ZATEBRADINE ATTENUATES CYCLIC AMP-RELATED POSITIVE CHRONOTROPIC BUT NOT INOTROPIC RESPONSES IN ISOLATED, PERFUSED RIGHT ATRIA OF THE DOG

1. Inhibition of I_f or I_ca by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03–1 μmol) decreased sinus rate from 104 ± 4.5 to 73 ± 4.9 beats/min dose-dependently, it selectively attenuated the positive chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10–0.18 μmol) for the chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of I_f but not I_ca in the dog heart.     

THE INOTROPIC AND CHRONOTROPIC EFFECTS OF PHYSOSTIGMINE AND NEOSTIGMINE ON GUINEA-PIG ISOLATED ATRIA

• 1 Physostigmine (0.1-1 mM) induced dose-dependent negative and neostigmine (0.1–1 mM) positive inotropic effects on driven guinea-pig isolated atria. Physostigmine decreased and neostigmine increased cardiac frequency of spontaneously beating atria.
• 2 The depression of amplitude of contraction by physostigmine cannot be attributed to its inhibitory effect on tissue cholinesterase. The negative inotropic action of physostigmine is not influenced by preincubation with atropine.
• 3 The positive inotropic effect of neostigmine is not caused by a nicotine-like action of the drug. Neostigmine (1 mM) counteracts the negative inotropic effect of acetylcholine. The possible mechanisms of action are discussed.

     

PERFUSION PRESSURE AND TRANSMURAL FLOW DISTRIBUTION IN THE LEFT VENTRICLES OF ISOLATED RAT HEARTS

1. The influence of perfusion pressure on flow distribution in the left ventricular wall was investigated with a newly developed microsphere method in Langendorff preparations of the rat heart. 2. Microspheres with a diameter of 10 μm stained with the fluorescent dye yellow-green were infused into the perfusion medium. The hearts were then relaxed with a calcium-chelator, fixed with formaldehyde and cut transversally with a freezing microtome. Photographs were taken of the 52 μm slices with a fluorescence photomacroscope. The ventricular wall was subdivided into four zones, evaluated planimetrically and the beads were counted for calculation of microsphere density. 3. Perfusion of groups of hearts, paced at 5 Hz, with Tyrode's solution at pressures of 30, 50, 80 or 120 cmH₂O for 30 min revealed an increase of left ventricular pressure amplitude, coronary flow, myocardial oxygen consumption and flow redistribution towards the endocardium of the left ventricular wall with increasing perfusion pressure. 4. The quotient of the sphere densities in the inner endocardium over that in the outer epicardium, however, was already maximal at a pressure of 80 cmH₂O and amounted to 1.59 ± 0.15. This quotient was only 0.52 ± 0.11 at a perfusion pressure of 30 cmH₂O, thus indicating massive change in flow distribution upon hypoperfusion. 5. These results indicate that transmural left ventricular flow redistribution in response to hypoperfusion in the isolated rat heart is similar to that in hearts of much larger species.     

POSITIVE INOTROPIC AND VASOCONSTRICTOR RESPONSES TO 14β-AMINOPREGNANE DERIVATIVES IN ISOLATED TISSUES FROM THE GUINEA-PIG

1. The objective of this study was to compare the positive inotropic and vasoconstrictor responses in guinea-pig isolated tissues of the aminosteroid derivatives LND 623 and LND 796 and the cardiac glycoside ouabain. 2. Ouabain (-log EC50, 6.66 +/- 0.04, n = 11) was more potent as a positive inotropic agent on guinea-pig right ventricular papillary muscles than either LND 623 (-log EC50, 6.26 +/- 0.08, n = 6) or LND 796 (-log EC50 5.66 +/- 0.05, n = 7). All compounds gave similar maximal increases in force of contraction. However, the ratio of the maximally effective concentration to the concentration giving 25% of the maximal response was approximately doubled for the aminosteroids compared with ouabain. 3. Ouabain (-log EC50 6.27), LND 623 (-log EC50 6.24) and LND 796 (-log EC50 5.43) produced slowly developing contractions of guinea-pig thoracic aortic rings. 4. These results indicate that, while the aminopregnane derivatives and ouabain produce qualitatively similar results, the therapeutic range for the positive inotropic responses is greater for the aminosteroids.     

