[Regional blood flow measurement with nonradioactive microspheres].
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Animals↗
Biomedical subjects
I Sakuma
Publications and source records attributed to I Sakuma.
The slow cyclic GMP increase caused by serotonin in NG108-15 cells is not inhibited by antagonists of known serotonin receptors: possible existence of a new receptor subtype coupled with membrane-bound guanylate cyclase.
Characterization of the serotonin (5-HT)-induced cyclic GMP (cGMP) elevation was investigated in comparison with bradykinin- and ANP-induced elevations in NG108-15 cells. At 20 s, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM, 100 microM), a membrane-permeabilized Ca2+ chelator, or N-monomethyl-L-arginine (NMMA, 300 microM), an inhibitor of L-arginine-derived nitric oxide (NO) synthesis, inhibited 5-HT-induced elevation by approximately 40%, and completely inhibited bradykinin-induced response. Neither 5-HT- nor ANP-induced cGMP elevation at 10 min was affected by BAPTA-AM or NMMA. The cGMP elevated by 5-HT as well as by ANP was effluxed to the extracellular medium. These results and our previous report suggest that 5-HT stimulates two subtypes of 5-HT receptors in NG108-15: first, 5-HT3 subtype stimulating Ca(2+)-sensitive cytosolic guanylate cyclase through NO derived from L-arginine and second, a probably novel 5-HT receptor subtype involved in activation of membrane-bound guanylate cyclase.
Animals↗
Studies of the development of optical fiber sensors for biochemical analysis.
An optical fiber sensor utilizing Thymol blue and an ion-exchange resin complex in a cellulose acetate membrane was developed. By monitoring several different chromophores of Thymol blue, the sensor could measure the pH of the solution from 1.0 to 12.0 with good reproducibility. An optical fiber glucose sensor utilizing a cellulose acetate membrane containing glucose oxidase, 2,7-diaminofluorene dihydrochloride, and sodium N-(3-sulfopropyl)-3,3',5,5'-tetramethylbenzidine was developed. Reflectance changes at 580 nm were large enough to trace changes in glucose concentration in physiological saline solution.
Biosensing Techniques↗
Effects of indomethacin, endothelium-denudation, methylene blue and L-NG-monomethyl arginine on the vasoactive effects of endothelin-3.
To clarify the mechanisms underlying the vasoactive effects of endothelin-3 (ET-3), we examined the effects of indomethacin, endothelium-denudation, methylene blue and L-NG-monomethyl arginine (L-NMMA) on the perfusion pressures of isolated rat mesenteric arteries infused with ET-3. ET-3 at 10(-15)-10(-8) M elicited significant vasodilations in a dose-related manner, in which 10(-9) and 10(-8) M ET-3 caused biphasic pressure changes involving a transient dilation and subsequent vasoconstriction. Five micromolar indomethacin did not affect the vasodilations and vasoconstrictions induced by ET-3. In endothelium-denuded arteries, 10(-13)-10(-8) M ET-3 elicited significant vasoconstriction in a dose-related manner without any vasodilation. In the presence of 30 microM methylene blue, the vasodilations induced by ET-3 disappeared. In the presence of 100 microM L-NMMA, 10(-15)-10(-8) M ET-3 elicited significant vasoconstrictions in a dose-related manner, and the vasodilation by ET-3 existed only at 10(-8) M ET-3. These data suggest that the vasodilating effects of low doses of ET-3 through the endothelium overcome the vasoconstricting effects, and that the vasodilating effects of ET-3 are associated with an endothelium-derived relaxing factor as an endothelium-derived nitric oxide.
Animals↗
Development of a compact extracorporeal membrane oxygenation (ECMO) system.
