Negative Chrono Research Articles

Time-dependent effects of metoprolol in patients with coronary heart disease and grade II–III angina pectoris

BACKGROUND: This study focused on the topical problem of studying the time-dependent effects of the cardioselective -adrenergic receptor blocking agent metoprolol in patients with coronary heart disease (CHD) and grade IIIII angina pectoris.
 AIM: This study aimed to analyze the effect of metoprolol when used at different times of the day based on the concept of chronopharmacology, which is based on the variability of adrenoreceptor sensitivity depending on the day-night cycle.
 MATERIALS AND METHODS: Acute clinical and pharmacological tests were performed in 20 patients with CHD and grade IIIII angina pectoris to determine the time-dependent effects of metoprolol. All patients underwent a study of the parameters of central and peripheral hemodynamics, as well as electrocardiography and echocardiography. The study results were subjected to statistical analysis.
 RESULTS: Metoprolol at 100 mg at different hours of the day causes a persistent negative chrono- and inotropic, hypotensive effect. The clinical and pharmacological test results registered the listed effects with favorable shifts in the first instance when taking the drug in the morning and midday hours. Circadian rhythms of sensitivity of several indicators of the cardiovascular system to metoprolol have been established.
 CONCLUSIONS: The study results on the time-dependent hemodynamic effects of metoprolol using acute pharmacological tests enabled to establish the presence of a circadian organization of several hemodynamic parameters with an acrophase of sensitivity to metoprolol at 15:00 and 14:00 h.

Myotropic Effects of Cholinergic Muscarinic Agonists and Antagonists in the Beetle Tenebrio molitor L.

In mammals, the cholinergic nervous system plays a crucial role in neuronal regulation of physiological processes. It acts on cells by two types of receptors - nicotinic and muscarinic receptors. Both signal transmission pathways also operate in the central and peripheral cholinergic nervous system of insects. In our pharmacological experiments, we studied the effects of two muscarinic agonists (carbachol, pilocarpine) and two muscarinic antagonists (atropine, scopolamine) on the muscle contractile activity of visceral organs in the beetle, Tenebrio molitor. Both antagonists, when injected to haemolymph at concentration 10-5 M, caused delayed and prolonged cardioinhibitory effects on heart contractility in ortho- and antidromic phases of heart activity in T. molitor pupa what was observed as negative chrono- and inotropic effects. Agonist of muscarinic receptors - carbachol evoked opposite effect and increased contraction rate but only in antidromic phase. Pilocarpine, the second agonist induced weak negative chronotropic effects in the antiand orthodromic phases of heart activity. However, neither agonists had an effect on semi-isolated beetle heart in vitro. Only atropine at the highest tested concentrations slightly decreased the frequency of myocardial contractions. These suggest the regulation of heart activity by muscarinic system indirectly. The tested compounds also affected the contractility of the oviduct and hindgut, but the responses of these organs were varied and depended on the concentration of the applied compounds. These pharmacological experiments suggest the possible modulation of insect visceral muscle contractility by the cholinergic nervous system and indirectly indicate the presence of muscarinic receptor(s) in the visceral organs of the beetle T. molitor.

A key role of TRPC channels in the regulation of electromechanical activity of the developing heart

It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the spontaneous activity of the developing heart. TRPC isoforms were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blotting and co-immunoprecipitation, we report for the first time that TRPC1, 3, 4, 5, 6, and 7 isoforms are expressed at the mRNA and protein levels and that they can form a macromolecular complex with the α1C subunit of the L-type voltage-gated calcium channel (Cav1.2) in atria and ventricle. Using ex vivo electrocardiograms, electrograms of isolated atria and ventricle and ventricular mechanograms, we found that inhibition of TRPC channels by SKF-96365 leads to negative chrono-, dromo-, and inotropic effects, prolongs the QT interval, and provokes first- and second-degree atrioventricular blocks. Pyr3, a specific antagonist of TRPC3, affected essentially atrioventricular conduction. On the other hand, specific blockade of the L-type calcium channel with nifedipine rapidly stopped ventricular contractile activity without affecting rhythmic electrical activity. These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis.