ENDOTHELIN STIMULATES INOSITOL PHOSPHATE ACCUMULATION IN RAT RIGHT AND LEFT ATRIA: A COMPARISON WITH NORADRENALINE

1. The effect of endothelin on phosphatidylinositol turnover in rat atria was investigated by measuring the generation of inositol phosphates following [3H]-inositol labelling. 2. In the presence of 10 mmol/L LiCl, endothelin caused dose-dependent increases in the accumulation of inositol mono, bis and trisphosphates which were maximal at 10(-6) mol/L endothelin. The dose-response relationship was similar in right and left atria, but right atria showed a higher maximal inositol phosphate response. 3. Endothelin produced a rapid and transient stimulation of inositol trisphosphate accumulation, which peaked at 15 s followed by a slower increase which continued linearly past 20 min. 4. The time course of inositol trisphosphate release under noradrenaline stimulation showed a similar profile but the maximum stimulation was smaller than endothelin. 5. As with endothelin, responses to noradrenaline also were higher in right atria compared with left atria. 6. These data demonstrate that endothelin receptors in rat atria are coupled to the stimulation of the phosphatidylinositol turnover pathway in an essentially similar manner to alpha 1-adrenoceptors. The phosphatidylinositol pathway may be important in mediating the reported cardiac actions of endothelin.     

PREJUNCTIONAL ACTIONS OF TACRINE ON AUTONOMIC NEUROEFFECTOR TRANSMISSION IN RABBIT ISOLATED PULMONARY ARTERY AND RAT ISOLATED ATRIA

1. This study investigated the effects of tacrine (1,2,3,4-tetrahydro-9-aminoacridine) on the resting and stimulation-induced (SI) release of radioactive substances from isolated preparations of rat atria and rabbit pulmonary artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline, and from rat atrial preparations in which cholinergic transmitter stores had been labelled with [3H]-acetylcholine. In addition, the effect of tacrine on the uptake of [3H]-noradrenaline by noradrenergic nerves in rat atria was determined. 2. Tacrine produced concentration-dependent increases in the resting efflux of radioactivity from both the [3H]-noradrenaline-loaded artery and atrial preparations. Blockade of neuronal amine transport with desipramine reduced the release of radioactivity evoked by tacrine from atria but not that evoked from artery preparations. Inhibition of monoamine oxidase by pargyline pretreatment markedly reduced the tacrine-evoked release of radioactivity in both atrial and artery preparations. 3. The radioactivity released from [3H]-noradrenaline-labelled rat atrial preparations by 30 mumol/L tacrine consisted entirely of the deaminated metabolite [3H]-DOPEG. The evoked release of [3H]-DOPEG from atria was reduced by approximately 50% by desipramine (1 mumol/L). When atrial monoamine oxidase had been inhibited by pargyline treatment in vivo and in vitro, 30 mumol/L tacrine evoked the release of [3H]-noradrenaline instead of [3H]-DOPEG. However, the amounts of [3H]-noradrenaline released by tacrine when monoamine oxidase was inhibited were only about 25% of the amounts of [3H]-DOPEG released in untreated atria. 4. Tacrine, in concentrations of 1 and 10 mumol/L, enhanced the release of radioactivity evoked by field stimulation of [3H]-noradrenaline-loaded rabbit pulmonary artery preparations. This effect was unaltered by desipramine or pretreatment with pargyline. However, in artery preparations pretreated with pargyline, a high concentration of tacrine (100 mumol/L) markedly reduced SI efflux. In contrast to the findings with artery preparations, tacrine (1-30 mumol/L) did not alter SI efflux in rat atrial preparations. 5. It is concluded that tacrine displaces noradrenaline from intraneuronal transmitter stores of sympathetically-innervated tissues, and that the displaced amine is totally metabolized by monoamine oxidase before leaving the nerve terminals. When deamination of neuronal cytoplasmic noradrenaline is prevented, only a portion of the noradrenaline displaced from storage vesicles passes to the extracellular space. It is likely that the transfer of cytoplasmic noradrenaline out of the terminals is limited by the activity of the amine transport mechanism.     