In recent years, extracorporeal membrane oxygenation (ECMO) has been used for treatment of neonates with respiratory failure. A prototype of a compact ECMO system for neonates was developed. A single-lumen catheter, inserted into the right atrium via a jugular vein, was used for withdrawal and infusion of blood through the catheter. An extracapillary flow hollow-fiber membrane lung made of microporous polypropylene has a total surface area of 0.6 m2. To prevent the increase of plasma free hemoglobin, the ratio of withdrawal/infusion is controlled by a microcomputer. The system is compact in size with a low priming volume (less than 90 ml), which allows for ECMO with no additional blood transfusions. Its potential application as a respiratory support system is evaluated in animal experiments. The total intermittent veno-veno bypass flow was 15-30 ml/min/kg. The O2 transfer rate was 20 ml/min and the CO2 transfer rate was 33 ml/min at a blood flow rate of 300 ml/min. The O2 and CO2 exchange with the ECMO system was efficient enough to eliminate the respiratory failure induced by mechanical ventilation. The increase in plasma free hemoglobin was only 4 mg/dl after 6 h of ECMO. The system was considered applicable to respiratory aid for neonates.
Animals↗
L-NG-monomethyl arginine inhibits the vasodilating effects of low dose of endothelin-3 on rat mesenteric arteries.
We have reported that low doses of endothelin-3 (ET-3) elicited continuous vasodilation of rat mesenteric arteries, which is possibly related to endothelium-derived relaxing factor (EDRF). In order to clarify whether or not the vasodilating effects of ET-3 are associated with EDRF, we examined the effects of L-NG-monomethyl arginine (L-NMMA), an analog of L-arginine, on low-dose ET-3 induced vasodilation of rat mesente-Hc arteries. Infusion of 50 microM L-NMMA inhibited the vasodilation induced by 10(-13) M ET-3 and rather elicited an increase in perfusion pressure, which itself was decreased by infusion of 150 microM L-arginine. In the presence of 50 microM L-NMMA, 10(-13) M ET-3 did not elicit any vasodilation of the mesenteric arteries preconstricted with NE, in which 150 microM L-arginine, but not D-arginine, caused considerable vasodilation. These data suggest that the vasodilating effects of low doses of ET-3 are associated with EDRF as an endothelium-derived nitric oxide.
Animals↗
Dipyridamole potentiates the anti-aggregating effect of endothelium-derived relaxing factor.
One effector of the anti-aggregatory property of endothelium is thought to be endothelium-derived relaxing factor. The best characterized of these, nitric oxide, inhibits platelet aggregation by increasing cyclic GMP levels. The effects of nitric oxide and dipyridamole (a cyclic GMP phosphodiesterase inhibitor), alone and in combination, on in vitro platelet aggregation were evaluated. Dipyridamole had no effect per se on platelet aggregation but potentiated the inhibition of aggregation due to nitric oxide. This was concomitant with an increase in platelet cyclic GMP concentration. The author suggests an alternative mechanism for the clinical efficacy of dipyridamole as an antiplatelet agent.
Cyclic AMP↗
Pharmacological differentiation of epithelium-derived relaxing factor from nitric oxide.
We examined the possibility that nitric oxide is one of the epithelium-derived relaxing factors in guinea pig airways. First we studied whether nitric oxide could relax isolated tracheal strips, and then we examined the effects of known inhibitors of endothelium-dependent relaxation (EDR) in the vascular system [hemoglobin, methylene blue, and NG-monomethyl-L-arginine (L-NMMA)] on epithelium-dependent relaxation (EpDR) induced by hyperosmotic stimuli in perfused whole tracheal preparations. Mannitol (160 mM in Krebs-Henseleit solution) applied to the epithelial surface was used as an osmotic stimulus to induce EpDR after carbachol-induced contraction (2 microM, serosal side). Nitric oxide produced concentration-dependent and complete relaxation of epithelium-denuded tracheal strips. Preincubation of the whole trachea with hemoglobin significantly inhibited osmotic-induced EpDR (P less than 0.05), but preincubation with methylene blue and L-NMMA did not. Hemoglobin introduced into the epithelial side after EpDR induced by hyperosmotic stimuli reversed relaxation, but methylene blue and L-NMMA did not. These results suggest that, although EpDR and vascular EDR have some pharmacological similarities and nitric oxide can relax airway smooth muscle, nitric oxide is not responsible for osmotic-induced EpDR.
Animals↗
Cardiac dysfunction caused by recombinant human C5A anaphylatoxin: mediation by histamine, adenosine and cyclooxygenase arachidonate metabolites.
