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Biomedical subjects

N Taira

Publications and source records attributed to N Taira.

At least 109 records · Page 6Linked to original sources
PubMed1989

Coronary vasodilator and cardiac effects of NKY-722, a novel hydrophilic 1,4-dihydropyridine derivative, in the blood-perfused dog heart.

The coronary vasodilator and cardiac effects of NKY-722, a novel hydrophilic 1,4-dihydropyridine derivative, were evaluated in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. NKY-722 was administered intraarterially. NKY-722 increased coronary blood flow in all preparations. In SA node preparations, NKY-722 reduced sinus rate and produced atrial standstill in large doses. The dose that produced a 15% (nearly half-maximum) decrease in sinus rate was about six times the dose that doubled coronary blood flow. In AV node preparations, NKY-722 prolonged AV conduction time and produced second- or third-degree AV block in large doses only when administered into the artery supplying the AV node. The dose that produced a 15% (nearly half-maximum) increase in AV conduction time was about 3.5 times the dose that doubled coronary blood flow. In paced papillary muscle preparations, NKY-722 reduced the force of contraction. However, the dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 100 times the dose that doubled coronary blood flow. In spontaneously beating papillary muscle preparations, NKY-722 failed to change the beating rate. The vasodilator effect of NKY-722 was of longer duration than the negative chronotropic, dromotropic, and inotropic effects. These results indicate that NKY-722 is highly vasoselective, and the cardiovascular profile of NKY-722 is essentially identical to that of currently available, lipophilic 1,4-dihydropyridine calcium antagonists.

Animals↗
PubMed1989

An explanation of bell-shaped, dose-positive inotropic effect curves for denopamine in canine right ventricular muscle.

We investigated mechanisms by which denopamine produces bell-shaped, cumulative concentration-response curves for positive inotropic effect in canine right ventricular muscle. As in our previous study, the curves ascended at 10(-8) to 10(-6) M, reached a maximum at 3 X 10(-6) to 10(-5) M, and descended at higher concentrations. The ascending limb gave 6.58 +/- 0.21 for the pD2 value. Denopamine, when administered cumulatively up to 3 X 10(-5) to 3 X 10(-4) M, caused rightward shifts of concentration-response curves for the positive inotropic effect of isoproterenol. Application of a two-component fitting model to the concentration-response curves for isoproterenol in the presence of denopamine yielded two pA2 values of denopamine; 6.59 +/- 0.19 for the high- and 5.05 +/- 0.21 for the low-affinity state of beta 1 receptors. The bell-shaped curves for denopamine were successfully computer-simulated with the following assumptions. (a) Denopamine produces a positive inotropic effect by binding to the high-affinity state of beta 1 receptors with an apparent dissociation constant of 10(-6.59) M. (b) The fraction of the high-affinity state decreases as denopamine binds to the low-affinity state with an apparent dissociation constant of 10(-5.05) M. Cyclic AMP levels were changed by denopamine, isoproterenol, and a combination of both, roughly in a parallel way to changes in positive inotropic effect.

Animals↗
PubMed1989

Differential antagonism of the negative inotropic effect of gentamicin by calcium ions, Bay K 8644 and isoprenaline in canine ventricular muscle: comparison with cobalt ions.

1. Gentamicin (10(-4)-10(-2) M) and Co2+ (10(-4)-10(-2) M) produced a decrease in developed tension of canine isolated ventricular muscles leading to near abolition at 10(-2) M. Their negative inotropic effects developed rapidly and wore off shortly after wash-out. 2. The concentration-negative inotropic effect curves for gentamicin were shifted to the right in a parallel manner by increasing external Ca2+, or by the presence of Bay K 8644 (10(-7)-10(-5) M) or isoprenaline (10(-7)-10(-5) M). IC50 values for gentamicin increased about 3-fold with about a 6 fold increase in external Ca2+. The Schild plot yielded a pA2 of 2.29 for Ca2+ and its slope was -1.17 (r = -0.79). 3. The concentration-negative inotropic effect curves for Co2+ were shifted to the right in a parallel manner by increasing external Ca2+, or by the presence of isoprenaline (10(-7)-10(-5) M). IC50 values for Co2+ increased about 5 fold with about a 6 fold increase in external Ca2+. The Schild plot gave a pA2 value of 2.60 for Ca2+ and its slope was -1.11 (r = -0.86). 4. The concentration-positive inotropic effect curves for Ca2+, which were computer-fitted to a logistic equation, gave 2.88 x 10(-3) M for EC50. This value was very close to the KCa calculated from pA2 values for Ca2+ based on antagonism between gentamicin or Co2+ and Ca2+ (5.13 x 10(-3) and 2.51 x 10(-3) M). 5. It is concluded that like Co2+, gentamicin molecules compete with Ca2+ for the same binding sites presumably located at the outer orifice of Ca-channels in the cardiac sarcolemma.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Interaction of potassium channel openers and blockers in canine atrial muscle.

