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N Taira

Publications and source records attributed to N Taira.

At least 145 records · Page 8Linked to original sources
PubMed1987

Comparison of vasodilator effects of DN-9693, a selective inhibitor of cyclic AMP phosphodiesterase, and isobutylmethylxanthine, a non-selective one, in dogs.

The present experiments were performed in anesthetized dogs in order to determine if DN-9693, a new antiplatelet agent known to selectively inhibit cyclic AMP phosphodiesterase (PDE), and isobutylmethylxanthine (IBMX), which inhibits both cyclic AMP and GMP PDEs, have different cardiovascular actions. With intra-arterial administration into the left anterior descending coronary, femoral, cranial mesenteric and renal arterial beds perfused at constant pressure with autologous blood, both agents increased blood flow in a similar dose range. DN-9693 was longer-acting than IBMX. Both agents were nearly equi-effective in the femoral circulation, but DN-9693 was 1.5-2 times less effective than IBMX in the others. With intravenous administration, both agents were equi-effective in increasing the maximum rate of rise of left ventricular pressure heart rate and myocardial oxygen consumption and in reducing mean blood pressure. However, DN-9693 was less effective in increasing coronary sinus outflow than IBMX. These results suggest the following: 1) Vasodilation in the somatic rather than the visceral circulation is important in reducing mean blood pressure. 2) Cyclic GMP may not be involved in the cardiac action of PDE-inhibitors. 3) Cyclic GMP may be involved in the vasodilator effect of PDE-inhibitors in the coronary, mesenteric and renal circulations but least involved in the femoral circulation.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Changes in membrane potentials and currents of ventricular cells of the guinea pig heart by a new cardiotonic drug, MCI-154.

Effects of MCI-154, a newly synthesized cardiotonic drug with vasodilator property, on the membrane potential and currents of the isolated papillary muscles and the single ventricular cells of the guinea pig were examined. MCI-154 (10(-7)-10(-4) M) increased the developed tension in a dose-dependent manner without significant changes in the action potential configuration of the guinea pig papillary muscle. The slow response action potential obtained by increasing the extracellular K+ concentration to 24 mM was augmented by MCI-154 (10(-6) and 10(-4) M). This effect of MCI-154 was not blocked by atenolol (10(-6) M). In voltage clamp experiments on single ventricular cells, the slow inward current was not affected, but the inward rectifier K+ current was reduced by higher concentration of MCI-154 (10(-4) M). Considering the "run down" phenomenon of the slow inward current, the possibility that MCI-154 might have a slight increasing effect on the slow inward current could not be ruled out. From these results, it can be concluded that the positive inotropic action of MCI-154 can be explained partially by the decrease in the inward rectifier K+ current, and probably by the increase in the Ca2+ sensitivity of the contractile protein system.

Action Potentials↗
PubMed1987

The mechanism of centrally mediated cardiovascular actions of the three structurally different calcium antagonists, verapamil, diltiazem and nicardipine, in rats.

Centrally mediated cardiovascular effects of the three structurally different calcium antagonists (Ca-antagonists), i.e., verapamil, diltiazem and nicardipine, were studied in rats. In conscious rats, when administered intracerebroventricularly (i.c.v.) in doses of 0.3, 1 and 3 micrograms/kg/min for 30 min, all the three Ca-antagonists induced dose-dependent increases in mean arterial pressure (MAP) and pulse rate (PR), whereas nicardipine administered intravenously (i.v.) caused a decrease in MAP and an increase in PR. In anesthetized rats all the three Ca-antagonists in a dose of 3 micrograms/kg/min for 60 min i.c.v. significantly potentiated the hypotensive and bradycardic effects of i.c.v. clonidine. Nicardipine, in a dose of 0.3 microgram/kg/min for 60 min i.c.v., attenuated the hypotensive and bradycardic effects of i.c.v. clonidine or B-HT 920, an alpha 2-adrenoceptor agonist, in anesthetized rats, whereas it did not modify the cardiovascular effect of i.c.v. angiotensin II or gamma-aminobutylic acid in conscious rats. Nicardipine, in a dose of 0.3 microgram/kg/min for 60 min i.v., did not modulate the hypotensive and bradycardic effects of i.c.v. clonidine. 3-Isobutyl-l-methylxanthine (IBMX), a cyclic AMP phosphodiesterase inhibitor, in a dose of 3 micrograms/kg/min for 60 min i.c.v., also attenuated the hypotensive and bradycardic effects of i.c.v. clonidine. Potentiation by the three i.c.v. Ca-antagonists of the hypotensive and bradycardic effects of clonidine would be explainable if their inhibitory effect on Ca-influx is exerted at presynaptic nerve terminals but not at postsynaptic. The mechanisms of the cardiovascular effect of i.c.v. Ca-antagonists still remain to be elucidated but may be independent of a central alpha 2-adrenoceptor mechanism. Dihydropyridine Ca-antagonists like nicardipine are also potent inhibitor of cyclic AMP phosphodiesterase. Since IBMX mimicked the effect of nicardipine, the effect of a low dose of i.c.v. nicardipine in attenuating the hypotensive and bradycardic effects of i.c.v. clonidine may be mediated by inhibition of cyclic AMP phosphodiesterase in the central nervous system.