硫酸锌对豚鼠心房肌的负性变力作用

硫酸锌(0.1mmol/L)明显抑制豚鼠心房肌收缩性,呈时间依赖性,抑制肾上腺素诱发的自律性,延长功能性不应期。硫酸锌(0.2mmol/L)对左心房能显著抑制频率递增引起的正阶梯现象,明显抑制静息后增强效应。并能非竞争性右移CaCl_2量效曲线,使最大反应压低。结果表明,硫酸锌妨碍豚鼠心房肌钙离子的转运过程。     

间硝苯吡啶与硝苯吡啶对离体心脏、血管钙拮抗作用的比较性研究

M-Nif对离体豚鼠左心房的钙拮抗作用PD₂′=7.05较Nif PD₂′=7.19弱,抑制心肌的IC₅₀=7.5×10^-8M亦较Nif IC₅₀=2.9×10^-6M弱2.6倍。在离体猪冠脉条实验中M-Nif PD₂′=7.06,Nif PD₂′=6.88,前者稍强,前者抑制血管的作用IC₅₀=6.166×10^-7M亦强于后者IC₅₀=7.02×10^-7M 114倍,Nif扩张血管作用较抑制心肌作用强10倍,提示M-Nif扩张血管与抑制心肌的宽度更大,对治疗心力衰竭、降压将更有利。     

间硝苯吡啶与硝苯吡啶对离体心脏、血管钙拮抗作用的比较性研究

M-Nif对离体豚鼠左心房的钙拮抗作用PD_2~′=7.05较Nif PD_2~′=7.19弱,抑制心肌的IC_(50)=7.5×10~(-8)M亦较Nif IC_(50)=2.9×10~(-6)M弱2.6倍。在离体猪冠脉条实验中M-Nif PD_2~′=7.06,Nif PD_2~′=6.88,前者稍强,前者抑制血管的作用IC_(50)=6.166×10~(-7)M亦强于后者IC_(50)=7.02×10~(-7)M 114倍,Nif扩张血管作用较抑制心肌作用强10倍,提示M-Nif扩张血管与抑制心肌的宽度更大,对治疗心力衰竭、降压将更有利。     

EFFECTS OF ALDOSE REDUCTASE INHIBITION WITH EPALRESTAT ON DIABETES-INDUCED CHANGES IN RAT ISOLATED ATRIA

1. Isoprenaline and cardiac responsiveness of isolated atria from 2 and 6 week streptozotocindiabetic rats, and their age-matched controls, was examined. The effects of chronic administration of epalrestat (40 mg/kg orally, by gavage) on diabetes-induced changes were also investigated. 2. Spontaneously beating atria, bathed in either normal or high glucose (30 mmol/ L) Krebs’ solution, from both 2 and 6 week diabetic rats beat more slowly and with greater force than atria from control rats. These changes in basal parameters were normalized by 2 weeks of insulin (5 U/day s.c.) treatment but not by 2 or 6 weeks of chronic treatment with epalrestat. 3. Isoprenaline (0.1 nmol-0.1 μmol/L) produced concentration-dependent increases in inotropy and chronotropy in atria from both control and diabetic rats. 4. Atria from 2 week diabetic rats displayed decreased sensitivity to the positive inotropic effects of isoprenaline. This change was normalized by chronic insulin treatment but not by chronic epalrestat treatment. 5. Atria from 6 week diabetic rats displayed increased sensitivity to the positive chronotropic effects of isoprenaline which was normalized by epalrestat. 6. These results suggest that changes observed in atria from 2 week diabetic rats may be due to hyperglycaemia per se whereas in atria from 6 week diabetic rats abnormal activity of the polyol pathway may be a contributing factor.     

