using the micro-chart method. The simulated nodule detection study was performed by using a chest phantom. The results were evaluated by means of ROC analysis. In the clinical study, both images of CXR and QR were evaluated in a case of metastatic lung tumor. In the experimental study, the spatial resolution of QR was 200 microns. QR was superior to CXR in detecting simulated nodules in all areas. In clinical cases, QR was superior to CXR in depicting not only normal structures but also retrocardiac and retrodiaphragmatic pulmonary nodules.

Carcinoma, Renal Cell↗

PubMed1994

Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia.

We recently demonstrated that reactive astrocytes express NADPH diaphorase activity, a marker for Nitric Oxide Synthase, following transient global ischemia (Neuroscience Letters 154: 125-128). There has been little evidence that astrocytes express Nitric Oxide Synthase or produce NO (nitric oxide) in vivo; although in vitro experiments have shown that cultured astrocytes can produce NO. To determine whether reactive astrocytes express inducible form of NOS (iNOS) in vivo, we studied the pathological changes of rat hippocampus by immunohistochemistry after 10 minutes of transient global ischemia, which results in the selective delayed death of CA1 pyramidal cells and marked gliosis in the CA1 subfield. In the normal hippocampus, astrocytes express neither NADPH diaphorase activity nor iNOS. After ischemia, the temporal and spatial pattern of iNOS, NADPH diaphorase, and GFAP are very similar, indicating that reactive astrocytes express iNOS. Double staining for NADPH diaphorase and GFAP, or iNOS and GFAP confirmed that reactive astrocytes express both NADPH diaphorase activity and iNOS immunoreactivity. These changes were observed three day after ischemia and increased in prominence from one week to one month. The staining pattern of OX42, an antibody that recognizes both microglia and macrophages, is spatially and temporally distinct from the pattern of NADPH diaphorase and iNOS staining. Thus, we conclude that transient global ischemia induces iNOS primarily in reactive astrocytes. This increase in NOS expression and, presumably, NO production by reactive astrocytes may play a role in the process of delayed neuronal death or in the remodeling responses that occur after ischemic damage.

Amino Acid Oxidoreductases↗

PubMed1994

[Significance of a mass survey for colorectal cancer at the workplace].

Two thousand four hundred and forty workers from 2 plants were enrolled in a mass survey for colorectal cancer using a single immunological fecal occult blood test as screening. The occult blood test was positive in 71 (4.0%) out of 1,759 subjects in whom the test was conducted. A further investigation, including total colonoscopy or barium enema, was performed on 52 (73.2%) of the 71. Colon cancer was detected in 5 cases: 1 with advanced cancer and 4 with early cancer (cancer in the adenoma). The advanced cancer was successfully resected by surgery and the early cancers were removed by endoscopic polypectomy. Adenomas were found in 21 cases, 11 of which were polypectomized. From these results, it can be seen that a survey for colorectal cancer at the workplace is important, and by expanding the number of subjects for the survey in the workplace we can expect more and earlier detections of colorectal cancer.

Adenoma↗

PubMed1994

Purification and characterization of Bordetella calmodulin-like protein.

Bordetella calmodulin-like protein was purified from culture supernatant fluid of B. pertussis, B. parapertussis and B. bronchiseptica by successive chromatography on hydroxyapatite, Toyopearl HW-50F and QAE-Toyopearl 550C columns. The purified calmodulin-like protein appeared to be homogeneous by SDS-polyacrylamide gel electrophoresis. The apparent molecular mass of calmodulin-like protein on SDS-polyacrylamide gel electrophoresis was 10 kDa, which was smaller than bovine brain calmodulin (17 kDa). The purified calmodulin-like protein activated both Bordetella adenylate cyclase and mammalian phosphodiesterase in a Ca(2+)-dependent manner. This activation was inhibited by calmodulin antagonists. The calmodulin-like protein, like calmodulin, was retained by a hydrophobic resin in the presence of Ca2+ and eluted by the addition of EDTA. These results indicated that the Bordetella calmodulin-like protein is closely related to calmodulin. As a putative calmodulin the extracellular calmodulin may be involved in Bordetella pathogenesis.

Adenylyl Cyclases↗

PubMed1994

The effects of theophylline on aequorin light transients and force in the isolated dog right ventricular myocardium.

