COMPARATIVE STUDY OF THE ACTION OF ANTIARRHYTHMIC DRUGS ON SINOATRIAL NODAL PACEMAKER ACTIVITY AND CONTRACTILITY IN THE ISOLATED BLOOD-PERFUSED ATRIUM OF THE DOG

1. The effects of five antiarrhythmic drugs (quinidine, procainamide, lignocaine, phenytoin and propranolol) were studied on pacemaker activity in the sinoatrial node and on contractility in twenty-three isolated, blood-perfused atrium preparations of dogs. Each drug was administered directly into the cannulated sinus node artery of an isolated atrium over a period of 4 s. 2. Quinidine produced negative chronotropic and inotropic effects. Occasionally, higher doses induced a biphasic inotropic effect, an initial negative phase being followed by an increase in contractility. 3. Three response patterns to procainamide were observed: negative chronotropic and inotropic effects; biphasic effects, initially negative chronotropic and inotropic effects being followed by positive effects; a biphasic inotropic effect and a negative chronotropic effect. The third pattern was most frequently produced by relatively high doses. 4. Lignocaine, phenytoin and propranolol induced dose-related negative chronotropic and inotropic effects. 5. All five of the antiarrhythmic drugs used caused sinus arrest in high doses. 6. Procainamide-induced positive chronotropic and inotropic effects were significantly inhibited by treatment with alprenolol or nadolol, but not by tetrodotoxin or desipramine. 7. These results indicate that procainamide-induced positive chronotropic and inotropic effects may involve an adrenergic mechanism.     

EFFECT OF SECRETIN ON PACEMAKER ACTIVITY AND CONTRACTILITY IN THE ISOLATED BLOOD-PERFUSED ATRIUM OF THE DOG

1. The effects of secretin on inotropic and chronotropic activity were investigated in nine isolated canine atrium preparations which were suspended in a bath and perfused with arterial blood from a carotid artery of a heparinized donor dog. 2. Secretin administered into the cannulated sinus node artery in a dose range of 0.1–10 units produced a dose-related positive inotropic and a biphasic chronotropic effect. 3. The positive chronotropic and inotropic responses to secretin were not suppressed by treatment with alprenolol in doses which blocked responses to noradrenaline. 4. The negative chronotropic response to secretin was not blocked by atropine in doses which blocked the response to acetylcholine. 5. After treatment with glucagon, secretin produced dose-related negative chronotropic and a positive inotropic effects. Thus glucagon may antagonize the positive chronotropic effect of secretin. 6. From these results, it is concluded that secretin has a direct effect on atrial rate and contractility.     

Hemodynamic effects of inosine in combination with positive and negative inotropic drugs: studies on rats in vivo.

Inosine applied as a continuous i.v. infusion of 400 mg/kg/h for 20 min had a negative chronotropic and inotropic effect in closed-chest, anesthetized rats. In the presence of adenosine deaminase (ADA, 133 U/kg/h), the reduction in heart rate was abolished indicating that adenosine is responsible for that effect. However, the negative inotropic effect persisted. It was characterized by a 38 and 56% decrease in left ventricular systolic pressure (LVSP) and diastolic aortic pressure, respectively, a 24% decline in LV dp/dtmax and a 16% fall in cardiac output. Total peripheral resistance was diminished by 38%. Inosine in combination with ADA antagonized the noradrenaline-induced positive inotropic effect and the increase in cardiac output. On the other hand, i.v. bolus injection of noradrenaline in rats pretreated with inosine and ADA did not increase blood pressure and total peripheral resistance. Inosine administered in animals pretreated with the beta-receptor blocker metoprolol or with the calcium antagonist verapamil aggravated the negative inotropic effect. Inosine in combination with ADA caused a decline in cardiac output in metoprolol-pretreated rats that was more pronounced than that induced by inosine alone. However, in rats pretreated with verapamil, inosine did not cause a reduction in cardiac output.     