COMPARATIVE STUDY OF CHRONOTROPIC AND INOTROPIC EFFECTS OF DOPAMINE AND SEVEN DERIVATIVES ON THE ISOLATED, BLOOD-PERFUSED DOG ATRIUM

1. The effects of seven dopamine amino acid conjugated derivatives were compared with those of dopamine on sinus rate and contractile force using the isolated, blood-perfused dog atrium preparation. 2. Each of these dopamine derivatives induced dose-related positive chronotropic and inotropic effects. 3. The positive chronotropic and inotropic effects were obtained with the same rank order of potency for each effect with six of the dopamine derivatives. Their rank order and relative potency (dopamine = 1000) were: N-Ileu-dopamine (3) greater than N-Glu-Pro-dopamine (1) = N-Ala-Glu-dopamine (1) greater than N-Gly-Gly-dopamine (0.3) = N-gamma-Glu-dopamine (0.3) greater than N-Gly-Gly-Leu-dopamine (0.1) greater than N-Gly-Gly-Pro-dopamine (0.01). 4. In doses producing equal positive inotropic effects, the positive chronotropic effect of N-Gly-Gly-Leu-dopamine was much less than with the other derivatives tested. Its potency compared to dopamine (= 1000) was 0.3 for the inotropic and 0.1 for the chronotropic effect. 5. The duration of action of doses of the derivatives producing approximately equal positive inotropic responses was in the order N-Ileu-dopamine = N-gamma-Glu-dopamine = N-Gly-Pro-dopamine = N-Ala-Glu-dopamine greater than N-Gly-Gly-dopamine = N-Gly-Gly-Leu-dopamine = N-Gly-Gly-Pro-dopamine greater than dopamine.     

吡喹酮及其对映异构体对离体大鼠心房肌生理特性的影响

吡喹酮(praziquantel,PQT)对心肌生理特性的影响有立体选择性。(-)-PQT对离体大鼠左心房的正性肌力作用的效能和强度均比(+)-PQT和(±)-PQT小。用维拉帕米可明显减弱PQT及其对映异构体的正性肌力作用。在浓度为100μmol/1时,PQT及其对映异构体对离体大鼠右心房均有负性频率作用,而当30μmol/1时仅(+)-PQT对频率有明显影响。它们尚可诱发右心房心律失常,其发生率以(+)-PQT最高,(-)-PQT最低,(±)-PQT居中。(+)-和(±)-PQT可明显缩短左房不应期。(+)-PQT还可明显降低左房自律性,而(-)-PQT对不应期,自律性均无影响。     

CARDIOVASCULAR ACTIVITY OF 14-DEOXY-11, 12-DIDEHYDROANDROGRAPHOLIDE IN THE ANAESTHETISED RAT AND ISOLATED RIGHT ATRIA

The cardiovascular activity of 14-deoxy-11,12-didehydroandrographolide (DDA) fromAndrographis paniculata(Burm.f.) Nees (Acanthaceae) was elucidated in anaesthetised Sprague–Dawley (SD) rats and isolated rat right atria. In anaesthetised rats, DDA produced significant falls in mean arterial blood pressure (MAP) and heart rate in a dose-dependent manner with the maximum decrease of 37.6±2.6% and 18.1±4.8%, respectively. The ED₅₀value for MAP was 3.43 mmol kg⁻¹. Pharmacological antagonist studies were done using this dose. The hypotensive action of DDA was not mediated through effects on the α-adrenoceptor, muscarinic cholinergic and histaminergic receptors, for it was not affected by phentolamine, atropine as well as pyrilamine and cimetidine. However, it seems to work via adrenoceptors, autonomic ganglia receptor and angiotensin-converting enzyme, since the hypotensive effect of DDA was negated or attenuated in the presence of propranolol, hexamethonium and captopril. In the isolated right atria, DDA caused negative chronotropic action and antagonised isoproterenol-induced positive chronotropic actions in a non-competitive and dose-dependent manner. These results further supported the bradycardia-inducing and β-adrenoceptor antagonistic properties of DDAin vivo.     

NALOXONE ATTENUATES AUGMENTATION OF cAMP LEVELS AND ARRHYTHMIAS FOLLOWING MYOCARDIAL ISCHAEMIA AND REPERFUSION IN THE ISOLATED PERFUSED RAT HEART

The effects of myocardial ischaemia and reperfusion on arrhythmias and cAMP levels were studied using the Langendoff isolated perfused rat heart preparation. Myocardial ischaemia and reperfusion caused arrhythmias and augmentation of cAMP levels concurrently, supporting the suggestion that myocardial cAMP is related to arrhythmias. Pretreatment with naloxone attenuated both arrhythmias and augmentation of cAMP levels to a similar extent. The results suggest that the anti-arrhythmic effect of naloxone may involve myocardial cAMP.     