Animals↗
PubMed1987

Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart.

Effects of OPC-8212, a new positive inotropic drug, and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, on membrane currents were examined in single ventricular cells of the guinea pig heart. Single ventricular cells were prepared by the collagenase dispersion procedure. Both OPC-8212 (0.1 mM) and IBMX (0.1 mM) augmented the plateau and increased the duration of the action potential without affecting the resting membrane potential. Under voltage clamp condition, OPC-8212 (0.1 mM) increased the inward calcium current and decreased the delayed outward and the inward-rectifying potassium current. IBMX (0.1 mM) increased not only the inward calcium but also the delayed outward current. The isolated inward calcium current obtained by intra- and extracellular perfusion with Cs+, was increased by both drugs. When the inward calcium current was abolished by superfusion with D600 (10 microM) or Co++ (0.9 mM), OPC-8212 (0.1 mM) decreased the delayed outward and the inward-rectifying potassium current. On the other hand, IBMX (0.1 mM) increased the delayed outward current. From these results it can be concluded that OPC-8212 augments the plateau and increases duration of the action potential not only by increasing the inward calcium but also by decreasing both the delayed outward and the inward-rectifying potassium current, and the effects can be a cause of the positive inotropic effect of this drug.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Similarity and dissimilarity in the mode and mechanism of action between nicorandil and classical nitrates: an overview.

Nicorandil, which is structurally a nitrate and also a nicotinamide, differs from classical nitrates such as nitroglycerin and isosorbide dinitrate in the following respects. It dilates preferentially resistive vessels (arterioles); and it produces the increase in potassium conductance in the membranes of cardiac and some vascular smooth muscle cells that is responsible for its negative inotropic and chronotropic and vasodilator effects. Nicorandil has the following characteristics of a nitrate. (a) It is capable of dilating large conductive coronary arteries, although the effect is weaker than that of classical nitrates. (b) It is capable of reducing venous return, although this effect is less pronounced than that of classical nitrates. (c) It produces an increase in intracellular cyclic guanosine-3',5'-monophosphate (cyclic GMP) in vascular smooth muscle. The activity of nicorandil to increase the membrane potassium conductance resides in the nicotinamide moiety. However, this activity is greatly enhanced by the presence of the nitrate group at an appropriate distance from the nicotinamide group. The nitrate moiety per se has also its own action. The presence of these two pharmacologically active groups in the molecule appears to cause nicorandil to have rather complex cardiovascular actions.

Animals↗
PubMed1987

Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP?

MCI-154 is a new positive inotropic agent with vasodilating property. Experiments were carried out in the canine isolated right ventricular muscle in order to elucidate whether or not cyclic AMP is involved in the positive inotropic effect (PIE) of MCI-154. MCI-154 (10(-7) to 10(-4) M) produced a concentration-dependent PIE amounting to 75% of the maximal effect of isoproterenol. MCI-154 did not affect the time to peak tension and had a tendency to shorten the relaxation time and total duration of contraction. Pindolol, reserpine-pretreatment or tetrodotoxin did not modify the PIE of MCI-154. MCI-154 increased the cyclic AMP levels only at 3 X 10(-4) M, whereas CI-914, of which chemical structure is similar to that of MCI-154, elevated definitely the cyclic AMP at the lower concentrations (10(-5) to 10(-4) M). Carbachol at a concentration known to decrease markedly the PIE of amrinone, milrinone and papaverine, did not affect the PIE of MCI-154. MCI-154 inhibited the activity of a crude phosphodiesterase (PDE) from the canine ventricular muscle and it enhanced the PIE of isoproterenol, which implied the involvement of cyclic AMP. However, the maximal inhibition of PDE by MCI-154 remained less than 18%. Amrinone, milrinone and papaverine inhibited more potently the PDE activity than MCI-154. These results suggest that the elevation of cyclic AMP levels is only partially involved in the PIE of MCI-154 in the canine right ventricular muscle, and that MCI-154 may have novel mechanisms of action different from those of amrinone, milrinone and CI-914 that are largely cyclic AMP-dependent.