1. The possibility that the interaction between potassium channel openers, e.g. cromakalim, pinacidil and nicorandil, and some potassium channel blockers involves a common site was investigated in canine atrial muscle. 2. Cromakalim, pinacidil and nicorandil produced a negative inotropic effect, their pD2 (-log EC50) values being 6.11 +/- 0.07, 5.37 +/- 0.09 and 4.55 +/- 0.07, respectively. 3. The potassium channel blockers, tetraethylammonium (TEA), tetrabutylammonium (TBA), 3,4-diaminopyridine (DAP), CsCl and BaCl2 all produced a positive inotropic effect. 4. The concentration-effect curves for the negative inotropic actions of pinacidil were shifted in a parallel way to the right by low concentrations of TEA, TBA or BaCl2. Maximum responses to pinacidil were depressed by higher concentrations of the blockers. An analysis of the non-competitive antagonism by TEA yielded pKA (-log KA) values of 4.00-4.05 for pinacidil. 5. The concentration-effect curves for cromakalim and nicorandil were shifted by TEA similarly to those for pinacidil, and a similar analysis yielded pKA values of 4.47-4.68 for cromakalim and 3.47-3.74 for nicorandil. 6. The KA values of cromakalim, pinacidil and nicorandil were about 10-30 times greater than their EC50 values, indicating that there are non-linear stimulus-effect relationships between the binding of the three potassium channel openers to their binding sites at potassium channels and their negative inotropic effects. 7. The dissociation constants for TEA could also be estimated from pA2 and pKB values for antagonizing competitively and non-competitively the negative inotropic effects of the three potassium channel openers; they were 3.47-3.89, and did not differ between the potassium channel openers. 8. The concentration-effect curves for the three potassium channel openers were not affected by DAP or CsCl. 9. These results suggest the following: (i) quaternary ammonium compounds like TEA and TBA antagonize the negative inotropic effect of cromakalim, pinacidil and nicorandil by binding to potassium channels, thus preventing binding of the channel openers to the same sites or closely related sites in canine right atrial muscles.

Animals↗
PubMed1989

Nitroglycerin relaxes canine coronary arterial smooth muscle without reducing intracellular Ca2+ concentrations measured with fura-2.

1. Changes in cytoplasmic Ca2+ concentration ([Ca2+]1) were measured simultaneously with force by a microfluorometric method using a calcium indicator, fura-2, in canine coronary arterial smooth muscle cells. 2. Depolarization by high (30-90 mM) KCl-physiological salt solution (PSS) produced concentration-dependent increases in force and [Ca2+]i. 3. The KCl-induced increase in [Ca2+]i abolished by Ca2+-free conditions and almost abolished by verapamil 10-5 M, suggesting that it was entirely due to the increased Ca2+ influx through voltage-dependent Ca2+ channels. 4. The [Ca2+]i force relationship in the presence of verapamil was not distinguishable from that of control. 5. Nitroglycerin produced a concentration-dependent, reversible contraction of the coronary artery that had been contracted by high KCl-PSS, without reduction of the increased [Ca2+]i. 6. The KCl-induced increase in [Ca2+]i was not affected by nitroglycerin and in a presence of nitroglycerin it was abolished by 10-5 M verapamil suggesting that it was caused by the influx of extracellular Ca2+. 7. The [Ca2+]-force curve was shifted to the right by nitroglycerin. 8. It is likely that nitroglycerin relaxes the coronary arterial smooth muscle b reducing the amount of myosin light chain phosphorylation even in the presence of raised [Ca2+]i produced by increased Ca2+ influx following depolarization.

