[A study on clinical training: involvement of the teacher in self evaluation].
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Education, Nursing↗
Biomedical subjects
N Taira
Publications and source records attributed to N Taira.
Cardiovascular profiles of the calcium antagonists nisoldipine and nifedipine in the blood-perfused dog heart.
The coronary vasodilator and cardiac effects of nisoldipine (Bay k 5552) were compared with those of nifedipine in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node and papillary muscle preparations of dogs with i.a. administration. Principally all preparations received both nisoldipine (0.01-10 micrograms) and nifedipine (0.3-3 micrograms). In all preparations both drugs increased (coronary) blood flow, and in this respect they were nearly equipotent. In SA node preparations nisoldipine reduced sinus rate and produced atrial standstill in large doses. Nifedipine also reduced sinus rate in the dose range tested. In this respect, too, both drugs were nearly equipotent. The ratio of the dose that produces a 15% (nearly half-maximum) decrease in sinus rate to the dose that doubles coronary blood flow was about 7 for nisoldipine and about 9 for nifedipine. In AV node preparations both nisoldipine and nifedipine prolonged AV conduction time and produced second- or third-degree AV block in large doses only when injected into the artery supplying the AV node but not into the artery supplying the His-Purkinje-ventricular system. In suppressing AV nodal conduction both drugs were nearly equipotent. The ratio of the dose that produces a 15% (nearly half-maximum) increase in AV conduction time to the dose that doubles coronary blood flow was about 3.3 for nisoldipine and about 5 for nifedipine. In paced papillary muscle preparations both nisoldipine and nifedipine reduced the force of contraction. In this respect, too, both drugs were nearly equipotent. The ratio of dose that reduces the force of contraction by half to the dose that doubles coronary blood flow was about 5 for both of them.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cardiovascular profile of Bay K 8644, a presumed calcium channel activator, in the dog.
Bay k 8644, although belonging to dihydropyridines, has been reported to exert effects directionally opposite to those of dihydropyridine calcium channel blockers such as nifedipine. The present experiments were carried out to elucidate whether this is indeed true. All experiments were done on isolated, blood-perfused dog-heart preparations described below, and Bay k 8644 was administered intra-arterially. In sinoatrial (SA) node preparations Bay k 8644 increased sinus rate by about 37% of the basal value at the highest dose (10 micrograms). In atrioventricular (AV) node preparations Bay k 8644 decreased AV conduction time by accelerating AV nodal but not intraventricular conduction. However, the decrease in AV conduction time remained at about 10 ms (about 7.8% of the basal value) even at the highest dose (10 micrograms). In papillary muscle preparations driven at a fixed rate of 120 stimuli/min Bay k 8644 increased the force of contraction by about 100% of the basal value at the highest dose (10 micrograms). In spontaneously beating papillary muscle preparations Bay k 8644 failed to increase the rate of automaticity although it increased the force of contraction. In all preparations Bay k 8644 decreased (coronary) blood flow down to about 20% of the basal value at the highest dose (10 micrograms). The positive chronotropic and dromotropic effects of Bay k 8644 reached respective peaks nearly at the same time as its vasoconstrictor effect, whereas its positive inotropic effect reached a peak after the vasoconstrictor effect had nearly worn off.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Nicardipine releases sustained coronary arterial constriction induced by acetylcholine in the rhesus monkey.
In five rhesus monkeys (Macaca mulatta) the vascular bed of the left anterior descending coronary artery (LAD) was perfused at constant pressure with autologous blood. Nicardipine (1-30 micrograms), a dihydropyridine calcium antagonist when injected into the LAD, increased LAD flow without producing significant changes in other cardiohemodynamic variables. With continuous infusions of acetylcholine into the LAD, the flow decreased by about 34% of the basal value. Under these conditions, intra-LAD nicardipine produced an increase in LAD flow almost to the same extent as in the control. The effects of nicardipine were qualitatively similar to those of other calcium antagonists observed in previous experiments and indicate that nicardipine would be useful as an antianginal drug.
Acetylcholine↗
Improvement by denopamine (TA-064) of pentobarbital-induced cardiac failure in the dog heart-lung preparation.
The efficacy of denopamine, an orally active beta 1-adrenoceptor agonist, in improving cardiac failure was assessed in dog heart-lung preparations. Cardiac functions depressed by pentobarbital (118 +/- 28 mg; mean value +/- SD) such that cardiac output and maximum rate of rise of left ventricular pressure (LV dP/dt max) had been reduced by about 35% and 26% of the respective controls were improved by denopamine (10-300 micrograms) in a dose-dependent manner. With 100 micrograms denopamine, almost complete restoration of cardiac performance was attained, associated with a slight increase in heart rate. No arrhythmias were induced by these doses of denopamine. The results warrant clinical trials of denopamine in the treatment of cardiac failure.