Biphasic inotropic response to endothelin-1 in the presence of various concentrations of norepinephrine in dog ventricular myocardium

The present study was undertaken to investigate the interaction between endothelin-1 (ET-1) and norepinephrine (NE) on contractile regulation in dog ventricular myocardium. ET-1 alone did not elicit any inotropic response in isolated dog ventricular trabeculae (37 degrees C, 0.5 Hz). In the presence of NE at a high concentration (10(-7) M), ET-1 (10(-8) M) elicited a long-lasting negative inotropic effect, while in the presence of NE at a moderate concentration (3 x 10(-8) M) it produced a biphasic inotropic effect: a sustained positive inotropic effect subsequent to a short-lasting negative inotropic effect. In the presence of a lower concentration (10(-9) M) that affected scarcely the basal force of contraction, ET-1 produced a pronounced positive inotropic effect in association with negative lusitropic and negative clinotropic effects in a concentration-dependent manner subsequent to a small transient negative inotropic effect. The presented results indicate that not only the extent, but also the quality of the inotropic response to ET-1 is determined by the level of NE in the biophase. The crosstalk of ET-1 with NE may play a crucial role in pathophysiological regulation of cardiac contractility in intact dog ventricular myocardium.     

COMPARATIVE STUDY OF CHRONOTROPIC AND INOTROPIC RESPONSES TO 5-(1-HYDROXY-2-ISOPROPYLAMINOBUTYL)-8- HYDROXYCARBOSTYRIL HYDROCHLORIDE HEMIHYDRADE (PROCATEROL), SALBUTAMOL, NORADRENALINE AND ISOPRENALINE IN THE DOG HEART

1. The cardiac chronotropic and inotropic responses to 5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrade (procaterol) and salbutamol have been compared to noradrenaline and isoprenaline in isolated blood-perfused canine atrial and ventricular preparations. 2. All four compounds induced dose-related positive chronotropic and inotropic effects, but different individual response patterns were observed. 3. Procaterol and salbutamol were partial agonists compared to noradrenaline and isoprenaline for causing chronotropic and inotropic responses. The order of efficacy for the adrenoceptors mediating both chronotropic and inotropic responses was isoprenaline, noradrenaline, salbutamol and procaterol. The slopes of the salbutamol dose-response curves were flatter than those for isoprenaline and noradrenaline; the slopes of the procaterol dose-response curves were flatter than those for salbutamol. 4. Because of these differences, the order of activity depended upon the level of response chosen for the comparison. When doses producing small chronotropic and inotropic responses were compared, the order of activity was isoprenaline, noradrenaline, procaterol and salbutamol; whereas with doses producing large responses the order was isoprenaline, noradrenaline, salbutamol and procaterol. 5. Procaterol was longer acting than salbutamol, and salbutamol was longer acting than noradrenaline.     

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.     

Sustained negative inotropism mediated by alpha-adrenoceptors in adult mouse myocardia: developmental conversion from positive response in the neonate.

1. Inotropic responses to alpha-adrenoceptor stimulation and the effects of antagonists were examined in isolated ventricular preparations from neonatal and adult mice. 2. Phenylephrine, in the presence of propranolol, produced positive inotropic responses in neonates up to 1 week after birth, while it produced negative inotropic responses in mice older than 3 weeks. 3. Both positive and negative responses to phenylephrine in neonates and adults, respectively, were antagonized by prazosin, WB4101 (2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane) and 5-methylurapidil, but not by atropine, yohimbine or chlorethylclonidine. 4. Noradrenaline (NA) produced positive inotropic responses both in the neonate and adult; the responses were observed in a lower concentration-range in the neonate than in the adult. WB4101 produced a significant leftward shift of the concentration-response curve for noradrenaline in adult preparations while only a slight rightward shift was observed in the neonate. 5. Our results demonstrate the presence of alpha-adrenoceptor-mediated inotropic responses in the mouse ventricular myocardia. The response to phenylephrine changes from a positive to a negative effect during postnatal development. The responses are mediated by alpha 1-adrenoceptors, and modulate the overall inotropic response to NA in the adult.     

