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N Taira

Publications and source records attributed to N Taira.

At least 91 records · Page 5Linked to original sources
PubMed1991

Comparison of the effects of the novel vasodilator FK409 with those of nitroglycerin in isolated coronary artery of the dog.

1. The vasorelaxant effects of FK409, a new nitrovasodilator synthesized from a microbial product, were compared with those of nitroglycerin in isolated coronary artery rings of the dog contracted with U46619 (10(-7) M). 2. FK409 (10(-11)-10(-5) M) and nitroglycerin (10(-9)-10(-4) M) each produced a concentration-dependent relaxation. Comparison of EC50 values showed that FK409 was about 25 times more potent than nitroglycerin. 3. Submaximum concentrations of nitroglycerin (10(-6) M) and FK409 (3 x 10(-8) M) elevated guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels, effects associated with vasorelaxation. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 4. The concentration-relaxation curves for nitroglycerin and FK409 were shifted to the right by methylene blue (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of soluble guanylate cyclase, and to the left by M&B22,948 (3 x 10(-6) - 3 x 10(-5) M), an inhibitor of cyclic GMP phosphodiesterase. 5. After exposure of coronary arteries to the maximally-effective concentration of nitroglycerin (10(-4) M), the mean EC50 value of FK409 did not change significantly, although that of nitroglycerin increased about 60 fold. After exposure to the maximally-effective concentration of FK409 (10(-5) M), the mean EC50 value of FK409 increased about 6 fold and that of nitroglycerin about 11 fold. 6. These results suggest that the vasorelaxant effect of FK409, like that of nitroglycerin, is due to activation of soluble guanylate cyclase and a resultant increase in intracellular cyclic GMP. However, compared with nitroglycerin, there was less self-tolerance to the relaxant effects of FK409 and relatively little cross-tolerance between the two agents.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

An analysis of the nitrate-like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle.

1. To clarify the mechanism of action of KRN2391, a new vasodilator containing a nitroxy group, its effects on intracellular Ca2+ concentration ([Ca2+]i) and force of contraction in canine coronary artery were compared with those of two derivatives lacking the nitro group. 2. KRN2391, its hydroxy and acetoxy derivative (Compound 2 and Compound 3, respectively) partially reduced [Ca2+]i in 5 or 30 mM KCl physiological salt solution (PSS), effects which were antagonized by glibenclamide. No KRN2391-induced change in [Ca2+]i was observed in 90 mM KCl-PSS. 3. The order of potency in reducing [Ca2+]i and inhibiting the contracture in 30 mM KCl-PSS was: KRN2391 greater than Compound 3 greater than Compound 2. 4. In 30 mM KCl-PSS, KRN2391 shifted the [Ca2+]i-force relationship so that a greater increase in [Ca2+]i was needed to produce force. Compounds 2 and 3 were ineffective. The [Ca2+]i-force curve obtained in 90 mM KCl-PSS was shifted to the right by KRN2391 (10(-4)M). 5. The ability of KRN2391 to reduce the force of contraction in both 30 mM and 90 mM KCl-PSS was inhibited by 10(-5) M methylene blue. 6. KRN2391 inhibited U46619-induced contractions; this effect was associated with a reduction of [Ca2+]i, which decreased below the basal level. 7. Thus, KRN2391 is a potent vasodilator in canine coronary artery. It possesses nitrate-like and potassium channel opening actions and can be designated as a nitrate-potassium channel opener (N-K) hybrid. The denitrate derivatives of KRN2391 are specific K channel openers. The nitroxy moiety in KRN2391 is important for not only its action as a nitrate but also its potency as a K channel opener.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Morphological observation of Toxocara vitulorum found in Japanese calves.