We had found previously that complement-derived anaphylatoxins C3a and C5a function as mediators/modulators of cardiac immune hypersensitivity reactions. The purpose of this study was to determine the secondary mediators responsible for the cardiac effects of C5a. Recombinant human C5a (rhC5a) caused dose-dependent tachycardia, slowing of atrioventricular nodal conduction, a short lasting increase followed by a prolonged decrease in left ventricular contractility, and coronary vasoconstriction. These changes were associated with the release of histamine, thromboxane A2 and adenosine into the coronary effluent. Our data indicate that the positive inotropic and chronotropic effects of rhC5a are mediated by histamine release and consequent activation of H2-receptors, the coronary-vasoconstricting effect is due to thromboxane release and the negative dromotropic effect is associated with adenosine release. Furthermore, the decrease in contractility caused by rhC5a is likely to result from the H1-mediated negative inotropic effect of histamine compounded by the ischemic conditions created by the coronary vasoconstricting effects of thromboxane A2 and, perhaps, leukotrienes. Our findings demonstrate that C5a has marked cardiac effects at concentrations approximating those attained in vivo in a multitude of pathophysiological conditions in which complement is activated, including myocardial infarction. Thus, anaphylatoxins may play a role in the development of ischemic cardiac dysfunction.
Adenosine↗
[Contrast medium-induced expansion of circulating blood volume: Comparison between nonionic and ionic contrast media].
We assessed whether the osmotic expansion of circulating blood volume (CBV) induced by nonionic contrast medium (NCM) is less than that induced by ionic contrast medium (ICM). Iohexol (Io) (NCM: 795 mO sm/kg H2O), 1.28 g iodine/kg, was injected intravenously into 5 mongrel dogs and blood samples were drawn at certain times. One week later, meglumine iothalamate (MI) (ICM: 1470 mOsm/kgH2O), 1.28 g iodine/kg, was injected into the same dogs. Another 5 dogs received MI first and Io one week later. Colloid oncotic pressure (COP) of the blood samples was measured by a needle osmometer, and changes in CBV were calculated from the COP values. The injection of Io or MI resulted in an immediate decrease in COP, and an increase in CBV at 1 min. MI induced significantly more severe and longlasting changes in COP and CBV than Io. Neither MI nor Io modified COP when they were added to the control blood samples. Thus, although NCM considerably expanded CBV, the magnitude of expansion induced by NCM was less than that induced by ICM. This may explain one of the reasons why NCM causes fewer adverse reactions than ICM.
Animals↗
Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide.
L-arginine-dependent synthesis of nitrite (NO2-) and nitrate (NO3-) by macrophages correlates with and is required for their execution of nonspecific cytotoxicity toward some tumor cells and microbes. However, the bioactive L-arginine metabolites responsible for cytotoxicity are unknown. Mammalian endothelial cells have recently been shown to release nitric oxide (NO.); we therefore determined if this reactive metabolite was synthesized by activated murine macrophages. Macrophage-derived NO. was detected by two independent methods: a bioassay for NO.-mediated relaxation of preconstricted rings of rabbit aorta; and a spectroscopic measurement of the reaction of NO. with clostridial ferredoxin, an Fe-S protein. After activation with IFN-gamma and LPS, macrophages continuously secreted a substance that relaxed rabbit aortic rings denuded of endothelium. Production of the vasorelaxant was enhanced by 0.5 mM L-arginine and inhibited reversibly by NG-methylated L-arginine analogs that block macrophage NO2-/NO3- synthesis. The vasorelaxant was scavenged by ferrous myoglobin, was labile, and was neither NO2- nor a cyclooxygenase metabolite. Activated M phi also secreted a substance that bleached Fd, a reaction carried out by NO. and NO2, but not NO2-. Macrophage bleaching of Fd correlated directly with time, cell number, and concomitant NO2-/NO3- production, required L-arginine, and was independent of reactive oxygen intermediates. Thus, activated murine M phi release NO. and/or a closely related, highly reactive nitrogen oxide such as NO2, during their conversion of L-arginine to NO2-/NO3-. NO. and NO2 may mediate L-arginine-dependent pathologic effects of M phi, as well as physiologic effects not previously considered for this widely distributed cell type.