THE CARDIOVASCULAR ACTIONS OF 1-METHYLISOGUANOSINE

1. 1-Methylisoguanosine was found to cause a potent long-lasting decrease in both blood pressure and heart rate after oral administration to conscious hypertensive rats. Dose-response curves to intravenously administered 1-methyliso-guanosine and adenosine in anaesthetized rats demonstrated qualitatively similar decreases in blood pressure and heart rate, with 1-methylisoguanosine being two to three times more potent than adenosine. 2. In guinea-pig isolated atria, 1-methylisoguanosine exhibited a negative inotropic and a negative chronotropic effect with a greater potency than adenosine. 3. In halothane-anaesthetized cats, 1-methylisoguanosine produced a biphasic response on cardiac output: a rapid initial decrease followed by a slow increase. 4. 1-Methylisoguanosine had no effect on the response to intralumenally administered noradrenaline in isolated perfused rat tail arteries but reduced the response to electrical stimulation. In these effects, 1-methylisoguanosine was similar to adenosine.     

Functional studies in atrium overexpressing A1-adenosine receptors

1. Adenosine and the A1-adenosine receptor agonist R-PIA, exerted a negative inotropic effect in isolated, electrically driven left atria of wild-type mice. 2. In left atria of mice overexpressing the A1-adenosine receptor, adenosine and R-PIA exerted a positive inotropic effect. 3. The positive inotropic effect of adenosine and R-PIA in transgenic atria could be blocked by the A1-adenosine receptor antagonist DPCPX. 4. In the presence of isoprenaline, adenosine exerted a negative inotropic effect in wild-type atria but a positive inotropic effect in atria from A1-adenosine receptor overexpressing mice. 5. The rate of beating in right atria was lower in mice overexpressing A1-adenosine receptors compared with wild-type. 6. Adenosine exerted comparable negative chronotropic effects in right atria from both A1-adenosine receptor overexpressing and wild-type mice. 7. A1-adenosine receptor overexpression in the mouse heart can reverse the inotropic but not the chronotropic effects of adenosine, implying different receptor-effector coupling mechanisms.     

Direct chronotropic and inotropic responses to guanosine and five different guanine nucleotides in isolated perfused dog atria.

The effects of guanosine and of five guanine nucleotides on sinus rate and contractile force were investigated using the isolated, blood-perfused dog atrium preparation. Guanosine consistently induced a positive chronotropic and inotropic effect which was not suppressed by treatment with a potent beta-adrenoceptor blocking agent, carteolol. GMP, GDP and CTP induced a biphasic chronotropic and inotropic effect. The potencies for inducing the positive effects of GMP, GDP and GTP were almost the same. However, their rank order of potency for inducing negative effects was GTP greater than or equal to GDP greater than GMP. The negative responses to GTP were not inhibited by atropine. Cyclic GMP and dibutyryl cyclic GMP produced only slight negative chronotropic and inotropic effects but not consistently even at larger doses. The positive chronotropic and inotropic responses to norepinephrine were not modified by treatment with dibutyryl cyclic GMP.     

Mechanism of inhibitory effect of citalopram on isolated guinea-pig atria in relation to adenosine receptor

The effect of citalopram (CTP), a selective serotonin reuptake inhibitor antidepressant was studied on the rate and force of contractions of isolated guinea-pig atria. CTP (2-32 microg/ml) caused a dose-dependent decrease in the contractile force (7%-62%) and in the rate of contractions (11%-72%). These negative inotropic and chronotropic effects of CTP (8 microg/ml) were not prevented by atropine (1 microg/ml) and 3,7 dimethyl-1-propargylxanthine (DMPX; 1.5 microg/ml), an adenosine A(2) receptor antagonist, but 1,3 dipropargyl-8-cyclopentylxanthine (DPCPX; 12 microg/ml), a specific adenosine A(1) receptor antagonist significantly blocked these effects (p < 0.001) and theophylline (30 microg/ml) a non-selective adenosine A(1)/A(2A) receptor antagonist also prevented the inotropic and chronotropic effects of CTP. These results suggest that the negative inotropic and chronotropic effect of CTP on isolated guinea-pig atria is probably mediated through an inhibition of the uptake of adenosine or the A(1) receptor mechanism.     