Animals↗
Bay K 8644, a dihydropyridine calcium agonist, augments vasoconstrictor responses to endogenous and exogenous noradrenaline in the peripheral vasculature of the dog.
The effect of Bay K 8644 (a substance known to increase calcium influx through the voltage-dependent calcium channel) on vasoconstrictor responses of resistance vessels to endogenous and exogenous noradrenaline (NA) was investigated in pentobarbitone-anaesthetized dogs which had also undergone spinal anaesthesia and bilateral vagotomy and received atropine. In these dogs the saphenous arterial bed was perfused at fixed flow rates with autologous blood to give perfusion pressure close to the systemic blood pressure. Electrical stimulation (3-30 Hz) of the saphenous nerve and single intra-arterial (i.a.) injections of noradrenaline (NA, 0.03-3 micrograms) produced an increase in perfusion pressure (vasoconstriction) in a frequency- and a dose-dependent manner, respectively. Intra-arterial infusions of Bay K 8644 (3 and 10 micrograms min-1) per se produced no significant change in perfusion pressure. However, these infusions augmented vasoconstrictor responses to both saphenous nerve stimulation (endogenous NA) and i.a. NA (exogenous NA). These results suggest that augmentation by Bay K 8644 of vasoconstrictor responses of resistance vessels to endogenous and exogenous NA is probably due to promotion of the calcium influx through calcium channels closely associated with alpha-adrenoceptors in smooth muscle cells there.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.
Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Amelioration of heart failure by MDL 17043 and MDL 19205, novel positive inotropic drugs, in dog heart-lung preparations.
The efficacies of MDL 17043 and MDL 19205 in ameliorating heart failure were assessed in dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. Six preparations were used for each drug. Both drugs in doses of 1-30 mumol similarly improved cardiac function in a dose-dependent manner and at 30 mumol improved it beyond control values. AV conduction impaired by pentobarbital was restored by 30 mumol of the 2 drugs. In these doses, however, neither of the drugs produced a significant increase in heart rate or arrhythmias. These results indicate that the 2 drugs would be of use in the treatment of heart failure.
Animals↗
Abolition of spontaneous rhythmic contractions of isolated monkey coronary arteries by diltiazem, nifedipine, verapamil and nicorandil but not by nitroglycerin.
Three of 12 coronary artery rings obtained from one of 9 rhesus monkeys (Macaca mulatta) (113 rings in all) and 4 of 12 coronary artery rings obtained from one of 2 patas monkeys (Erythrocebus patas patas) (28 rings in all) developed spontaneous rhythmic contractions. In 5 of these 7 coronary artery rings, rhythmic contractions occurred long enough to be subjected to examinations of drug effects. In these preparations the effects of the calcium entry blockers, diltiazem, nifedipine and verapamil, and nicorandil, a nitrate vasodilator thought to produce vasodilatation by an increase in membrane potassium permeability, and nitroglycerin were investigated on rhythmic contractions. Diltiazem (10(-7) and 10(-6) M), nifedipine (10(-8) and 10(-7) M), verapamil (10(-7) and 10(-6) M) and nicorandil (10(-5) and 10(-4) M) suppressed rhythmic contractions in a concentration-dependent manner, but nitroglycerin (10(-7)-10(-5) M) was entirely ineffective. The results were discussed in relation to the mechanisms underlying spontaneous rhythmic contractions of coronary arteries and their role in vasospastic angina pectoris.
Animals↗
Abolition by nicorandil of spontaneous action potentials of the small atrio-ventricular node preparation of the dog.
Effects of carbachol and nicorandil on spontaneous action potentials were examined in the small atrio-ventricular (A-V) node preparation of the dog. Carbachol (3 X 10(-6) M) definitely hyperpolarized the membrane potential and abolished the spontaneous activity. Nicorandil (3 X 10(-4) M) also abolished the spontaneous activity but the membrane potential became quiescent at -65 mV, which was less negative than the maximum diastolic potential. From these results it appears that nicorandil may increase the potassium conductances but not hyperpolarize the membrane potential because the background potassium conductance is little developed in the nodal cells.
Action Potentials↗
Is antagonism by Bay k 8644 of the negative dromotropic effect of nifedipine pharmacological?
