Positive Chronotropy Research Articles

Physiological and pharmacological investigation of the nonvascularized marine teleost heart with adrenergic and cholinergic agents

Teleost hearts can be classified as either vascularized (coronaries) or nonvascularized, based on the arrangement of the ventricular myocardium. Anatomical investigation of the buffalo sculpin (Enophrys bison) heart has revealed that it lacks coronary circulation. To see if Starling's law was applicable in the nonvascularized teleost heart and to characterize the heart as to the type of adrenergic receptors present, isolated sculpin hearts were attached by the sinus venosus to a modified Langendorff perfusion apparatus. A pressure transducer was placed in series between the bulbus arteriosus and a vertical 15-cm length of glass tubing so that the heart was forced to work against a pressure head of 15 cm H2O (1.5 kPa). Heart rate, pressure, and cardiac output were monitored. As atrial perfusion pressure was increased, the sculpin heart responded with a positive inotropy and an increase in cardiac output. Heart rate did not change. Epinephrine caused an increase in heart rate and a lowered stroke volume. Acetylcholine resulted in negative chronotropy and elevated stroke volume. The data indicate that the contractility increases with elevated filling pressure, demonstrating Starling's law. Isoproterenol administration resulted in positive chronotropy which could be blocked by propranolol. Methoxamine was without effect. The buffalo sculpin heart appears to be under the control of beta adrenergic receptors.

Pharmacological studies of ganglionic transmission: Antagonism by histamine and imidazole-4-acetic acid against the stimulant effect of angiotensin II on cardiac sympathetic agnglia in dogs

Histamine (HA), imidazole-4-acetic acid (IAA) and angiotensin II (AT II) were administered to the cardiac sympathetic ganglia through the right subclavian artery (i.a.) in spinal dogs. IAA, a metabolite of HA, at a dose of 500 ug, induced a marked inhibition of the rate increase produced by 1 and 2 μg AT II, 10 and 20 μg bethanechol (BCH), and 5 and 10 μg dimethylphenylpiperazinium (DMPP). This inhibition was strongly antagonized by i.a. injection of Picrotoxin, 5 mg, and partly inhibited by the’ same dose of bicuculline. Single i.a. injection of HA did not inhibit the positive chronotropism induced by these three ganglionic stimulants, but three repeated i.a. injections of 50 or 100 ug HA, at the interval of 5 min rendered the ganglion insensitive to the same dose of HA and also inhibited the positive chronotropism produced by AT II and BCH, but not by DMPP. The inhibition by the repeated HA administration of the AT II and BCH-induced rate increase was not antagonized by i.a. injection of Picrotoxin or i.v. injection of 10 mg/kg aminoguanidi ne, an inhibitor of histaminase and monoamine oxidase. The results suggest that IAA counteracts ganglionic stimulant effects of AT II, BCH and DMPP by acting on γ-aminobutyric acid (GABA) receptors located at the ganglia as similarly does GABA, whereas the repeated administration of HA inhibits the ganglionic stimulant effects of AT II and BCH through mechanisms other than the GABA-ergic one which is mediated via endogenous IAA formed by exogenous HA.

Enkephalins modulate the responsiveness of rat atria in vitro to norepinephrine

Potential interactions between opiate peptides and catecholamines in mammalian heart were examined using isolated spontaneously beating rat atria as a test system. Methionine-enkephalin (ME), leucine-enkephalin (LE), phe-met-arg-phe amide (FMRFamide), D-ala 2, N-methyl-phe 4, met (O) 5-ol-enkephalin (FK 33-834), methionine-enkephalin arg 6 arg 7 (ME arg 6 arg 7) and β-endorphin had no effect on basal beating rate of isolated atria at all concentrations up to 10 −5 M. The positive chronotropic effect of norepinephrine (NE) on atrial rate is, however, significantly attenuated by enkephalin peptides. Thus, the maximal chronotropic effect of NE (an increase from 317±7.0 to 473±7.3 beats per minute (bpm) in 250 gm rats at a dose of 10 −5 M NE) is decreased by 42% in the presence of 10 −7 m ME. The action of ME is completely blocked by addition of 10 −7 M naloxone, which by itself has no effect on NE-induced positive chronotropy or basal beating rate. The dose-effect curve for ME attenuation of NE-induced positive chronotropy is bell-shaped, i.e., both 10 −8 M and 10 −5 M ME have no significant effect on NE positive chronotropy. Other enkephalin peptides acted in a similar manner to ME; LE (10 −7 M) and FK 33-834 (10 −8 M) decreased maximal NE-induced positive chronotropy 42 and 27%, respectively. The molluscan cardioexcitatory peptide FMRFamide (10 −7 M) also decreased maximal NE positive chronotropy, about 30%. In contrast, β-endorphin did not significantly affect NE stimulation of atrial rate. We conclude that enkephalins can modulate the noradrenergic responsiveness of rat atria in vitro. The possible physiological relevance of this interaction is discussed.