Increased sensitivity of neonatal mouse myocardia to autonomic transmitters

1 Chronotropic and inotropic responses to noradrenaline and acetylcholine were examined in isolated right atrial and ventricular preparations from neonatal and adult mice. 2 Noradrenaline and acetylcholine produced positive and negative chronotropic responses, respectively, in the atria from both ages. Noradrenaline produced positive inotropic responses in ventricular preparations from both ages. In all cases, the sensitivity, expressed in terms of pD₂ values, was higher in neonatal preparations. 3 In the ventricle, desipramine produced a leftward shift of the concentration–response curve for noradrenaline in the adult, but no such shift was observed in the neonate. The sensitivity to isoprenaline of ventricular preparations was higher in the neonate than in the adult. 4 Our results demonstrated developmental decreases in sensitivities to autonomic transmitters in mouse myocardia. As for the inotropic response to noradrenaline of ventricular muscle, both pre- and postjunctional mechanisms were responsible for the developmental decrease in sensitivity.     

EFFECTS OF QUINIDINE ON BLOOD FLOW RATE AND DEVELOPED TENSION IN BLOOD-PERFUSED CANINE PAPILLARY MUSCLE

1. The effects of quinidine on blood flow rate and developed tension were studied in isolated, blood-perfused papillary muscle preparations of the dog. Drugs were injected into the anterior septal artery. 2. Quinidine caused a dose-related increase in blood flow rate; the mean dose producing a 100% increase in blood flow rate was about 0·3 mg. 3. Quinidine in doses of 0·01–0·1 mg produced a positive inotropic response. With 0·3–1 mg of quinidine the positive inotropic response was preceded by a transient negative inotropic response. With 3 mg there was a monophasic negative inotropic response, the developed tension being reduced by about 40% of control. 4. Propranolol had no statistically significant effects on the responses of the blood flow rate and developed tension caused by quinidine. 5. These results indicate that quinidine has an action on coronary vessels in lower doses than on the myocardium, and that in low doses it has a positive inotropic action rather than the well-known negative inotropic action exerted with higher doses.     

COMPARISON OF INOTROPIC AND CHRONOTROPIC RESPONSES IN RAT ISOLATED ATRIA AND VENTRICLES

1. The positive inotropic and chronotropic responses to adrenoceptor agonists (noradrenaline, phenylephrine), to compounds which increase cAMP by post-adrenoceptor mechanisms (forskolin, theophylline and dibutyryl cAMP) and to calcium chloride were measured in isolated rat atria and papillary muscles from both ventricles. 2. Noradrenaline produced similar maximal inotropic responses to calcium chloride in all tissues. Forskolin gave similar responses to calcium chloride in atrial but not ventricular tissues; the reverse was observed with dibutyryl cAMP. Phenylephrine and theophylline produced significantly smaller inotropic responses than calcium chloride in all tissues, especially in ventricular tissues. 3. Maximal chronotropic responses to noradrenaline, theophylline and dibutyryl cAMP were similar. Forskolin produced significantly greater responses while calcium chloride and phenylephrine produced significantly smaller responses than noradrenaline. 4. These results show that the maximal positive inotropic response of some agonists is markedly dependent on the tissue chosen. Further, chronotropic responses in right atria do not mimic inotropic responses in left atria.     