The dromotropic effect of Bay k 8644 and its interaction with the negative dromotropic effects of nifedipine, verapamil, MnCl2 and tetrodotoxin were investigated by use of isolated, blood-perfused atrioventricular (AV) node preparations of dogs. These agents were injected into the AV node artery. Single injections of Bay k 8644 (0.1-10 micrograms) shortened AV conduction time, but the decrease remained only about 9 msec at 10 micrograms. This effect was not modified by nadolol. Dose-response curves for the negative dromotropic effect of nifedipine were shifted to the right by about 0.5 log units with infusions of Bay k 8644 into the AV node artery at rates of 3 and 10 micrograms/min. A similar shift of dose-response curves to verapamil occurred at 10 micrograms/min of Bay k 8644. However, Bay k 8644 (3 and 10 micrograms/min) failed to modify dose-response curves to MnCl2 and tetrodotoxin. Bay k 8644 (10 micrograms) produced a greater decrease in AV conduction time during the negative dromotropic effect of verapamil (10 or 30 micrograms) and a far greater decrease during the negative dromotropic effect of nifedipine (3 or 10 micrograms) than under control conditions. In contrast, Bay k 8644 (10 micrograms) produced a decrease in AV conduction time nearly to the same extent during the negative dromotropic effect of MnCl2 (10 or 30 mumol) or tetrodotoxin (10 or 30 micrograms) as under control conditions. From these results Bay k 8644 can be described as a rather specific pharmacological antagonist for dihydropyridine slow channel blockers.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Undifferentiated effects of calcium antagonists on pressor responses to selective alpha-1 and alpha-2 adrenoceptor agonists in anesthetized, spinal dogs.
Whether pressor responses mediated by alpha-2 adrenoceptors are more susceptible to calcium antagonists than those mediated by alpha-1 adrenoceptors was investigated in anesthetized, spinal dogs. All drugs were administered i.v. Methoxamine (3-100 mu/kg) or xylazine (3-300 micrograms/kg) produced a sustained increase in mean arterial pressure but almost no effect on heart rate. Both the initial and the sustained phase of the pressor response to methoxamine were selectively antagonized by prazosin, whereas those to xylazine were selectively antagonized by yohimbine. These results indicate that the peripheral arterial bed of the dog comprises alpha-1 and alpha-2 adrenoceptors and that both the initial and sustained phases of the pressor response to methoxamine are predominantly mediated by alpha-1 adrenoceptors, whereas those to xylazine are mediated by alpha-2 adrenoceptors. The calcium antagonists, i.e., nifedipine (0.3-3 micrograms/kg), diltiazem (10-100 micrograms/kg) and KB-944 (10-100 micrograms/kg), administered during the sustained phase of the pressor responses to equieffective doses of methoxamine (100 micrograms/kg) and xylazine (1000 micrograms/kg), lowered mean arterial pressure. The three calcium antagonists in these doses also lowered the baseline mean arterial pressure but to a lesser extent than the elevated one. These results altogether indicate that the calcium antagonists were more effective in lowering mean arterial pressure elevated by either an alpha-1 or alpha-2 adrenoceptor agonist than the base-line mean arterial pressure and that the sustained phase of the pressor response mediated by alpha-1 adrenoceptors would involve Ca++ influx as much as or more than those mediated by alpha-2 adrenoceptors.
Adrenergic alpha-Agonists↗
Differential effects of sulmazole (AR-L 115 BS) on contractile force and cyclic AMP levels in canine ventricular muscle: comparison with MDL 17,043.
MDL 17,043 [1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one] and AR-L 115 BS [sulmazole, 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b] pyridine] produced substantial positive inotropic effects in a concentration-dependent manner (10(-5) to 10(-3) M) in the isolated canine ventricular trabeculae in the presence of pindolol (3 X 10(-8) M). Both agents exhibited equal potency and intrinsic activity in this preparation. The time to peak tension, relaxation time and total duration of contraction were shortened by MDL 17,043 in a concentration-dependent manner up to the highest concentrations tested (10(-3) M). In contrast, AR-L 115 BS shortened these times in concentrations of 3 X 10(-4) M and lower, but prolonged them in higher concentrations. The positive inotropic effects of MDL 17,043 and AR-L 115 BS were associated with increases in the cyclic AMP levels of the muscles. The time course of the increase in cyclic AMP levels differed for the two drugs. The elevation in cyclic AMP and the positive inotropic effect produced by MDL 17,043 followed a similar time course. By contrast, the rise in the cyclic AMP level became significant only after the positive inotropic effect produced by AR-L 115 BS had reached a steady level. Carbachol, a muscarinic agonist, converted the positive inotropic effect of 10(-3) M MDL 17,043 into a negative inotropic effect, but did not alter the positive inotropic effect of 10(-3) M AR-L 115 BS.(ABSTRACT TRUNCATED AT 250 WORDS)
3',5'-Cyclic-AMP Phosphodiesterases↗
[Study on the method of teaching in clinical nursing training: with special reference to the records of the actions involved in clinical training].