Experiments were carried out to investigate the changes in intracellular Ca2+ transients associated with biphasic contractions that were elicited during interaction of theophylline with isoproterenol in the dog ventricular myocardium. For this purpose, effects of theophylline and isoproterenol on aequorin light transients and isometric contractions were assessed in the isolated canine ventricular trabeculae, superficial cells of which had been microinjected with the Ca2+ sensitive bioluminescent protein aequorin. The positive inotropic effect of theophylline (0.1-0.3 mM) was consistently associated with an increase in the amplitude of aequorin light transients. Theophylline at concentrations of 0.6 mM and higher decreased the amplitude of aequorin light transients, but the force of contraction increased further in association with a prominent prolongation of time to peak force. Theophylline (0.3 mM) enhanced the forskolin-induced increase in aequorin light transients and force. Theophylline (2 mM) inhibited the isoproterenol-induced increase in aequorin light transients associated with early phase of contraction in a reversible manner. A late phase of aequorin light transients was induced in association with late phase of contraction in the presence of both isoproterenol and theophylline. Thus, both the early and late phase of contraction were accompanied by corresponding phases of aequorin light transients. The relation between the amplitude of force and Ca2+ transients was markedly different and the late phase of contraction was associated with much lower aequorin light transients. The late phase of aequorin light transients induced by theophylline at a high concentration (10 mM) was enhanced by isoproterenol. These results indicate that theophylline (0.1-0.3 mM) increases the amplitude of Ca2+ transients through an accumulation of cyclic AMP by inhibition of the cyclic AMP phosphodiesterase activity. In concentrations of 0.6 mM and higher theophylline decreases the amplitude of the early phase aequorin light transients probably by inhibition of release of Ca2+ from the sarcoplasmic reticulum and induces simultaneously the late phase of contraction that may be associated with an increase in responsiveness to Ca2+ of myofibrils.

Aequorin↗

PubMed1994

Transient global ischemia induces dynamic changes in the expression of bFGF and the FGF receptor.

To study the roles of bFGF and its receptor in the process of neuronal cell death and the wound repair response, we induced 10 min of transient global cerebral ischemia in rats and measured changes in expression of both bFGF and the FGF receptor, flg. CA1 pyramidal cells are selectively vulnerable to ischemia and die one to 3 days after 10 min of ischemia. In these cells, bFGF mRNA was induced by 6 hours, reached a maximal level by 24 h after ischemia, and subsequently decreased. Message for the FGF receptor, flg, was present in the pyramidal cells layer, and vanished almost completely in parallel with neuronal death. In the granule cell layer of dentate gyrus, the expression of bFGF mRNA increased more rapidly. It was maximal by 6 h and returned to the basal level by 3 days. In the hilus of the dentate gyrus, bFGF expression was maximal at 24 h and returned to control levels by 3 days. Despite the rapid changes in expression of bFGF mRNA, there was no significant change of bFGF immunoreactivity in either the CA1 pyramidal cell layer or in the granule cell layer of dentate gyrus within 3 days after ischemia. The apparent failure of the message to be efficiently translated supports the idea that translation is impaired under conditions where ischemia leads to delayed neuronal cell death. Expression of bFGF mRNA, FGFR mRNA and bFGF immunoreactivity increased dramatically in a broad area of CA1 subfield from 7 days until 30 days after ischemia because of increased expression by reactive glial cells. We suggest that these rapid and complex changes in the expression of bFGF mRNA and bFGF protein may be part of a coordinated response to ischemic injury that is designed to minimize the severity of neuron death.

Animals↗

PubMed1994

Expression of the neural form of nitric oxide synthase by CA1 hippocampal neurons and other central nervous system neurons.