Between 1982 and 1988, ascarid nematodes were found in the feces of Japanese calves in Kyushu and Okinawa districts. Seven males and 21 females of the ascarids were observed morphologically for identification of species. Male and female ascarids were 15.64 (14.0-18.0) cm and 25.75 (16.5-34.0) cm in average length, respectively. Eggs were 81.6 microns and 71.8 microns in large and small diameters, respectively. The body of ascarids was translucent and soft. The boundary between the enlabium and prelabium of lip was clearly visible and the esophageal ventriculus was also observed. The vulva was situated at a distance of about 1/7 approximately 1/9 of body length from the anterior end of body. The surface of egg shell was relatively smooth, without rugose albuminous coat. These morphological features coincided with those of Toxocara vitulorum.

Animals↗
PubMed1991

Is staurosporine a specific inhibitor of protein kinase C in intact porcine coronary arteries?

We assessed the specificity of staurosporine, a putative protein kinase C inhibitor, for the enzyme in intact porcine coronary arteries by examining its effects on changes in intracellular free calcium level ([Ca++]i) and force induced by a phorbol ester, high KCl and caffeine. [Ca++]i was measured simultaneously with force by the fura-2 microfluorimetric method. Phorbol 12,13-dibutyrate (PDBu, 10(-6) M) produced a slowly developing and sustained contraction; however, [Ca++]i only increased slightly and transiently in the initial phase and then decreased gradually. On the other hand, 90 mM KCl elicited a contraction with a sustained increase in [Ca++]i. Staurosporine (10(-10) to 10(-7) M) applied 20 min before the addition of PDBu inhibited the PDBu-induced changes in [Ca++]i and force in a concentration-dependent manner. In contrast, staurosporine only at 10(-7) M reduced an increase in [Ca++]i and contractile force produced by 90 mM KCl. The inhibitory effects of staurosporine on PDBu- and KCl-induced contractions depended on exposure time. The [Ca++]i-force relationship obtained with variable concentrations of KCl was shifted slightly to the right by staurosporine at 10(-7) M. Furthermore, staurosporine even at 10(-7) M did not affect an increase in [Ca++]i by caffeine (25 mM), although it slightly attenuated a caffeine-induced contraction. These results suggest that staurosporine is a relatively specific inhibitor of protein kinase C in intact arteries at lower concentrations. At higher concentrations it may have actions unrelated to its inhibitory effect of protein kinase C, which include the inhibition of calcium influx into smooth muscle cells through the voltage-dependent Ca++ channel.

Alkaloids↗
PubMed1990

Phorbol 12,13-dibutyrate increases vascular tone but has a dual action on intracellular calcium levels in porcine coronary arteries.

The effects of phorbol 12,13-dibutyrate (PDBu). a protein kinase C activator, on the tone and intracellular calcium level (Cai2+) of vascular smooth muscles were simultaneously measured by use of a force-displacement transducer and the fura-2 microscopic fluorometric technique in porcine coronary arteries. Cumulatively applied PDBu produced a slowly developing and concentration-dependent contraction in the concentration range of 10(-8)-10(-6) mol/l. Contractions induced by PDBu were sustained after removal of PDBu. Changes in Cai2+ produced by PDBu were very slight, although Cai2+ was increased at lower concentrations (3 x 10(-8) and 10(-7) mol/l) and decreased at higher concentrations (3 x 10(-7) and 10(-6) mol/l). Verapamil 10(-6) mol/l partially inhibited the contractions throughout the concentration range of PDBu and the increase in Cai2+ induced by lower concentrations of PDBu. When the effects of PDBu were compared with those of the 90 mmol/l KCl medium, the force of contraction induced by a single concentration of 10(-7) mol/l PDBu was about 50% and the increase in Cai2+ was about 10%. Removal of extracellular calcium by 1 mmol/l EGTA decreased Cai2+ by about 20% but vascular tone did not change. PDbu (10(-7) mol/l) produced a small contraction without an increase in Cai2+ in the Ca2+-free medium. Depolarization by the 20 mmol/l KCl medium increased Cai2+ by about 20%, whereas vascular tone did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Nicorandil increases coronary blood flow predominantly by K-channel opening mechanism.