Animals↗
Positive inotropic effect of the thromboxane analog U-46619 on guinea pig left atrium: mediation by specific receptors and association with increased phosphoinositide turnover.
U-46619, a stable epoxymethano analog of thromboxane A2 elicited a direct positive inotropic effect on guinea pig left atrium paced at a constant rate (EC50 = 2.5 nM). This novel observation contrasts with previous reports of a decrease in myocardial contractility by thromboxane mimetic compounds in coronary-perfused preparations, an action recognized as secondary to vasoconstriction. The positive inotropic effect of U-46619 was competitively antagonized by the specific thromboxane receptor blocker L-655,240 (pA2 = 8.02; identical to that reported in smooth muscle), but was unaffected by blockers of alpha 1-, beta 1-, and H1-receptors and by cyclooxygenase and lipoxygenase inhibitors. Increased tissue levels of inositol phosphates, but not cAMP, were associated with the positive inotropic action of U-46619, in analogy to the actions of alpha 1- and H1-receptor agonists. However, the inotropic effect of U-46619 and the concomitant increase in phosphoinositide breakdown were both selectively antagonized by L-655,240. Thus, U-46619 acts on specific thromboxane receptors in guinea pig left atrium and elicits a positive inotropic effect that probably results from an increase in phosphoinositide metabolism.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Differential effects of histamine mediated by histamine H1- and H2-receptors on contractility, spontaneous rate and cyclic nucleotides in the rabbit heart.
The effects of histamine on the contractile force, spontaneous rate of contraction, and cyclic AMP and cyclic GMP content were investigated in isolated rabbit cardiac preparations. Histamine had a positive inotropic effect in the left atrium and papillary muscle, and a positive chronotropic effect in the right atrium. Both effects were produced in a concentration-dependent manner. Impromidine also induced the same effect in the left and right atrium as histamine did. The effects produced by histamine and impromidine were antagonized by cimetidine and tiotidine. On the other hand, the positive inotropic response of papillary muscle to histamine was antagonized by mepyramine and chlorpheniramine and was mimicked by 2-(2-pyridyl)ethylamine. Impromidine at a high concentration induced a small increase in the contractile force, an effect which was antagonized by cimetidine. Histamine significantly increased the cyclic AMP levels in both atria but not in papillary muscles. The increase in cyclic AMP was abolished by cimetidine. Histamine also increased cyclic GMP levels in all of the preparations. The increase in cyclic GMP was abolished by chlorpheniramine. The results suggest that both H1- and H2-receptors exist in all parts of the rabbit heart. However, the positive inotropic and chronotropic effects induced by histamine in left and right atrium are mediated predominantly via H2-receptors, whereas the positive inotropic effect in papillary muscle is predominantly mediated via H1 receptors.
Animals↗
Identification of arginine as a precursor of endothelium-derived relaxing factor.
Nitric oxide (NO) is a major endothelium-derived relaxing factor (EDRF) released in response to vasodilating amines, peptides, proteins, ionophores, and nucleotides. EDRF is an important regulator of smooth muscle tone and platelet aggregation and adhesion. Histamine and acetylcholine relax the intact norepinephrine-constricted guinea pig pulmonary artery by an EDRF-dependent mechanism in a medium free of amino acids. N omega-Monomethylarginine (N-MeArg; 0.25 mM) inhibited this relaxation by 64-73%. Inhibition by N-MeArg developed rapidly and was immediately and completely reversed by excess L-arginine but not by D-arginine or by citrulline. N-MeArg did not diminish relaxation induced by nitroprusside, an NO-generating agent, indicating that N-MeArg acts on endothelium rather than on smooth muscle. These observations strongly suggest that, in the intact guinea pig pulmonary artery, EDRF originates from enzymatic action on the guanido nitrogen(s) of an endogenous pool of arginine. This is strikingly similar to the origin of reactive nitrogen intermediates in activated macrophages.
Acetylcholine↗
Development of motion analyzing system for implanted tilting disk valves.