Positive inotropic effect of bay K 8644: cAMP-independence and lack of inhibitory effect of adenosine

Summary The aim of the present study was to characterize the positive inotropic effect of the Ca²⁺ channel activator Bay K 8644. In isolated guinea-pig papillary muscles we investigated whether adenosine and the R site adenosine receptor agonist (–)-N⁶-phenylisopropyladenosine (PIA) were able to antagonize the positive inotropic effect of Bay K 8644. The effect of Bay K 8644 and adenosine or PIA on myocardial cAMP content was also measured. The influence of adenosine and PIA on the positive inotropic effect of the -adrenoceptor agonist isoprenaline and of the phosphodiesterase inhibitor amrinone was studied for comparison.Adenosine and PIA antagonized the positive inotropic effects of isoprenaline and amrinone in a concentration-dependent manner. In contrast, adenosine or PIA did not affect the positive inotropic effect of Bay K 8644.The positive inotropic effect of Bay K 8644 was not accompanied by a change in the cAMP content of the papillary muscles. Additionally applied adenosine or PIA also failed to affect the cAMP content.It is concluded that an increased myocardial cAMP content is not involved in the positive inotropic effect of Bay K 8644. Moreover, the results support the view that adenosine and PIA only antagonize the positive inotropic effects of drugs known to increase myocardial cAMP content and that an increased myocardial cAMP content is a prerequisite for the manifestation of a negative inotropic effect of the nucleosides in ventricular cardiac muscle.     

Presynaptic inhibitory actions of lignocaine in canine isolated, blood-perfused atrial preparations

1. Cardiac effects of lignocaine on sinoatrial nodal pacemaker activity and atrial contractility were investigated in five canine isolated, blood-perfused right atria that were perfused with heparinized blood from support dogs. The effects of lignocaine on responses to intracardiac nerve stimulation and administered acetylcholine and noradrenaline were also examined. 2. Lignocaine was injected into the support dog intravenously or administered selectively to the sinus node artery of the isolated atrium. At doses that did not produce significant depressor action (0.3, 1.0 and 3.0 mg/kg), lignocaine produced no significant changes in heart rate. A large dose of 10 mg/kg lignocaine caused significant depressor effects and slight bradycardia. Direct administration of lignocaine (0.3, 1.0, 3.0, 10.0 and 30.0 mumol) into the sinus node artery of the isolated atrium consistently caused slight negative chronotropic and rather marked negative inotropic effects. 3. After treatment with a relatively large dose of lignocaine, electrical stimulation-induced negative chronotropic and inotropic responses were significantly inhibited in a dose-related manner, but positive chronotropic and inotropic responses were slightly depressed only at an extremely high dose of lignocaine (10.0 mumol). 4. Noradrenaline-induced positive chronotropic and inotropic effects were not modified by any doses of lignocaine used (0.3, 1.0, 3.0 and 10.0 mumol). Acetylcholine-induced negative chronotropic and inotropic effects were slightly, but significantly, depressed by 10 mumol lignocaine. 5. These results suggest that a relatively large dose of lignocaine has a dominant presynaptic inhibitory action, particularly on the parasympathetic component.     

Positive chronotropic and inotropic effects of angiotensin II in the dog heart

The effects of angiotensin II on sinus rate and atrial contractility were investigated in 17 isolated canine atria and 5 isolated paced ventricular preparations perfused with arterial blood conducted from a heparinized donor dog. When angiotensin II was injected into the cannulated sinus node artery, positive chronotropic responses were dose-dependently produced starting from the 0.01 microgram dose although inotropic responses to angiotensin II were not consistently induced. Angiotensin II produced a similar inotropic response pattern in the paced ventricular preparation. Moreover, when angiotensin II was given into the jugular vein of the donor dog, similar positive chronotropic and inotropic responses were also shown in the isolated atrium. Angiotensin II-induced positive chronotropic and slight inotropic effects were not influenced by treatment with the beta-adrenoceptor blocking agents, propranolol and carteolol, but significantly suppressed by saralasin which has been reported to be a competitive antagonist of angiotensin II. From these results, it is suggested that angiotensin II induced a positive chronotropic and slight positive inotropic effect via angiotensin II receptors in the dog heart.     