Nitric oxide can act as a neurotransmitter and a retrograde modulator of synaptic transmission, but uncontrolled nitric oxide synthase activity has been associated with neural degeneration. Although earlier studies using immunohistochemistry, in situ hybridization, and NADPH-diaphorase staining had suggested that nitric oxide synthase is not expressed in the CA1 neurons of the hippocampus, we have recently demonstrated that NADPH-diaphorase activity can be detected in CA1 neurons of the hippocampus. To confirm that this diaphorase activity reflects nitric oxide synthase, we have developed a more sensitive in situ hybridization procedure, and an RNase protection assay to detect message for constitutive nitric oxide synthase, the form constitutively expressed in many neurons. Message for constitutive nitric oxide synthase is expressed in the hippocampus, and it is localized to neural cell layers CA1, CA3, the dentate gyrus and some displaced neurons, but not to CA2. Expression of constitutive nitric oxide synthase message in the CA1 region was lost when pyramidal neurons died due to transient forebrain ischemia, supporting the conclusion that CA1 pyramidal cells express constitutive nitric oxide synthase. Although constitutive nitric oxide synthase message is strongly expressed in CA3 and the dentate gyrus, there is little diaphorase activity in these cells, suggesting that there may be post-transcriptional controls that limit constitutive nitric oxide synthase expression in some cells. Message for constitutive nitric oxide synthase is also present in a number of other regions, including the amygdala, several hypothalamic nuclei, the cerebellum, the olfactory bulb, two distinct regions of the perirhinal cortex, the subthalamic nuclei, a neuronal layer in the retrosplenial granular cortex, the lateral geniculate nucleus, the presubiculum, the inferior colliculus, the superior colliculus, the pedunculopontine tegmental nucleus, and scattered individual neurons in the cortex, hippocampus and brainstem. These studies support a role for nitric oxide in multiple regions of the central nervous system. In particular, nitric oxide synthase, the enzyme responsible for the synthesis of nitric oxide, is expressed in the CA1 region of the hippocampus, where there is evidence that nitric oxide may play a major role in long-term potentiation. CA1 hippocampal neurons are an example of a population of neurons that express constitutive nitric oxide synthase but are very sensitive to excitotoxicity and ischemic insults.

Amino Acid Oxidoreductases↗

PubMed1994

Fc alpha R expression on polymorphonuclear leukocyte and superoxide generation in IgA nephropathy.

Superoxide (O2-) production and Fc alpha R antigen expression of circulating polymorphonuclear leukocytes (PMNL) isolated from patients with IgA nephropathy (IgAN) and non-IgA mesangial proliferative glomerulonephritis (PGN) and healthy volunteers were investigated to establish their biological importance in the immunopathogenesis of mesangial proliferative glomerulonephritis. PMNL from both patient groups showed increased O2- production when stimulated with N-formyl methionyl leucyl phenylalanine (FMLP) and phorbol myristate acetate (PMA). The increased O2- generation demonstrated a positive correlation with the degree of proteinuria. Aggregated IgA caused enhanced O2- production only in patients with IgAN who also showed a significant correlation with proteinuria. Increased expression of Fc alpha R on circulating PMNL was observed in IgAN patients as determined by flow cytometric analysis. The amount of Fc alpha R on PMNL was positively correlated with O2- generation triggered with IgA aggregates. These results suggest that: 1. Circulating PMNL may potentially be participating in the pathogenesis of glomerular injury in mesangial proliferative glomerulonephritis, and 2. IgA aggregates/immune complexes may contribute to the immunopathogenesis of IgAN through augmenting the Fc alpha receptor-mediated generation of superoxide anion.

Adult↗

PubMed1994

Effects of a novel cardiotonic agent (+-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolino ne (OPC-18790) on contractile force, cyclic AMP level, and aequorin light transients in dog ventricular myocardium.

We studied the effects of a novel cardiotonic agent OPC-18790 [(+-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)- quinolinone] on isometric contractions, intracellular aequorin light transients, and cyclic AMP levels in isolated dog ventricular trabeculae. The positive inotropic effect (PIE) of OPC-18790 (1-30 microM) was consistently associated with an abbreviation of contractions and an increase in the amplitude of aequorin light transients. The maximum responses of Ca2+ transients and force to OPC-18790 were approximately 40% of the isoproterenol-induced maximum. Carbachol (3 microM) markedly attenuated the increases in force, light transients, and cyclic AMP accumulation induced by OPC-18790. These results indicate that OPC-18790 is a cardiotonic agent with moderate effectiveness, and that the PIE of OPC-18790 may be produced mainly by an increase in intracellular Ca2+ transients induced by cyclic AMP accumulation. For a given increase in amplitude of Ca2+ transients, OPC-18790 produced a more pronounced increase in force of contraction (FOC) than did isoproterenol, suggesting that OPC-18790 does not produce as great a decrease in Ca2+ sensitivity of contractile proteins as does isoproterenol. These observations indicate that among cardiotonic agents acting through cyclic AMP pathway, regulation of contractility produced by the selective cyclic AMP phosphodiesterase III (PDE-III) inhibitor OPC-18790 is qualitatively different from the regulation induced by isoproterenol that acts on cyclic AMP generation in intact myocardial cells.

Aequorin↗