Animals↗
PubMed1986

Comparative study of cardiovascular profiles of milrinone and amrinone by use of isolated, blood-perfused dog heart preparations.

The cardiac and coronary vasodilator effects of milrinone and amrinone were compared in isolated, blood-perfused papillary muscle and sinoatrial (SA) node and atrioventricular (AV) node preparations of dogs. Milrinone (0.3-100 nmol) and amrinone (0.01-3 mumol) were administered intra-arterially. Both drugs increased the force of contraction of paced and unpaced papillary muscles and the rate of automaticity of the latter; they increased sinus rate and accelerated AV nodal conduction. However, both drugs were not homogeneously effective on cardiac variables but affected them in the following order: The force of contraction of the ventricular muscle greater than SA nodal automaticity divided by AV nodal conduction greater than ventricular automaticity. In producing these cardiac effects, milrinone was 30-60 times more potent than amrinone. Both drugs increased (coronary) blood flow in all preparations. In this respect milrinone was about ten times more potent than amrinone. As a result, milrinone can be characterized as having almost equal cardiotonic and coronary vasodilatory effects, whereas amrinone is more coronary vasodilatory than cardiotonic. These differences in cardiovascular profile may contribute to their differential salutary mechanisms in the treatment of heart failure. Both drugs induced neither AV nodal tachycardia nor ventricular arrhythmia.

Amrinone↗
PubMed1986

Comparative study of MDL 17043 and MDL 19205, new positive inotropic agents, by use of isolated, blood-perfused dog-heart preparations.

The cardiac and coronary vasodilator effects of MDL 17043 and MDL 19205 were compared in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. In these preparations, MDL 17043 (0.01-3 mumol) and MDL 19205 (0.01-3 mumol) were injected intra-arterially. Both drugs increased the force of contraction of papillary muscles paced at a rate of 120 stimuli/min, and a ten-fold increase in dose produced about a 100% increase in the force. The two drugs increased the sinus rate in SA node preparations, and a tenfold increase in dose resulted in about a 12% increase in sinus rate with MDL 17043 and about a 17% increase with MDL 19205. These drugs increased the rate of automaticity of spontaneously beating papillary muscles and also the force of contraction. With a ten-fold increase in dose, the increase in the rate was about 16% for MDL 17043 and about 9% for MDL 19205. No ventricular arrhythmias were produced by either drug. The drugs equally decreased AV conduction time by accelerating AV nodal conduction in AV node preparations whose right atria were paced at a rate of 150 stimuli/min. However, the decrease remained about 5% with a ten-fold increase in dose of both drugs. No AV junctional tachycardia was produced. In all preparations, both drugs increased (coronary) blood flow. In paced papillary muscle preparations a tenfold increase in dose resulted in about a 37% increase in blood flow with MDL 17043 and about a 42% increase with MDL 19205.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs.

The effect of the dihydropyridine calcium agonist Bay K 8644 on the coronary, femoral, mesenteric and renal circulations was investigated and compared with that of noradrenaline in pentobarbitone-anaesthetized dogs. The left anterior descending coronary, femoral, cranial mesenteric and renal arteries were cannulated and their arterial beds perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 (0.1-300 nmol) and noradrenaline (0.1-300 nmol) were injected intra-arterially. Bay K 8644 decreased blood flow (vasoconstriction) in all 4 arterial beds. A maximum decrease was attained at 100 nmol and a further increase in dose did not appear to result in a further decrease in blood flow. At maximum effects blood flow decreased to about 35% of the basal value in coronary, 30% in femoral, 20% in renal and 15% in mesenteric circulation. Normalized ED50 values (ED50 divided by basal flow) of Bay K 8644 were 0.07 +/- 0.02 nmol in the femoral, 0.08 +/- 0.01 nmol in the coronary, 0.16 +/- 0.06 nmol in the mesenteric and 0.55 +/- 0.19 nmol in the renal circulation. At 100 nmol, the values for the half-duration of Bay K 8644 vasoconstrictor effects were about 196 s in the renal, 78 s in the mesenteric, 84 s in the femoral and 21 s in the coronary circulation. Noradrenaline produced a dose-dependent decrease in blood flow in femoral, mesenteric and renal circulations, and was about 2 times in femoral, 4 times in mesenteric and 9 times in renal circulation more potent than Bay K 8644. 8. Bay K 8644 produced slight increases in the maximum rate of rise of left ventricular pressure and intraluminal pressure of the ileum. However, the increases did not appear to impede blood flow. 9. Bay K 8644 produced slightly but significantly greater femoral vasoconstriction in normal dogs than in reserpine-pretreated dogs. 10. From these results it was concluded that differences in potency, effectiveness and duration of the vasoconstrictor effects of Bay K 8644 between the 4 arterial beds probably derive from differences in characteristics ofthe smooth muscle ofresistance vessels there. In arterial beds where alpha-adrenoceptors are dominant, potentiation of the vasoconstrictor effect ofendogenous catecholamines by Bay K 8644 seems to contribute to its vasoconstrictor effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Cardiac versus coronary vasodilator actions of isobutylmethylxanthine in dogs: comparison with theophylline.