Inhibitory Effects of Tiamulin on Contractile and Electrical Responses in Isolated Thoracic Aorta and Cardiac Muscle of Guinea-pigs

The inhibitory effect of tiamulin, an antibiotic produced by Pleurotus mutilis, on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs was studied. In the thoracic aorta, tiamulin with an IC50 of 9.7 x 10(-6) M inhibited sustained contractions induced by isosmotically added 60 mM KCl. The inhibitory effect of tiamulin on a Ca(2+)-induced contraction in a depolarized muscle was competitively antagonized by raising external Ca2+ concentration. Bay K 8644 (10(-7) M) antagonized tiamulin's inhibition of the Ca(2+)-induced contraction. Tiamulin (2 x 10(-5) M) decreased the elevated cytoplasmic Ca2+ level measured by the fura 2 AM method in the depolarized muscle. In high K(+)-isoprenaline-treated left atria, tiamulin (2 x 10(-5)-2 x 10(-4) M) produced negative inotropic effects. On the other hand in the membrane action potential of papillary muscles, tiamulin (2 x 10(-6)-2 x 10(-4) M) produced decreases in action potential and durations and 2 x 10(-4) M tiamulin depressed the slow response action potential in depolarized muscles. Tiamulin produced prolongations of the PR interval in ECG, negative chrono- and inotropic effects, and an increase in perfusion flow in guinea-pig isolated and perfused hearts. These effects of tiamulin on the aorta or cardiac muscle were similar to those of verapamil and nifedipine. These results suggest that both the inhibitory action of tiamulin on the high K(+)-induced contraction in the aorta and the negative inotropic effect of tiamulin on the cardiac muscle are due to an inhibition of Ca2+ entry through the voltage-dependent Ca2+ channels of cells of both these muscles.

Ventricular but not atrial electro-mechanical delay of the embryonic heart is altered by anoxia-reoxygenation and improved by nitric oxide

Excitation-contraction coupling is modulated by nitric oxide (NO) which otherwise has either beneficial or detrimental effects on myocardial function during hypoxia-reoxygenation. This work aimed at characterizing the variations of electromechanical delay (EMD) induced by anoxia-reoxygenation within the developing heart and determining whether atrial and ventricular EMD are modulated by NO to the same extent. Hearts of 4 or 4.5-day-old chick embryos were excised and submitted in vitro to normoxia (45 min), anoxia (30 min) and reoxygenation (60 min). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout experiment. Anoxia-reoxygenation-induced chrono-, dromo-and inotropic disturbances and changes in EMD in atrium (EMDa) and ventricle (EMDv) were investigated in control hearts and in hearts exposed to 0.1, 1, 10, 50 and 100 microM of DETA-NONOate (a NO donating agent) or to 50 microM of L-NAME (a NOS inhibitor). Under normoxia, heart rate, PR interval, ventricular shortening velocity, EMDa and EMDv were similar in control, L-NAME-treated and DETA-NONOate-treated hearts. Under anoxia, cardiac activity became markedly erratic within less than 10 min in all groups. At the onset of reoxygenation, EMDv was increased by about 300% with respect to the preanoxic value while EMDa did not vary significatively. Compared to control conditions, L-NAME or DETA-NONOate had no influence on the negative chrono-, dromo- and inotropic effects induced by anoxia-reoxygenation. However, L-NAME prolonged EMDv during anoxia and delayed EMDv recovery during reoxygenation while 100 microM DETA-NONOate had the opposite effects. EMDa was neither affected by NOS inhibitor nor NO donor. At the end of reoxygenation, all the investigated parameters returned to their basal values. This work provides evidence that a NO-dependent pathway is involved in regulation of the ventricular excitation-contraction coupling in the anoxic-reoxygenated developing heart.