A motion-analyzing system was developed to quantitatively evaluate functions of the implanted tilting disk valve, e.g., an open angle and a duration of valve open and/or shut. In this system a picture of the valve on an x-ray cinefilm is displayed on the CRT screen by the TV camera for extraction of valve position. Data extracted are stored in the computer and are used to calculate parameters for motion analysis of the valve. The reliability of this system was confirmed within 3 degrees of error using the valve model prior to the evaluation of cinefilms clinically procured. With the aid of this motion analyzing system, complicated motions of the tilting disk valve were easily quantified and the useful information as given for clinical diagnosis and further valve development.
Computer Graphics↗
Vasomotor effects of leukotrienes C4 and D4 on cavian pulmonary artery and aorta. Characterization and mechanisms.
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Animals↗
Positive inotropic effect of histamine on guinea pig left atrium: H1-receptor-induced stimulation of phosphoinositide turnover.
The purpose of this study was to investigate the mechanism of histamine's H1-receptor-mediated positive inotropic effect, a response which is not associated with an increase in cyclic AMP levels. We found that the concentration-response curve for the positive inotropic effect of histamine on cavian left atrium was similar to that of the alpha-1 agonist phenylephrine, in terms of slope and maximum response. Additionally, both agents slightly prolonged time-to-peak tension and relaxation times. In contrast, the concentration-response relationship for the beta-agonist isoproterenol, whose positive inotropic effect is mediated by an increase in cyclic AMP, had a steeper slope and a much greater maximum. Furthermore, isoproterenol abbreviated time-to-peak tension and relaxation times. As reported previously for alpha-1 agonists, the development of the contractile response to a submaximal histamine concentration (10 microM) coincided with a rapid increase in left atrial tissue levels of inositol triphosphate. The concentration-response curves for histamine effects on contractility and phosphoinositide (PI) turnover were both unaffected by the H2-antagonist tiotidine, but were shifted markedly to the right by the H1-antagonist pyrilamine. High-performance liquid chromatography techniques were applied to resolve the various inositol mono-, di- and tri-phosphate isomers and to assess the possible production of higher phosphates (IP4, IP5 and IP6) in control and histamine-treated (10 microM) atria. Under both conditions IP products were qualitatively similar, but quantitatively greater after treatment with histamine; these products included inositol(1)phosphate, inositol(4)phosphate,inositol(1,4)diphosphate and inositol(1,4,5)triphosphate. No evidence of higher phosphate production was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Adenosine promotes histamine H1-mediated negative chronotropic and inotropic effects on human atrial myocardium.
Because histamine and adenosine are coreleased from the ischemic heart, we investigated the effects of their interaction on human myocardium. Surgical specimens of human right atrium (i.e., pectinate muscles) responded to histamine with increases in spontaneous rate and contractile force. Adenosine, and the A1-selective adenosine agonist N6-cyclopentyladenosine (CPA), reduced the spontaneous rate and suppressed the positive chronotropic and inotropic effects of histamine. CPA was more potent than adenosine in slowing the spontaneous rate and in suppressing histamine's positive chronotropic effect, suggesting that the responses to CPA and adenosine are A1-mediated. CPA was also more potent than adenosine in attenuating histamine's positive inotropic effect on human ventricular papillary muscle. The adenosine-induced suppression of histamine's effects on pectinate muscles was mimicked by carbachol, which like adenosine is known to attenuate H2-mediated histamine-induced adenylate cyclase activation. The H1-selective histamine antagonist pyrilamine potentiated histamine's chronotropic and inotropic responses, and inhibited the attenuation of these responses by adenosine or carbachol. In contrast, pyrilamine failed to modify the adenosine-induced attenuation of the cardiac stimulatory effects of dimaprit, an H2-selective histamine agonist. Our data suggest that adenosine-induced suppression of histamine's positive chronotropic and inotropic effects on human myocardium results both from an A1-mediated attenuation of H2-stimulatory effects and from the uncovering of H1 negative chronotropic and inotropic effects. Thus, the results of the histamine-adenosine interaction may exceed the "retaliatory" purpose of adenosine release and uncover H1-mediated myocardial depression.
Adenosine↗