Nicorandil has a hybrid property between nitrates and potassium (K)-channel openers. In order to clarify which mechanism of action is responsible for its effect in increasing coronary blood flow, we investigated how this effect was antagonized by glibenclamide, which was recently found to behave as a pharmacologic antagonist of K-channel openers. Cromakalim, one of the most specific K-channel openers currently available, and nitroglycerin were used as reference drugs. In isolated, blood-perfused papillary muscle preparations of dogs, intraarterial injections of nicorandil and cromakalim increased (coronary) blood flow, and at high doses a negative inotropic effect and ventricular fibrillation occurred. Dose-response curves for the increase in coronary blood flow produced by nicorandil or cromakalim were shifted to the right in a parallel manner and to similar extents by glibenclamide given intravenously to support dogs. Schild analysis yielded pA2 values of 6.08 and 6.34 for glibenclamide versus nicorandil and cromakalim, respectively. Nitroglycerin injected intraarterially produced only an increase in coronary blood flow. This effect was not affected by glibenclamide. These results indicate that the effect of nicorandil in increasing coronary blood flow, like that of cromakalim, is predominantly due to its mechanism of action as a K-channel opener. The negative inotropy and ventricular fibrillation seen with high doses of nicroandil and cromakalim were also antagonized by glibenclamide, indicating that these effects are also due to K-channel opening.

Adenosine Triphosphate↗
PubMed1990

Cardiac versus coronary dilator effects of SD-3211, a new nondihydropyridine calcium antagonist, in isolated, blood-perfused dog hearts.

Coronary and cardiac effects of SD-3211 were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. SD-3211 was administered intraarterially. In all preparations SD-3211 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate, and in high doses atrial standstill occurred. The dose that produced a 15% decrease in sinus rate was about 5.6 times the dose that doubled coronary blood flow. In AV node preparations, when injected into the artery supplying the AV node, the drug produced an increase in AV conduction time, and in high doses second- or third-degree AV block occurred. The dose that produced a 15% increase in AV conduction time was about 1.6 times the dose that doubled coronary blood flow. In the same preparations the drug slightly increased AV conduction time only at high doses when injected into the artery supplying the His-Purkinje-ventricular system. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. The dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 50 times the dose that doubled coronary blood flow. The drug was virtually ineffective on ventricular automaticity. In short, in doses that doubled coronary blood flow, SD-3211 depressed only AV nodal conduction. This cardiovascular profile differs from those of diltiazem and verapamil, which do not discriminate between coronary vasculature and the SA and the AV node.

Animals↗
PubMed1990

Selective beta 1-receptor full agonists, T-0509 and T-1583, increase the force monophasically and cyclic AMP biphasically in canine ventricular muscle.

In canine right ventricular muscle, we investigated the mechanism of action of the positive inotropic effects of T-0509 and T-1583, derivatives of denopamine, a new selective beta 1-partial agonist. T-1583 has already been characterized as a selective beta 1 full agonist (pD2 = 7.39). T-0509 also behaved as a full agonist (pD2 = 8.27) and its positive inotropic effect was antagonized competitively by atenolol (pA2 = 7.53) and noncompetitively by carbachol, and potentiated by 3-isobutyl-1-methylxanthine. With increasing concentrations of T-0509 (10(-9) to 10(-7) M) and T-1583 (10(-8) to 10(-6) M), cyclic AMP increased and increases reached plateaus approximately 40% above the baseline levels with approximately 10(-7) M T-0509 and approximately 10(-6) M T-1583, at which their positive inotropic effects reached maxima. However, with further increasing concentrations, cyclic AMP again started to increase and increases amounted to approximately 120% above the baseline levels with 10(-5) M T-0509 and with 10(-4) M T-1583. These results suggest the following: Like denopamine, the selective beta 1 full agonists, T-0509 and T-1583, at lower concentrations produce positive inotropic effects accompanied by only a small increase in cyclic AMP via stimulation of high-affinity beta 1-receptors. In higher concentrations, unlike denopamine, the two full agonists produce large increases in cyclic AMP loosely coupled to positive inotropy via stimulation of low-affinity beta 1-receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Cytoplasmic calcium and the relaxation of canine coronary arterial smooth muscle produced by cromakalim, pinacidil and nicorandil.