POTENTIATION OF THE NEGATIVE CHRONOTROPIC AND INOTROPIC EFFECTS OF ADENOSINE BY 2-PHENYLAMINOADENOSINE

1. Effects of 2-phenylaminoadenosine on SA nodal pacemaker activity and atrial contractility were studied, using eleven isolated, blood-perfused dog atrial preparations. The compounds were administered via the cannulated sinus node artery of the isolated atrium. 2. 2-Phenylaminoadenosine induced negative chronotropic and inotropic effects and was 100 times less potent than adenosine in this action. 3. The interaction between adenosine and 2-phenylaminoadenosine was studied. 2-Phenylaminoadenosine potentiated the effect of adenosine on atrial muscle, but not that of acetylcholine.     

EFFECTS OF RESERPINE TREATMENT ON ARRHYTHMOGENESIS DURING ISCHAEMIA AND REPERFUSION IN THE ISOLATED RAT HEART

1. The effects of reserpine treatment on the myocardial contents of catecholamines and enkephalins and the incidence of ventricular arrhythmias during ischaemia and reperfusion in the isolated rat heart were studied. 2. Reserpine treatment almost completely depleted the heart of noradrenaline (NA). It also significantly depleted the heart of adrenaline and dopamines. It did not, however, alter the myocardial contents of enkephalins. 3. Reserpine-treatment attenuated significantly, but did not abolish, cardiac arrhythmias induced by ischaemia and reperfusion in the isolated heart preparation. 4. The results of the present study indicate that myocardial catecholamines especially NA are a contributing factor to arrhythmogenesis during ischaemia and reperfusion.     

INVOLVEMENT OF α1-ADRENOCEPTORS IN CHRONOTROPIC RESPONSES TO ENDOGENOUSLY RELEASED AMINES IN THE PITHED RAT

1. In pithed rats, yohimbine (1 mg/kg i.v.) enhanced the positive chronotropic responses to spinal stimulation of cardiac sympathetic nerves with eight pulses delivered at 2 or 4 Hz, indicating that auto-inhibition was operating, but did not increase responses to shorter lengths of trains of 8 pulses at 8, 16 or 32 Hz which did not allow sufficient time for auto-inhibition to come into effect. 2. The positive chronotropic response to cardiac sympathetic nerve stimulation with eight pulses at 8 Hz of about 60 beats/min was not affected by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg), but was reduced to about 20% of the control value by propranolol (1 mg/kg). 3. In the presence of propranolol, the residual positive chronotropic responses to cardiac sympathetic nerve stimulation were virtually abolished by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg). 4. The positive chronotropic response to tyramine (0.1 mg/kg i.v.) was reduced from 100 to 12 beats/min by propranolol (1 mg/kg), and the residual response was abolished by prazosin. 5. The findings indicate that noradrenaline released from cardiac sympathetic terminals by nerve stimulation or by tyramine acts on alpha 1-adrenoceptors to produce a positive chronotropic response that is revealed when beta-adrenoceptors are blocked.     

ADRENORECEPTOR-MEDIATED RESPONSES IN THE ISOLATED PORTAL VEIN OF THE HYPOTHYROID RAT

1 The effect of hypothyroidism, induced by methimazole, upon the respone of the isolated portal vein of the rat to adrenoreceptor agonists and antagonists, to angiotensin II and to papaverine has been investigated. 2 The positions and maxima of log dose-response curves, to the vasoconstrictor agonists, noradrenaline and angiotensin II, and to the vasodilator agonists isoprenaline and papaverine, were unaffected by methimazole treatment. 3 The α-adrenoreceptor antagonist phentolamine competitively inhibited the effects of noradrenaline to a similar extent in preparations from control and hypothyroid animals. The competitive antagonism of isoprenaline by the β-adrenoreceptor antagonist propranolol was similarly unaffected by hypothyroidism. 4 These results taken together indicate that hypothyroidism is without significant effect upon either the properties of postjunctional α- β-adrenoreceptors in the rat portal vein, or upon the reactivity of this blood vessel to the vasoactive agonists studied.