Temporary pacemakers for non-cardiac surgery

EDITOR: Indications for permanent pacemaker implantation have changed considerably in the last two decades. The American Heart Association (AHA) and the American College of Cardiology (ACC) latest guidelines [1] deny the need for permanent pacemaker implantation in moderate sinus node or conduction disturbances (e.g. asymptomatic sinus bradycardia). Other guidelines provide the indications for electrophysiological examinations, e.g. the presence of Mobitz type I atrioventricular block (AVB) [2]. Furthermore, in some cases the permanent pacemaker implantation is based on pure haemodynamic considerations when an individually programmed permanent pacemaker generator, with a short atrioventricular delay, can improve the quality of life of patients with a failing left ventricle and prolonged PQ time [3]. Frequently, the anaesthetist is the first doctor who examines the patient's electrocardiograph recording and suspects the potential for intraoperative dysrhythmias during the preoperative visit. Some rhythm disturbances have no effect on the everyday life of the patient - nevertheless, they may present a potential danger during surgery and anaesthesia or in the postoperative period [4-6]. Therefore, it is of prime importance to select the patients who need further cardiac examination before surgery. We implemented a diagnostic algorithm for the identification of patients who might produce potentially dangerous rhythm problems during non-cardiac surgical operations (Fig. 1).Figure 1: Diagnostic protocol for the selection of patients for perioperative temporary pacemaker therapy. HR: heart rate; AVB: atrioventricular block.Between January 1997 and April 1999, 14090 elective surgical operations were performed under general or regional anaesthesia in our department. Among them, 104 patients (0.17%) were identified as having either bradycardia (resting heart rate < 50 beats min−1) or intraventricular conduction disturbance (first- or second-degree AVB with QRS complexes >100 ms). Patients were subjected to an atropine test or carotid massage (Fig. 1). Twenty-four patients (23%) met the criteria for the insertion of a temporary pacemaker electrode preoperatively. The distribution of dysrrhythmia diagnoses is shown in Table 1. Forty-nine patients (47%) received atropine premedication (1.0 mg subcutaneously 30 min before operation) to prevent episodes of critical bradycardia (<45 beats min−1) during anaesthesia. The remaining 31 patients (29%) were regarded as low risk and neither temporary pacemaker insertion nor atropine premedication were used and the standard intraoperative monitoring was considered as sufficient. Three other patients who were not subjected to the diagnostic procedure shown in Figure 1 also needed temporary pacemaker treatment: one patient had third-degree AVB and narrow QRS complexes; two had first-degree AVB and a bifascicular block.Table 1: Indications for preoperative temporary pacemaker insertion.The electrodes were inserted through the basilar vein at the antecubital fossa in nine patients and central veins were used (internal jugular or subclavian vein) in 15 cases. Following the AHA/ACC guidelines, permanent pacemakers were implanted in four patients in the postoperative period. The negative chrono- and dromotropic effects of drugs used for the induction and maintenance of general anaesthesia can significantly worsen existing rhythm disturbances. Our protocol has to be applied cautiously since not only the dysrhythmia, but also the type of the operation, as well as patients' concomitant diseases, need to be taken into account [7] (e.g. atropine cannot be administered to glaucoma patients, and operations with severe blood loss or thoraco-abdominal procedures require temporary pacing more frequently). The benefit of our protocol is supported by the fact that patients without permanent pacemakers did not develop any rhythm disturbances that would have needed admission to an intensive care unit. The temporary pacemakers were set to a rate limit of 60 beats min−1 and all of them triggered the myocardium during the surgical intervention. Patients with temporary pacemakers had no complications related to their insertion. We conclude that when using our algorithm, the patients scheduled for non-cardiac surgery can be classified into different risk categories for perioperative heart rhythm complications. Further prospective clinical trials are warranted to examine the false-positive and -negative results of the diagnostic protocol. Cs. Csontos L. Bogar L. Melczer Department of Anaesthesia and Intensive Care; University of Pécs and Heart Institute; Pécs, Hungary

Adenosine infusion inhibits adenosine-induced cardiac actions but enhances acetylcholine-induced actions in isolated dog atria.

Using isolated, blood-perfused canine atrial preparations, adenosine was continuously administered at various infusion rates into the cannulated sinus node artery. Adenosine induced negative chrono- and inotropic effects in an infusion-rate related manner. The inotropic responses to the adenosine infusion apparently faded but the chronotropic responses did not. Effects of a bolus injection of adenosine, acetylcholine (ACh), or norepinephrine and effects of intracardiac autonomic nerve stimulation (ICNS) were examined before and during the adenosine infusion. During the adenosine infusion, adenosine-induced effects were significantly reduced but ACh-induced ones were significantly potentiated, and the norepinephrine-induced effects were slightly depressed. ICNS readily induced negative and positive chrono- and inotropic responses which were blocked by atropine and propranolol. These negative responses were enhanced but positive ones were slightly but insignificantly depressed during the adenosine infusion. From these results, it is concluded that adenosine infusion (1) produces a stable continuous bradycardia but in the developed tension an initial decrease is followed by a gradual recovery response showing the fade phenomenon, (2) causes an acute desensitizing action on a subsequent bolus dose of adenosine, and (3) induces a weak antiadrenergic effect, while enhancing cholinergic effects in isolated canine atria.