Cardiac and coronary vasodilator effects of isobutylmethylxanthine (IBMX) and theophylline were compared in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. IBMX (1 nmol-1 mumol) and theophylline (30 nmol-10 mumol) were injected intra-arterially. In paced papillary muscle preparations, both agents increased the force of contraction. In spontaneously beating papillary muscle preparations, both agents increased the rate of ventricular automaticity. In SA node preparations, both agents increased sinus rate. In AV node preparations, both agents decreased AV conduction time only when they were injected into the artery supplying the AV node. In all preparations, both agents increased coronary blood flow. However, both agents were not homogeneously effective on these cardiovascular variables, but showed selectivity in the following order: Ventricular muscle contraction not equal to coronary blood flow greater than SA nodal automaticity not equal to AV nodal conduction greater than ventricular automaticity. These results indicate that IBMX and theophylline have almost an identical profile in their cardiac and coronary vasodilator effects. The two agents were different in that IBMX was 40-50 times as potent as theophylline in producing these effects. Thus, both agents appeared to express their cardiovascular profiles mainly through inhibition of cyclic AMP phosphodiesterase, although theophylline has been claimed to have additional actions.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Cardiohemodynamic effects of nipradilol (K-351) in the dog: comparison with propranolol, nadolol and prazosin.

The cardiohemodynamic effects of nipradilol (K-351) were studied in comparison with those of propranolol, nadolol and prazosin in anesthetized, open-chest dogs. All drugs were administered intravenously. Nipradilol produced dose-dependent decreases in systemic blood pressure (BP), heart rate (HR), venous return (VR) and cardiac output (COP), but virtually no change in right atrial pressure (RAP). Propranolol decreased HR, tended to decrease VR and COP and increased RAP, but produced no change in systemic BP. Nadolol also decreased HR, VR and COP and increased RAP, but did not change systemic BP. Prazosin decreased systemic BP, VR and COP and tended to decrease RAP, but scarcely affected HR. After propranolol or nadolol, nipradilol failed to reduce HR, but still produced definite decreases in systemic BP, VR and COP and a slight decrease in RAP. After prazosin, nipradilol still produced decreases in systemic BP, HR, VR and COP. These results suggest that nipradilol decreases VR and COP mainly by increasing venous capacitance through direct venodilator action and in part by increasing resistance to VR through beta-adrenoceptor blockade. This effect also appears to be responsible for its hypotensive effect.

Adrenergic beta-Antagonists↗
PubMed1986

Modification by nicorandil and carbachol of the inward calcium current in single cells of the guinea-pig heart.

Effects of nicorandil and carbachol on the inward calcium current were studied in single heart cells isolated from the guinea-pig using a collagenase dispersion method. The inward calcium current was obtained in the absence of outward potassium currents by intra- and extra-cellular perfusion of the cell with Cs+-solutions. Nicorandil (0.3 mM) failed to modify the inward calcium current in the atrial cell. In the ventricular cell the inward calcium current was increased by isoproterenol (1 micron). The augmentation of the inward calcium current was abolished by carbachol (1 micron) but was not changed by nicorandil (0.3 mM). From these results it can be concluded that nicorandil has no direct effect on the inward calcium current even when the inward calcium current is previously augmented by isoproterenol.

Animals↗
PubMed1986

Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle.