Evidence that the positive inotropic effects of the alkylxanthines are not due to adenosine receptor blockade.

We investigated the possibility that the positive inotropic effects of the alkylxanthines are due to adenosine receptor blockade. The potency of 8-phenyltheophylline, theophylline and enprofylline as adenosine antagonists was assessed in vitro, using the guinea-pig isolated atrium, and in vivo, using the anaesthetized dog. The order of potency of the alkylxanthines as antagonists of the negative inotropic response to 2-chloroadenosine in vitro, and of the hypotensive response to adenosine in vivo was 8-phenyltheophylline greater than theophylline greater than enprofylline. The order of potency of the alkylxanthines as positive inotropic and chronotropic agents in the anaesthetized dog was enprofylline greater than theophylline greater than 8-phenyltheophylline. The results of this study indicate that the inotropic effects of the alkylxanthines in the anaesthetized dog are not due to adenosine receptor blockade.     

A Na+/Ca2+ exchanger inhibitor, KB-R7943, caused negative inotropic responses and negative followed by positive chronotropic responses in isolated, blood-perfused dog heart preparations

Effects of a Na+/Ca2+ exchanger inhibitor, KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), on the sinoatrial nodal pacemaker activity, atrial contractility and ventricular contractility were investigated in the isolated and blood-perfused right atrium and left ventricle of the dog. KB-R7943 (0.03- 3 micromol) induced negative inotropic effects and negative followed by positive chronotropic effects in the right atrium and negative inotropic effects in the left ventricle. Neither atropine nor hexamethonium affected the cardiac responses to KB-R7943. Propranolol attenuated the positive chronotropic response to KB-R7943 but imipramine did not. Tetrodotoxin potentiated the positive chronotropic response to KB-R7943 in 6 of 11 isolated atria. When NaCl infusion increased atrial contractile force and atrial rate, KB-R7943-induced negative inotropic and chronotropic responses were attenuated in a dose-dependent manner. CaCl2 infusion potentiated the negative chronotropic response to KB-R7943 but did not affect the inotropic response significantly. On the other hand, ouabain (17 nmol) attenuated the negative inotropic response, but not chronotropic response, to KB-R7943. These results suggest that KB-R7943-induced cardiac effects relate to the Na+ activity, probably mediated through the Na+/Ca2+ exchanger, and the Na+/Ca2+ exchanger modifies the pacemaker activity and myocardial contractility in the dog heart.     

Cardiovascular effects of the toxin(s) of the Australian paralysis tick, Ixodes holocyclus, in the rat.

An extract of toxin(s) from the Australian paralysis tick, Ixodes holocyclus, produced positive inotropic responses in rat left ventricular papillary muscles and positive contractile responses in rat thoracic aortic rings. There was no measurable chronotropic response in rat right atria, but positive inotropic concentrations in papillary muscles produced arrhythmias in right atria. Positive inotropic responses were attenuated by verapamil, but unaffected by metoprolol, cimetidine, pyrilamine, tetrodotoxin and pinacidil. Microelectrode studies on isolated left ventricular papillary muscles demonstrated that the extract prolonged action potential duration at 20, 50 and 90% of repolarisation and delayed ventricular papillary muscle relaxation. Cardiovascular tissues isolated from rats with experimentally induced tick paralysis showed no myocardial damage as identified by histological and ultrastructural examination. The basal rate and force of contraction of isolated cardiac tissues were lower from tick-paralysed than normal rats. Concentration-response curves to dobutamine and calcium chloride were similar between tissues from tick-paralysed and normal rats. Thus, the Australian paralysis tick, I. holocyclus, produces one or more toxins with direct cardiovascular effects which mimic the effects produced by direct blockade of cardiac and vascular K+ channels.