1. In order to investigate the vasodilator mechanisms of the K+ channel openers, cromakalim, pinacidil and nicorandil, we measured changes in cytoplasmic Ca2+ concentration [( Ca2+]i) simultaneously with force by a microfluorimetric method using fura-2, a calcium indicator, in canine coronary arterial smooth muscle cells. 2. The three K+ channel openers all produced a concentration-dependent reduction of [Ca2+]i in 5 and 30 mM KCl physiological salt solution (PSS) but failed to affect [Ca2+]i in 45 and 90 mM KCl-PSS. 3. Cromakalim only partly inhibited (-45%) the 30 mM KCl-induced contractures, whereas pinacidil and nicorandil nearly abolished contractions produced by 45 mM, 90 mM and 30 mM KCl-PSS. 4. Tetrabutylammonium (TBA), a nonselective K+ channel blocker, or glibenclamide, a supposed adenosine 5'-triphosphate (ATP)-sensitive K+ channel blocker, abolished the reduction of [Ca2+]i caused by the three K+ channel openers and the relaxant effect of cromakalim, whereas they only slightly attenuated the relaxant effects of pinacidil and nicorandil. 5. The increase in [Ca2+]i produced by 45 or 90 mM KCl-PSS in the presence of pinacidil or nicorandil was abolished by 10(-5) M verapamil, indicating that the increase in [Ca2+]i was caused by the influx of extracellular Ca2+ and that pinacidil and nicorandil did not affect the voltage-dependent Ca2+ channel directly. 6. The [Ca2+]i-force relationship in the presence of cromakalim was not distinguishable from that of control. 7. The [Ca2+]i-force curve was shifted to the right by pinacidil and nicorandil. 8. These results show that cromakalim is a more specific K+ channel opener than pinacidil and nicorandil, and that vasodilatation produced by cromakalim in this study is predominantly a result of a reduction of [Ca2+]i due to the closure of voltage-dependent Ca21 channels by hyperpolarization. In contrast, additional mechanisms are involved in the vasodilator actions of pinacidil and nicorandil. One of these is related to a reduction in the sensitivity of contractile proteins to Ca2 . The latter mechanism of nicorandil is akin to that of nitroglycerin. K+ channels opened by these K+ channel openers may be ATP-sensitive ones which are blocked by glibenclamide.

Adenosine Triphosphate↗
PubMed1990

Specific but differential antagonism by glibenclamide of the vasodepressor effects of cromakalim and nicorandil in spinally-anaesthetized dogs.

1. Whether the vasodepressor effects of cromakalim and nicorandil, potassium channel openers, were differentially antagonized by glibenclamide, a supposed specific antagonist of potassium channel openers, was investigated in spinally-anaesthetized dogs in which arterial pressure was maintained elevated by i.v. infusion of noradrenaline. 2. Cumulative administration of cromakalim (3-100 micrograms kg-1, i.v.), nicorandil (30-1000 micrograms kg-1, i.v.), diltiazem (3-300 micrograms kg-1, i.v.) and nitroglycerin (0.3-100 micrograms kg-1, i.v.) caused dose-dependent decreases in mean arterial pressure. In dogs which received glibenclamide (3 mg kg-1, i.v.), the dose-vasodepressor response curves for cromakalim and nicorandil were located on the right in parallel to the respective curves determined in control dogs, but those for diltiazem and nitroglycerin were not different. ED50% values increased about 6.7 fold for cromakalim and 2.2 fold for nicorandil. 3. The depression of LV dP/dtmax produced by a high dose of cromakalim (100 micrograms kg-1, i.v.) was abolished by glibenclamide and that produced by nicorandil was not only antagonized but converted to an increase. 4. These results suggest that the vasodepressor action of cromakalim is due predominantly to potassium channel opening, but that of nicorandil involves not only potassium channel opening but its action as a nitrate.