The neuroendocrine control of atrial natriuretic peptide release.

In the initial experiments reviewed here, we show that atrial natriuretic peptide (ANP) plays an important inhibitory role in the control of sodium chloride and water intake since injections of ANP into the third ventricle (3V) caused a reduction in dehydration-induced drinking and also the drinking of salt in salt-depleted rats. Attention was then turned to the possible role of the brain ANP neurons in producing natriuresis which had earlier been shown to be caused by stimulations within the anterior ventral third ventricular region (AV3V). Stimulation in this region by carbachol produced natriuresis accompanied by a dramatic increase in plasma ANP concentrations and increased content of the peptide in medial basal hypothalamus (MBH), neurohypophysis (NH) and anterior pituitary gland (AP), without alterations in the content of ANP in lungs or atria. This suggested that the natriuresis resulting from the stimulation is brought about, at least in part, by the release of ANP from the brain. Conversely, there was a dramatic decline in plasma ANP at both 24 and 128 h after AV3V lesions had been placed. In view of the much larger quantities of the peptide stored in the atria, it is probable that the changes in the atrial release of the peptide were the main factors altering plasma ANP, but that there was concomitant alteration in the release of brain ANP as well. Blood volume expansion (BVE) by intraatrial injection of isotonic saline in the rat is a profound stimulus for ANP release. Lesions in the AV3V region, median eminence, or neurohypophysectomy blocked BVE-induced release of ANP indicating the crucial participation of the CNS in the response of ANP and natriuresis. Baroreceptor impulses from the carotid-aortic sinus regions and the kidney are important in the neuroendocrine control of ANP release since deafferentation of these regions lowered basal plasma ANP concentrations and prevented the increase after BVE. The evidence indicates that the ANP release, in response to BVE, is mediated by afferent baroreceptor impulses to the AV3V, which mediates the increased ANP release via activation of the hypothalamic ANP neuronal system. Our recent data support the hypothesis that BVE causes the release of ANP from ANPergic neurons in the hypothalamus that in turn stimulates release of oxytocin from the neurohypophysis. This oxytocin acts to release ANP from the right atrium that has negative chrono- and inotropic effects in the right atrium to reduce cardiac output, thereby reducing effective circulating blood volume. Then, the released ANP circulates to the kidneys and evokes natriuresis to return circulating blood volume to normal. This is further accomplished by reduction in intake of water and salt mediated also by brain ANP.

Oxytocin releases atrial natriuretic peptide from rat atria in vitro that exerts negative inotropic and chronotropic action.

Our previous experiments suggested that natriuresis induced by blood volume expansion, was brought about by oxytocin (OT)-stimulated atrial natriuretic peptide (ANP) release from the right atrium. We hypothesized that the ANP released might exert effects on the atrium itself and therefore carried out in vitro experiments to test this hypothesis. Heart rate and isometric tension were recorded from isolated rat atria mounted in an organ bath. Oxytocin exerted a dose-related, negative chrono- and inotropic effect with a minimal effective concentration (MEC) of 3 microM, 10-fold higher than required for ANP to exert comparable effects. The effects of OT were not blocked by atropine suggesting that they were not mediated via release of acetylcholine. Eight-bromoguanosine 3'-5'-cyclic monophosphate (cGMP) had similar effects to those of OT and ANP, suggesting that the effects of ANP were mediated by cGMP. When isolated ventricles, left or right atria, were incubated in vitro, OT had a dose-related effect to stimulate the release of ANP into the medium only from right atria with a MEC of 0.1 microM. A specific OT antagonist, F792 (1 microM), inhibited basal release of ANP and blocked the stimulatory action of OT on ANP release. The results support the hypothesis that OT, acting on its putative receptors in the right atrium, stimulates the release of ANP which then exerts a negative chrono- and inotropic effect via activation of guanylyl cyclase and release of cGMP. The ability of the oxytocin antagonist to reduce basal release of ANP from atria incubated in vitro supports the hypothesis that these effects could be physiologically significant. We hypothesize that blood volume expansion via baroreceptor input to the brain causes the release of OT which circulates to the heart and stimulates the release of ANP from the right atrium. This ANP then has a negative ino- and chronotropic effect in the atrium and possibly a negative inotropic effect in the right ventricle, left atrium and left ventricle, to produce an acute reduction in cardiac output that, coupled with its peripheral vasodilating actions, causes a rapid reduction in effective circulating blood volume. The ANP released would also act on the kidneys to cause natriuresis and ANP acts within the brain to inhibit water and salt intake leading to a gradual recovery of circulating blood volume to normal.