Animals↗
PubMed1989

Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

We examined K+-induced relaxation instead of contraction in the presence of Ca-antagonists by measuring isometric tension in the tracheal smooth muscle isolated from guinea pigs. Cumulative administration of KCl (10-90 mM) induced a concentration-dependent contraction. When the muscle was pretreated with low concentrations of Ca-antagonists, cumulative administration of KCl caused a mild contraction, followed by a moderate relaxation. In the muscle pretreated with high concentrations of Ca-antagonists, KCl revealed a concentration-related relaxation without contraction. The potency ratios of Ca-antagonists to reverse the KCl-induced contraction to relaxation were nifedipine : verapamil : diltiazem = 94:4:1. This order of potency was quite similar to that of Ca-antagonists to relax the muscle precontracted with KCl (30 mM). Magnitudes of KCl (30 m,)-induced relaxation in the presence of Ca-antagonists were similar to those caused by Ca-antagonists in the KCl (30 mM)-precontracted muscles. Thus, K+-induced relaxation in the airway smooth muscle in the presence of Ca-antagonists may be due to the voltage-dependent increase in binding of Ca-antagonists to calcium channels.

Animals↗
PubMed1989

Artificial infection by transplantation of juvenile Fasciola worms into the abdominal cavity of rats.

Rats were successfully infected with Japanese Fasciola sp. by transplantation of juvenile worms (JW) or metacercariae (MC) into the abdominal cavity. Moreover, the rat was investigated on its suitability for different experiments with liver flukes. JWs or MCs transplanted intraperitoneally (IP) matured in the bile duct of rats. Moreover, more stable infections were established by inoculation of JWs than MCs. About 3 of 10-15 JWs transplanted into the abdominal cavity of a rat matured and laid eggs in the bile duct. The mean prepatent period was 63.5 days in the JW inoculated group. EPG values were kept constant at a level of 10(2)-10(3) about 100 to 230 days after the transplantation of JWs. The life span of Japanese liver flukes was estimated to be about 400 days in rats. From these results, it was concluded that the rat is suitable for various experiments with Fasciola sp.

Animals↗
PubMed1989

Mechanisms of beta-adrenoceptor mediated increase in delayed rectifier potassium current.

Experiments were carried out in single ventricular cells of the guinea-pig heart. Isoproterenol, forskolin, intracellularly applied cyclic AMP and 3-isobutyl-1-methylxanthine increased the delayed rectifier potassium current (IK). The effect of isoproterenol was abolished by intracellularly applied guanosine 5'-O-(3-thio-triphosphate). These results indicate that isoproterenol stimulates beta-adrenoceptors to activate adenylate cyclase by mediation through the stimulatory GTP-binding protein, and causes an increase in intracellular cyclic AMP levels. Then IK is probably increased by phosphorylation of the IK-channel protein by cyclic AMP-dependent protein kinase.

Animals↗
PubMed1989

Differential coupling to positive inotropic responses of cyclic AMP produced by stimulation of beta 1- and beta 2-adrenergic receptors.

In canine right ventricular muscle, isoproterenol, a nonselective beta-agonist, and T-1583, a selective beta 1-agonist, produced positive inotropic effects (PIE) as full agonists. Their PIEs were antagonized by atenolol, a selective beta 1-antagonist, (pA2 = 7.71 for isoproterenol and pA2 = 7.82 for T-1583). The PIE of T-1583 was also antagonized by practolol, a selective beta 1-antagonist (pA2 = 6.55). Procaterol known as a selective beta 2-agonist gave a biphasic concentration-response curve with a maximum that was approximately half those of isoproterenol and T-1583. The PIE of procaterol at low concentrations (pD2 = 7.93), which maximum was approximately 10% of the maximum of isoproterenol, was antagonized by ICI 118,551, a selective beta 2-antagonist (ICI; pA2 = 8.84) and that at high concentrations (pD2 = 5.12) by atenolol (pA2 = 7.56). Increases in cyclic AMP content produced by isoproterenol were reduced greatly by atenolol and slightly by ICI, whereas those produced by T-1583, which were smaller than those by isoproterenol, were abolished by atenolol but not changed by ICI. Procaterol (10(-7) M) produced an increase in cyclic AMP, which was abolished by ICI but not changed by atenolol, to almost the same extent as procaterol (10(-5) M) did, which was abolished by atenolol and slightly reduced by ICI. These results indicate that increased cyclic AMP through beta 1- but not beta 2-receptors couples well to PIE.

Adrenergic beta-Antagonists↗
PubMed1989

Electrophysiological effects of the new antiarrhythmic drug 3-(diisopropylaminoethylamino)-2',6'-dimethylpropionanilide++ + on dog cardiac muscle.