Anesthesia, Spinal↗
PubMed1990

Histamine increases vascular tone and intracellular calcium level using both intracellular and extracellular calcium in porcine coronary arteries.

Effects of histamine on the tone and intracellular calcium level (Ca2+i) in porcine coronary arteries were simultaneously investigated by use of the fura-2 microscopic fluorometric method. Histamine (10(-6)-10(-4) M) induced concentration-dependent increases in tone and Ca2+i, but these responses were not sustained. Histamine induced a larger contraction than did KCl with a similar increase in Ca2+i. Depletion of the caffeine-sensitive Ca2+ store with ryanodine (3 x 10(-5) M) and repetitive applications of caffeine (2.5 x 10(-2) M) scarcely affected contractile and Ca2+i responses to histamine. In Ca2(+)-free medium or in the presence of verapamil (10(-6) M), histamine produced a briefer increase in Ca2+i and a smaller contraction than in normal medium. When histamine or caffeine was repetitively applied in Ca2(+)-free medium, the first application produced an increase in Ca2+i but the second application produced no increase. Although caffeine increased Ca2+i after repetitive histamine applications, histamine failed to increase Ca2+i after repetitive caffeine applications in Ca2(+)-free medium. These results indicate that vascular contraction induced by histamine may involve the following mechanisms: an increase in Ca2+ influx through Ca2+ channels, release of Ca2+ from the intracellular Ca2+ store which has an interaction with the caffeine-sensitive Ca2+ store, and sensitization of contractile proteins to Ca2+.

Animals↗
PubMed1990

Specific antagonism by glibenclamide of negative inotropic effects of potassium channel openers in canine atrial muscle.

The mode of antagonism by glibenclamide, a potassium channel blocker, of the negative inotropic effects of potassium channel openers, cromakalim, pinacidil and nicorandil, was investigated in canine atrial muscle. Glibenclamide shifted the concentration-negative inotropic effect curves for cromakalim, pinacidil and nicorandil to the right without affecting the basal force of contraction. Schild analysis yielded uniform pA2 values of 6.06-6.35 for glibenclamide against the three potassium channel openers. The force of contraction of atrial muscles previously reduced by cromakalim was also antagonized by increasing concentrations of glibenclamide. Glibenclamide affected neither the concentration-negative inotropic effect curves for carbachol, an opener of the muscarinic receptor-coupled potassium channel, nor those for nifedipine, a calcium channel blocker. From these results, it became evident that glibenclamide behaved as a pharmacological antagonist of cromakalim, pinacidil and nicorandil in cardiac inotropy. The antagonism seems to involve competition of glibenclamide and these potassium channel openers, presumably at the ATP-sensitive channel in canine right atrial muscles.

Animals↗
PubMed1990

Differential modulation by beta adrenoceptors of inward calcium and delayed rectifier potassium current in single ventricular cells of guinea pig heart.

This study was designed to investigate the modulation of the high-threshold (L-type) inward calcium current (ICa) and the delayed rectifier potassium current (IK) by beta adrenoceptor stimulation in single ventricular cells of guinea pig heart. Single ventricular cells were prepared by the collagenase dispersion procedure, and membrane currents were recorded with a patch electrode by use of the whole-cell voltage clamp method. ICa was obtained by intra- and extracellular perfusion with the Cs(+)-solutions that suppressed potassium currents. IK was evaluated in Co+(+)-Tyrode's solution in which 0.9 mM Co+(+) was substituted for equimolar Ca+(+) to abolish ICa. Isoproterenol, a nonselective beta adrenoceptor agonist, increased not only ICa but also IK at the same threshold concentration (1 nM). In contrast, the threshold concentration of T-1583, a selective beta-1 adrenoceptor agonist, for increasing ICa (1 nM) was distinctly lower than that for increasing IK (100 nM). These results suggest that ICa and IK can be differentially modulated by beta adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1989

Nicorandil as a hybrid between nitrates and potassium channel activators.