Acute presynaptic inhibition by doxorubicin of negative chrono- and inotropic responses to parasympathetic nerve stimulation in isolated, blood-perfused dog atrium.

The clinical use of doxorubicin, an anthracycline antineoplastic agent, is limited by its cardiotoxicity. Although several previous reports have shown neurotoxic effects of doxorubicin, there is little information about the acute effects of doxorubicin on the autonomic nerve functions in the heart. Accordingly, to evaluate the effects of doxorubicin on the cardiac responses to autonomic nerve activation, we studied the effects of doxorubicin on the negative chrono- and inotropic responses to intracardiac parasympathetic nerve stimulation and acetylcholine (ACh), and the positive chrono- and inotropic responses to norepinephrine (NE) in the isolated, blood-perfused dog atrium. Doxorubicin (0.01-3 mumol), injected into the sinus node artery of the isolated atrium, induced negative inotropic effects dose dependently and weak negative chronotropic effects. Doxorubicin inhibited the negative chrono- and inotropic responses to parasympathetic nerve stimulation dose dependently. However, doxorubicin affected neither the negative chrono- and inotropic responses to ACh nor the positive chrono- and inotropic responses to NE. These results indicate that doxorubicin interacts with neither muscarinic receptors nor beta-adrenoceptors and suggest that doxorubicin inhibits the negative cardiac responses to parasympathetic nerve activation due to the inhibition of ACh release from nerve varicosities in the heart.

O-286 - Inhibition of glibenclamide on the negative chrono- and inotropic responses to K+ channel openers in isolated, blood-perfused dog heart preparations.

O-286 - Inhibition of glibenclamide on the negative chrono- and inotropic responses to K+ channel openers in isolated, blood-perfused dog heart preparations.

Muscarinic receptor subtypes mediating negative chrono‐ and inotropic responses in isolated, blood‐perfused dog right atria

1. Negative chrono- and inotropic responses to both carbachol (CCh) into the sinus node artery and electrical stimulation of vagal nerve fibres (ES) were studied in the isolated, blood-perfused canine right atrium, using four muscarinic receptor antagonists, atropine, 4-DAMP, AF-DX 116 and pirenzepine. 2. ES and CCh evoked negative chrono- and inotropic responses in a frequency-dependent manner and in a dose-related manner, respectively. 3. Each antagonist inhibited these negative chrono- and inotropic responses in a dose-dependent manner. The ranking order of blocking potency (ID50) was atropine greater than or equal to 4-DAMP greater than AF-DX 116 greater than pirenzepine. 4. The ID50 of atropine, 4-DAMP or AF-DX 116 against sinus rate decreases induced by CCh or ES was not significantly different from that against the atrial tension decreases. In contrast, the ID50 of pirenzepine against sinus rate decreases evoked by CCh (17 nmol) or ES (20 nmol) was significantly smaller than that for the atrial tension decrease (CCh, 200 and ES, 53 nmol, respectively). 5. These results suggest that, in the isolated dog atrium, M2-receptor-mediated-responses are predominant. However, M1-receptor activation may also be involved in sinus rate response.

Pharmacological analysis of cardiac effects of a central cholinergic agent, WEB 1881-FU, in isolated canine heart preparations.

The cardiovascular effects of the novel compound WEB 1881-FU (4-amino-methyl-1-benzyl-pyrrolidine-2-one-fumarate) were investigated using cross-circulated dog atrial preparations. Intravenous injections of WEB 1881 induced a hypotensive effect with slight tachycardia at a large dose in anesthetized dogs. At the same time, it produced slight positive chronotropic and inotropic effects in the isolated atrium perfused with the donor's arterial blood. Direct injections of WEB 1881 into the sinus node artery of the isolated and perfused atrium induced positive chrono- and inotropic effects in a relatively small dose range. At higher doses, it caused biphasic chrono- and inotropic effects, i.e., initial brief negative effects followed by long-lasting positive chrono- and inotropic effects. The negative chrono- and inotropic responses to WEB 1881 were not blocked by atropine in doses which significantly suppressed ACh-induced negative chrono- and inotropic responses. The positive chrono- and inotropic responses to WEB 1881 were significantly inhibited either by a beta-blocker (propranolol) or by an uptake blocker (imipramine). From these results, it is concluded that WEB 1881 has a tyramine-like, catecholamine releasing property. Although a large dose of WEB 1881 has a direct cardiac depressant action, it does not affect muscarinic mechanisms in the heart.