The effects of 3-(diisopropylaminoethylamino)-2',6'-dimethylpropionanilide (AN-132), a new antiarrhythmic drug, on the electrical activities of dog ventricular muscles and Purkinje fibers were studied using standard microelectrode techniques. In ventricular muscles, AN-132 (10(-5)-10(-4) mol/l) decreased the overshoot potential and the maximum rate of rise of the action potential without changing the resting membrane potential, the plateau potential and the action potential duration at a driving rate of 0.5 Hz. These results indicate that AN-132 belongs to class 1 antiarrhythmic drugs. Lidocaine (10(-6)-10(-4) mol/l) failed to affect these parameters under the same conditions. In Purkinje fibers, both drugs decreased the plateau potential and shortened the action potential duration. To subclassify AN-132 among class 1 antiarrhythmic drugs, the kinetics of onset of rate-dependent effect of AN-132 (10(-4) mol/l) was compared with that of lidocaine (10(-4) mol/l), and AN-132 was found to have the slower onset kinetics than lidocaine.

Action Potentials↗
PubMed1988

Inhibition of calmodulin function by CV-159, a novel dihydropyridine compound.

1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester (CV-159), a new compound synthesized from dihydropyridine, was examined for its effect on calmodulin (CaM) function. The concentration of CV-159 producing 50% inhibition of Ca2+/CaM activated myosin light chain kinase (MLC kinase) was 6.2 microM. The apparent Ki value of CV-159 was 0.8 microM for MLC kinase. On the other hand, the concentration of CV-159 producing 50% inhibition of Ca2+/CaM activated cyclic nucleotide phosphodiesterase (Ca2+-PDE) was 0.55 microM. CaM antagonized competitively the CV-159-induced inhibition of activation of both MLC kinase and Ca2+-PDE. Interaction of CV-159 with CaM was also demonstrated by fluorescence studies using dansyl-CaM (5-dimethylaminonaphthalene-1-sulfonylated CaM). CV-159 produced a decrease in fluorescence intensity of dansyl-CaM, in a Ca2+-dependent fashion, and the concentration of this drug producing 50% inhibition of dansyl-CaM fluorescence was 1.2 microM. However, the concentration of nicardipine producing 50% inhibition of MLC kinase exceeded 100 microM. CaM did not antagonize the nicardipine-induced inhibition of Ca2+-PDE. These results suggest that the action of CV-159 is unique in that it inhibits both Ca2+-PDE and MLC kinase, through interaction with calmodulin. CV-159 seems to be a different class of drug from known dihydropyridine compounds.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1988

T-1583 and forskolin are similar in their cardiac effects and dissimilar in their vascular effects.

The cardiac and coronary vascular effects of T-1583, a selective beta 1-adrenoceptor full agonist, and forskolin, a direct activator of adenylate cyclase, were compared in isolated, blood-perfused papillary muscle, sinoatrial node, and atrioventricular (AV) node preparations of dogs. Both agents were injected intra-arterially. The two agents increased the force of contraction of the paced papillary muscle and the unpaced one, and the rate of automaticity of the latter. They increased sinus rate and accelerated AV nodal conduction. In producing these effects T-1583 was 50 to 80 times more potent than forskolin, indicating that both agents have similar cardiac profiles. At the doses that produced a 50% increase in the force of contraction of the papillary muscle, both agents produced about a 20% increase in sinus rate. Such degrees of force-rate separation were close to those obtained with most new positive inotropic agents with an inhibitory action on cyclic AMP phosphodiesterase. T-1583 differed distinctly from forskolin in that the former increased only slightly coronary blood flow, whereas the latter increased it greatly. Thus, forskolin is more coronary vasodilatory than positively inotropic, and more positively inotropic than positively chronotropic. T-1583 is a more positively inotropic than positively chronotropic and more positively chronotropic than coronary vasodilatory.

Adrenergic beta-Antagonists↗
PubMed1988

Total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure.

One hundred twenty-eight patients with chronic renal failure and secondary hyperparathyroidism underwent total parathyroidectomy with forearm autograft. Postoperative clinical improvement was remarkable. In all cases, the grafted tissue functioned well, and reimplantation of the cryopreserved parathyroid tissues was unnecessary. Intact 1-84 parathyroid hormone was more sensitive than C-terminal parathyroid hormone in parathyroid hormone level (PTH) gradient assays of grafted and nongrafted forearm. The study of hypocalcemia was also helpful in obtaining more distinct PTH gradients. Five of 119 patients had supernumerary parathyroid glands (4.2%), which preoperative noninvasive image diagnosis of parathyroid glands was helpful in detecting.