Nicorandil, although structurally a nitrate, differs from classic nitrates in several respects. It preferentially dilates resistive vessels. Its effect on venous return in dogs is not unanimously a decrease but rather an increase. In high doses or concentrations it suppresses myocardial contraction and ventricular automaticity, nearly sparing sinoatrial nodal automaticity and atrioventricular nodal conduction. It shortens the effective refractory period of myocardium. These cardiac effects of nicorandil have been explained by its mechanism of action as a potassium (K) channel activator. However, what part of the vascular effects of nicorandil this mechanism is responsible for has not been determined. BRL 34915 and pinacidil, nonnitrate vasodilators with a K-channel activator action, have essentially the same cardiovascular profile as nicorandil in isolated, blood-perfused canine heart preparations. In anesthetized, open-chest dogs the 2 K-channel activators decreased systemic blood pressure and increased venous return and cardiac output without elevating heart rate, unless the cardiodepressant effect emerged. The increase in venous return or cardiac output survived elimination of baroceptor functions. These results taken together with previous results on nicorandil suggest the following: (1) The property of nicorandil as a resistive vessel dilator highly selective for vasculature originates in its mechanism of action as a K-channel activator. The nonunanimous effect of nicorandil on venous return is a result of the opposing actions as a capacitive (action as a nitrate) and a resistive vessel dilator. Nicorandil, with its hybrid nature, is advantageous over specific K-channel activators and classic nitrates in therapeutic implications.

Animals↗
PubMed1989

Beta 2-adrenoceptor-mediated increase in the slow inward calcium current in atrial cells.

The effects of procaterol (beta 2-adrenoceptor agonist) on the slow inward calcium current (Isi) were examined in single cells of guinea-pig heart. Procaterol increased Isi in atrial cells, in the presence of atenolol (beta 1-adrenoceptor antagonist). The effect was abolished by ICI-118551 (beta 2-adrenoceptor antagonist). However, procaterol did not modify the membrane currents in ventricular cells. These results suggest that beta 2-adrenoceptor agonists bind to beta 2-adrenoceptors in atrial cells and augment Isi, but beta 2-adrenoceptors are not present in ventricular cells.

Adrenergic alpha-Agonists↗
PubMed1989

Cardiohemodynamic effects of cromakalim and pinacidil, potassium-channel openers, in the dog, special reference to venous return.

The cardiohemodynamic effects of the potassium-channel openers, cromakalim and pinacidil, were studied by the use of the closed-loop method (for both drugs) and the cardiopulmonary bypass technique (for cromakalim only) in anesthetized, open-chest dogs. In closed-loop preparations, both drugs (cromakalim, 3 to 100 micrograms/kg; pinacidil, 10 to 300 micrograms/kg) administered intravenously decreased systemic blood pressure and increased venous return (sum of the flow through the inferior and the superior vena cava) and cardiac output (CO). With the highest doses of both drugs, venous return and CO decreased in some preparations in which right atrial pressure rose, and the maximum rate of rise of left ventricular pressure (LV dP/dt max) diminished. Except such preparations, right atrial pressure, heart rate, and atrioventricular conduction time remained virtually unchanged. The fall in systemic blood pressure produced by intermediate doses of pinacidil was greater in the preparations in which baroceptor reflexes were eliminated (denervated preparations) than in those with the reflexes left intact (nerve-intact preparations). The increases in venous return and CO, however, were not different when comparing the nerve-intact and the denervated preparations. In cardiopulmonary-bypass preparations, higher doses of cromakalim increased venous return while producing a fall in systemic blood pressure, suggesting that the decreased venous return and CO seen with higher doses of the potassium-channel openers in the closed-loop preparations were secondary to the decreased cardiac contractility. The potassium-channel openers should be characterized as vasodilators, which preferentially reduce afterload and increase venous return.

Animals↗