Cardiovascular effects of 2-amino-N-(2,6-dimethylphenyl)-N-(3-(3-pyridyl)propyl)propionamide dihydrochloride(Ro 22-9194) in the isolated, cross-perfused atrium of the dog.

The cardiovascular effects of 2-amino-N-(2,6-dimethylphenyl)-N-[3- (3-pyridyl)propyl]propionamide dihydrochloride (Ro 22-9194) were investigated in the canine isolated atrial preparation perfused with arterial blood from another donor dog. Intravenous administration of Ro 22-9194 (0.3-3 mg/kg) reduced heart rate and systemic arterial blood pressure of the donor dog. Simultaneously, in the isolated atrium perfused with donor's blood, negative chronotropic and inotropic responses were induced in a dose-dependent manner. Direct administration of Ro 22-9194 (1-300 micrograms) into the sinus node artery of the isolated atrium induced negative chrono- and inotropic responses and a transient increase in coronary blood flow in a dose-related manner. Mexiletine (1-300 micrograms) also induced negative chrono- and inotropic responses. The potency of Ro 22-9194 for negative cardiac effects was similar to that of mexiletine. The negative cardiac effects of Ro 22-9194 were not modified by atropine in doses which significantly inhibited the cardiac effects of acetylcholine. Ro 22-9194 did not affect the cardiac responses to norepinephrine and to acetylcholine significantly. These results suggest that Ro 22-9194 has non-cholinergic cardiac depressant properties with its vasodilating action, and it has neither anti-adrenergic nor anti-cholinergic actions on the dog heart.

Comparative Effects of Arotinolol, Labetalol and Propranolol on Regional Myocardial Dysfunction Induced by Flow-Limiting Coronary Stenosis in Anesthetized Dogs

Effects of arotinolol, a combined alpha- and beta-adrenoceptor blocking agent, on regional myocardial dysfunction produced by severe coronary stenosis in anesthetized dogs were examined and compared with those of labetalol and propranolol. Doses of these three antagonists were selected to produce a comparable degree of the negative chrono- and inotropic effect but a different potency of alpha-adrenoceptor blockade (labetalol>arotinolol). Regional myocardial function measured as segment shortening (%SS) was decreased to around 2-3% by constriction of the left circumflex coronary artery (LCX), and then drug or saline was administered i.v. The stenosis of LCX was released 30 min after the administration. No significant alteration in hemodynamic and contractility parameters was seen as compared to the predrug value up to at least 30 min after saline i.v. Arotinolol and propranolol both reduced heart rate and peak positive left ventricular dP/dt (LVdP/dt) without a significant change in LCX flow. Concomitantly, %SS distal to a coronary stenosis was significantly improved by arotinolol and propranolol. On the other hand, labetalol significantly reduced LCX flow probably due to systemic hypotension and failed to improve %SS in the ischemic area, although the agent markedly decreased heart rate and LVdP/dt. These results indicate that arotinolol improves impaired regional myocardial function distal to a coronary stenosis in a similar manner with propranolol.

Ionic basis of depressed automaticity and conduction by acetylcholine in rabbit AV node.

To investigate the ionic mechanisms underlying the negative chrono- and dromotropic effects of acetylcholine (ACh) on the atrioventricular (AV) node, experiments were carried out in rabbit AV node preparations with the use of double-microelectrode techniques. In current-clamp experiments (n = 6), 10(-6) M ACh hyperpolarized the resting membrane from -42.3 to -58.2 mV, decreased the specific membrane resistance from 2.54 to 1.27 k omega.cm2, decreased the space constant from 556 to 384 microns, and reduced the membrane time constant from 23.0 to 12.4 ms. Under voltage-clamp conditions, 10(-6) M ACh decreased the slow inward current by 11% and activated an ACh-sensitive outward K+ current (IACh). IACh possessed an inward rectifying property and exhibited a relaxation phenomenon with a time constant of 60-100 ms at a membrane potential of 0 to -80 mV. Its reversal potential varied with a slope factor of 56 mV per 10-fold increase in external K+ concentration. These results suggest that 1) IACh is selective for K+, 2) IACh inhibits phase 4 and phase 0 depolarizations and reduces the space constant for electronic current spread in the AV node, and 3) the negative chrono- and dromotropic actions caused by IACh may be augmented by the ACh-induced reduction in the slow inward current.