Adult↗
PubMed1988

Is the cardiovascular profile of BRL 34915 characteristic of potassium channel activators?

To see whether the cardiovascular profile of BRL 34915, a potent vasodilator, is characteristic of potassium channel activators, we investigated its cardiac effects by use of isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. BRL 34915 was injected intraarterially. It produced an increase in (coronary) blood flow in all preparations. In paced papillary muscle preparations, BRL 34915, although in large doses, produced a decrease in the force of contraction, leading nearly to abolition. The negative inotropic effect of BRL 34915 was accompanied by a marked acceleration of the repolarization of field cardiac action potentials. In some preparations, fibrillation occurred after profound negative inotropy and subsided spontaneously. In unpaced papillary muscles, BRL 34915 in large doses decreased rate of ventricular automaticity. In SA node preparations, BRL 34915 in large doses reduced sinus rate down to approximately 64% of the basal rate and produced atrial standstill in some. In AV node preparations, BRL 34915 in large doses slightly prolonged AV conduction time only when injected into the AV node artery. Nevertheless, it produced third-degree AV block in some. These cardiac effects of BRL 34915 are very similar to those of nicorandil and pinacidil, whose cardiac effects result exclusively from an increase in membrane K conductance in cardiac muscle cells. Like nicorandil and pinacidil, BRL 34915 was highly vasoselective.

Action Potentials↗
PubMed1988

Details of mode and mechanism of action of denopamine, a new orally active cardiotonic agent with affinity for beta 1-receptors.

We investigated the detailed mode and mechanism of action of denopamine in canine right ventricular muscle. When administered in single doses, denopamine produced a positive inotropic effect (PIE) and increased cyclic AMP levels. Concentration--response curves for both variables were sigmoid. The maximum PIE of denopamine was almost the same as that produced by isoproterenol. However, the maximum increase in cyclic AMP caused by denopamine was approximately 65% of that attained with isoproterenol. When administered cumulatively, concentration--PIE curves for denopamine were bell-shaped, ascending at 10(-7) to 10(-6) M, reaching a maximum at approximately 3 X 10(-6) M which was approximately 75% of that attained with single administrations, and descending at higher concentrations. The bell-shaped curve, which was computer-fitted, suggested that denopamine behaves as an agonist with pD2 of 6.12 and as an antagonist with pD2 of 4.50. The PIE of denopamine was antagonized by atenolol (pA2 = 7.66) but not by ICI 118,551 (less than 10(-7) M), indicating that denopamine is a selective beta 1-receptor agonist. The PIE of denopamine was augmented by 3-isobutyl-1-methyl-xanthine. The PIE and increase in cyclic AMP level caused by 3 X 10(-6) M denopamine were abolished by 10(-6) M atenolol or 3 X 10(-6) M carbachol. From these results we concluded that the PIE of denopamine is derived from the mechanism of action as a selective beta 1-receptor partial agonist. We suggested the close coupling of the beta 1-receptor-adenylate cyclase-cyclic AMP system to positive inotropy.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Differential antagonism by Bay K 8644 of vasodilator effects of nifedipine, diltiazem, nicorandil and nitroglycerin in dog femoral circulation.

1. The modification by Bay K 8644 of the vasodilator effects of nifedipine, diltiazem, nicorandil and nitroglycerin was investigated in the femoral arterial bed of anaesthetized dogs. 2. The right femoral artery was cannulated and its arterial bed was perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 was infused intra-arterially (i.a.) and the 4 vasodilators were injected i.a. as bolus doses. 3. The vasodilator effects of nifedipine (0.3-10 nmol), diltiazem (0.01-1 mumol), nicorandil (0.1-10 mumol) and nitroglycerin (0.3-100 nmol) were all suppressed by infusions of Bay K 8644 (3-100 nmol min-1). 4. The dose-response curve of nifedipine was shifted parallel to the right by the infusion of Bay K 8644 and the dose-ratio was the greatest of the 4 drugs. 5. The dose-response curve of diltiazem was also shifted to the right by Bay K 8644. However, the dose-ratio was far smaller than that of nifedipine. 6. The vasodilator effect of nicorandil was not antagonized as much by Bay K 8644 as that of nitroglycerin. This less effective antagonism of nicorandil by Bay K 8644 can be explained if nicorandil, which although structurally a nitrate, can in addition cause relaxation of vascular smooth muscle by hyperpolarizing the membrane which would result in Bay K 8644 being less effective.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