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Education, Nursing↗
Effects of a new calcium entry blocking agent, KB-944, on the membrane potential and currents of mammalian ventricular muscle cells.
KB-944 (10(-5)-10(-4) M) decreased the action potential duration measured at 30% repolarization and hyperpolarized the resting membrane potential in ventricular trabeculae of the dog heart. In single ventricular cells of the guinea-pig heart, KB-944 (10(-4) M) abolished the slow inward current and produced an outward shift of the late current measured at the end of 200 msec clamp pulse. From these results it appears that KB-944 selectively blocks the slow inward current and may increase the background potassium conductance.
Action Potentials↗
Differential effects of Bay k 8644, a presumed calcium channel activator, on sinoatrial nodal and ventricular automaticity of the dog heart.
Bay k 8644 is suggested to increase calcium influx through the voltage-dependent calcium channel. In isolated, blood-perfused sinoatrial node preparations of the dog. Bay k 8644 injected intra-arterially increased sinus rate as isoprenaline did. In isolated, blood-perfused papillary muscle preparations of the dog isoprenaline injected intra-arterially increased both the force of contraction of the papillary muscle and its spontaneous beating rate. In these preparations, however, Bay k 8644 failed to increase the beating rate, although it increased the force of contraction. These results are consistent with the concept that the slow inward current plays a role in sinoatrial nodal automaticity but not in automaticity of Purkinje fibres which was reflected as ventricular automaticity of the papillary muscle preparations used here.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Increase in the slow inward current by intracellularly applied nifedipine and nicardipine in single ventricular cells of the guinea-pig heart.
It has long been discussed why dihydropyridine calcium antagonists are less cardioactive than other calcium antagonists at doses equally effective on vascular smooth muscle [5, 12]. Recently, it has been reported that dihydropyridine calcium antagonists, unlike other calcium antagonists, inhibit adenosine 3',5'-cyclic monophosphate phosphodiesterase in various tissue preparations [2, 8, 10]. It has also been reported that intracellularly applied adenosine 3',5'-cyclic monophosphate increases the slow inward current in heart cells [1, 11, 13]. Therefore, present experiments were carried out to elucidate the effects of intracellularly applied calcium antagonists on the slow inward current of single ventricular cells with the patch-clamp, 'whole-cell recording', technique [3]. Nifedipine, nicardipine and isobutylmethylxanthine, when applied intracellularly using the patch-clamp microelectrode, increased the plateau and the duration of action potentials of single ventricular heart cells of the guinea-pig. The augmentation of the action potential was abolished by superfusing the cell with nifedipine. D600 and diltiazem when applied either intra- or extra-cellularly decreased the plateau and the duration of the action potential. Under voltage clamp conditions, intracellularly applied nifedipine, nicardipine and isobutylmethylxanthine increased the slow inward current, whereas D600 and diltiazem decreased the current. The holding current and the current at the end of 200-ms clamp pulses were not modified. Thus, dihydropyridine calcium antagonists probably increase the slow inward current from the inside of the cell and attenuate the calcium entry blocking activities in heart cells. This must partly be a reason why dihydropyridine calcium antagonists are less cardioactive than D600 and diltiazem at doses equally effective on vascular smooth muscle.
1-Methyl-3-isobutylxanthine↗
Involvement of cyclic AMP in the positive inotropic effect of OPC-8212, a new cardiotonic agent, on the canine ventricular muscle.
OPC-8212 is a new positive inotropic drug which scarcely produces an increase in heart rate and vasodilatation. The positive inotropic effect of OPC-8212 was investigated in relation to cyclic AMP metabolism in canine isolated ventricular muscle. The positive inotropic effect of OPC-8212 was accompanied by accumulation of cyclic AMP in the tissue: the cyclic AMP level was elevated before the increase in force of contraction and elevated in a concentration-dependent manner in the presence of a beta-adrenoceptor antagonist, atenolol (10(-6) M). The OPC-8212-induced increases in force of contraction and cyclic AMP level were abolished by carbachol (3 X 10(-6) M). The relationship between the force of contraction and cyclic AMP level in the presence of OPC-8212 was changed by neither carbachol nor isoproterenol. OPC-8212 enhanced the positive inotropic effect of isoproterenol as cyclic AMP phosphodiesterase inhibitors did. OPC-8212 shortened the time to peak tension and had a tendency to shorten the relaxation time of single contractions. These results altogether suggest that change in cyclic AMP metabolism is involved at least in the positive inotropic effect of OPC-8212 on canine ventricular muscle.
Animals↗