Chronotropic, dromotropic and inotropic effects of dilazep in the intact dog heart and isolated atrial preparation.

When dilazep was administered intravenously to the anesthetized donor dog, mean systemic blood pressure was dose dependently decreased. At a dose of 0.1 mg/Kg i.v., the mean blood pressure was not changed but a slight decrease in heart rate was usually observed in the donor dog. At the same time, a slight but significant decrease in atrial rate and developed tension of the isolated atrium was induced. Within a dose range of 0.3 to 1 mg/Kg i.v., dilazep caused a dose related decrease in mean blood pressure, bradycardia in the donor dog, and negative chronotropic, dromotropic and inotropic effects in the isolated atrium. At larger doses of 3 and 10 mg/Kg i.v., dilazep caused marked hypotension, frequently with severe sinus bradycardia or sinus arrest, especially in isolated atria. When dilazep was infused intraarterially at a rate of 0.2-1 micrograms/min into the cannulated sinus node artery of the isolated atrium, negative chrono- and inotropic effects were dose dependently induced. With respect to dromotropism, SA conduction time (SACT) was prolonged at infusion rates of 0.2 and 0.4 micrograms/min. But at 1 microgram, dilazep caused an increase or decrease of SACT, indicating a shift of the SA nodal pacemaker. It is concluded that dilazep has direct negative chrono-, dromo- and inotropic properties on the heart at doses which produced no significant hypotension.

Effects of four antiarrhythmic drugs on sino-atrial conduction time in isolated, blood-perfused dog atria

We examined effects of four antiarrhythmic drugs (quinidine, disopyramide, procainamide and propranolol) on sinus cycle length (SCL), sino-atrial conduction time (SACT) measured by a constant atrial pacing technique, and developed tension (DT), using isolated dog atrial preparations perfused with blood from anesthetized donor dogs. Control SCL and SACT were 600-700 msec and 60-70 msec, respectively. When quinidine, disopyramide and procainamide were continuously infused into the sinus node artery at rates of 10-40 ug/min and propranolol was infused at a rate of 1-4 pg/min, all 4 agents prolonged SCL and SACT and reduced DT dose-dependently. At higher doses quinidine and disopyramide tended to prolong SACT more than procainamide and propranolol. When 2 mg/kg of quinidine, disopyramide and procainamide and 0.2 mg/kg of propranolol were given i.v. to the donor dog, all the drugs except procainamide prolonged SCL, but only propranolol lengthened SACT in the isolated atrium. Our results indicate that these four antiarrhythmics cause a dose-related increase on SCL and SACT and decrease in DT, and propranolol is 10 times as potent as the other agents in negative chrono-, dromo- and inotropisms.

EFFECTS OF THE ADRENERGIC DRUGS ON THE CHRONO- AND INOTROPIC RESPONSES TO THE CHOLINERGIC STIMULATION OF THE ISOLATED GUINEA-PIG’S ATRIA

Hukovic (1) was the first to suggest the existence of the cholinergic fibers in the sympathetic nerve of the rabbit's atria. He showed that stimulation of the sympathetic nerve in the isolated reserpinized heart produced the negative chrono and inotropic effects which were potentiated by eserine and abolished by atropine. A series of experiments in this laboratory (2-5) have excluded an essential role of the heart catecholamine on initiation and maintenance of the spontaneous contraction and action potential of the rabbit's atria. Recently, Misu (6, 7) and Misu and Takaori (8) in this laboratory have demonstrated that the atrial action potentials abolished by the concentration of 10-5 of dibenarnine, chlorpromazine and yohimbine, are restarted by adrenaline as well as by acetylcholine, and that noradrenaline mainly shortens the repolarization phase of the potential, while acetylcholine serves to restore the depolarization phase. This suggests a modulating role of the endogenous noradrenaline in the rhythmic contraction or action potential of the heart, and led us to study the effects of catecholamine-relating drugs on the atrial responses to cholinergic stimulation.