In isolated canine ventricular trabeculae and papillary muscles driven electrically at 0.5 Hz at 37 degrees C, the positive inotropic effects of milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and forskolin were all associated with simultaneous elevations in tissue cyclic AMP levels. After the administration of sulmazole (AR-L 115 BS), the increase in force preceded that of cyclic AMP levels. Bay k 8644 increased the force of isometric contractions without producing any change in cyclic AMP levels. None of these agents affected the cyclic GMP level. Intracellular calcium transients were determined in similar preparations in which multiple superficial cells had been microinjected with the Ca++-sensitive bioluminescent protein aequorin. The aequorin signals increased in parallel with increases in force in response to cumulative administration of milrinone, amrinone, MDL 17,043, OPC-8212, forskolin, and low concentrations of sulmazole (less than or equal to 3 X 10(-4) M). Forskolin and sulmazole produced larger increases in the amplitude of the calcium transients than the other agents, and their inotropic effects were less variable in magnitude. High concentrations (greater than 3 X 10(-4)M) of sulmazole decreased the amplitude of the calcium transients while increasing further the force. The increases in cyclic AMP levels, calcium transients, and force produced by all of the inotropic agents except Bay k 8644 and high concentrations of sulmazole were effectively antagonized by carbachol. These results indicate that the accumulation of cyclic AMP resulting from the inhibition of cyclic AMP phosphodiesterase plays an important role in the action of new positive inotropic agents, milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and sulmazole (less than or equal to 3 X 10(-4)M), on dog ventricular muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Comparative study of coronary vasodilator and cardiac effects of nitrendipine by use of isolated, blood-perfused dog heart preparations.

The coronary vasodilator and cardiac effects of 3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009) were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node and papillary muscle preparations of dogs with i.a. administration. In all preparations nitrendipine increased (coronary) blood flow. In SA node preparations nitrendipine reduced sinus rate but the reduction remained only about 13% of the basal value even at the highest dose. The dose estimated to produce a 15% (nearly a half maximum) decrease in sinus rate was about 8 times the dose which doubled coronary blood flow. In AV node preparations nitrendipine prolonged AV conduction time when injected into the artery supplying the AV node but the prolongation remained only about 12% of the basal value even at the highest dose. The dose estimated to produce a 15% (nearly a half maximum) increase in AV conduction time was about 11 times the dose which doubled coronary blood flow. When injected into the artery supplying the His-Purkinje ventricular system of AV node preparations, nitrendipine was entirely ineffective on AV conduction. In paced papillary muscle preparations nitrendipine reduced force of contraction. The reduction, however, remained less than 50% of the basal value even at the highest dose. The dose estimated to reduce force of contraction by half was about 11 times the dose which doubled coronary blood flow. Nitrendipine was entirely ineffective on ventricular beating rate of spontaneously beating papillary muscle preparations. These results indicate that nitrendipine is highly vasoselective, and warrant its high efficacy as an antianginal drug.

Animals↗
PubMed1986

General pharmacology of the novel angiotensin converting enzyme inhibitor alacepril. 1st communication: Effects on cardiovascular, visceral and renal functions and on blood.

The effects of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) an antihypertensive compound with angiotensin converting enzyme inhibitory activity, and its metabolite, desacetyl-alacepril (DU-1227), on the cardiovascular and autonomic nervous systems and on the blood were compared with those of captopril in the experimental animals. Alacepril and DU-1227 at the i.v. dose of 10 mg/kg gradually lowered the diastolic blood pressure in pentobarbital anesthetized dogs. Captopril showed similar effects. However, the former two compounds showed triphasic effects on the carotid blood flow, i.e., transient increase immediately after the injection, second increase 2 min later, and gradual decrease 20-30 min later. The second increase by DU-1227 was more potent than that by alacepril. Alacepril, DU-1227 and captopril did not affect the pressor responses induced by norepinephrine in anesthetized cats. The contractions of the nictitating membrane in cats induced by electrical stimulation of the cervical sympathetic nerve or epinephrine were depressed with high doses of these three compounds. Captopril potentiated the contractions induced by bradykinin in isolated guinea-pig ileum, while alacepril and DU-1227 were without effect. These three compounds neither affected the resting tension of isolated ileum in guinea-pigs and rabbits nor the contractions induced by acetylcholine, histamine, serotonin and nicotine of isolated guinea-pig ileum. Alacepril at the oral dose of 60 mg/kg decreased the total acidity in pylorus ligated rats, and at higher doses depressed the intestinal charcoal meal passage in mice. Alacepril at comparatively low doses decreased the urine volume with slight reduction of Na+ and K+ excretions in saline-loaded rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