Denervation supersensitivity in the canine heart: Catecholamine-enhanced positive chronotropy without altered arrhythmogenicity

5. Lepley D Jr, Flemma RJ, Mullen DC, Singh H, Chakravarty S: Late evaluation of patients undergoing valve replacement with the Bjiirk-Shiley prosthesis. Ann Thorac Surg 24:131, 1977. Moreno-Cabral RJ, McNamara JJ, Mamiya RT, Brainard SC, Chung GKT: Acute thrombotic obstruction with BjorkShiley valves. J Thorac Cardiovasc Surg 75:321, 1978. Copans H, Lakier JB, Kinsley RH, Colsen PR, Fritz VU, Barlow JB: Thrombosed BjSrk-Shiley mitral prostheses. Circulation 61:169, 1980. Karp RB, Cyrus RJ, Blackstone EH, Kirklin JW, Kouchoukos NT, Pacific0 AD: The BjBrk-Shiley valve: Intermediateterm follow-up. J Thorac Cardiovasc Surg 61:602, 1981. Bjiirk VO, Henze A: Ten years’ experience with the BjBrkShiley tilting disc valve. J Thorac Cardiovasc Surg 76:331, 1979.

Extracellular calcium concentration and calcium blocking agents on the action of ouabain on isolated rat atrium

Summary The influences of calcium blocking agents and different[Ca 2+ ] o on the non toxic (positive inotropism without changes in frequency or resting tension) and toxic (positive chronotropism, negative inotropism, contracture, arrhythmia) effects of ousbain upon isolated rat stris were explored. Decreasing the [Ca 2 ] o from 1.2 to 0.3 mM or tresting the auricles with verapamil, D-600 or diltiazem potentisted the positive inotropic influences of ouabain and attenuated and delayed the onset of toxic actions. On the contrary increasing [Ca 2+ ] o from 1.2 to 2.7 mM, reduced the non toxic effect of ouabain and facilitated the toxic action of the drug. These findings suggest that factors known to induce changes in the intracellular calcium concentration (i.e. calcium blocking agents, and variable extracellular calcium concentrations) produce a remarkable modification of the influence of ouabain on rat myocardium.

Antagonism by gamma-aminobutyric acid of the stimulant effect of angiotensin II on cardiac sympathetic ganglia in spinal dogs.

The effects of angiotensin II and neuro-aminoacids administered through the right subclavian artery (i.a.) to the cardiac sympathetic ganglia were investigated in spinal dogs. Angiotensin II (1--8 micrograms) elicited a dose-dependent positive chronotropic effect which was reduced after i.a. injection of saralasin (100 micrograms). The effect of angiotensin II was not reduced after combined treatment with either hexamethonium (10 mg/kg) plus atropine (0.1 mg/kg) or hemicholinium-3 (5 mg/kg) plus preganglionic stimulation. The dose-dependent response to angiotensin II of heart rate was inhibited by GABA (50, 500 micrograms), GABOB (500 micrograms) and muscimol (50, 100 micrograms). The inhibition of the response to angiotensin II by a small dose of GABA (50 micrograms), but not by a high one (500 micrograms), was antagonized by i.a. injection of picrotoxin (2 mg). The positive chronotropism induced by bethanechol (25, 50 micrograms) and a small dose of acetylcholine (25 micrograms) were significantly inhibited by a high dose (500 micrograms) but not by a low dose (50 micrograms) of GABA. These results confirm that angiotensin II stimulates cardiac chronotropism by acting on the angiotensin II receptor located at the cardiac ganglia and show that this stimulant effect is antagonized by GABA.

Emergence of beta-adrenergic sensitivity in the developing chicken heart.

Muscle cells dissociated from 5-day embryonic chicken hearts showed dose-dependent increases in both chronotropic rates of contraction and cyclic AMP (cAMP) levels in response to epinephrine (EPI), an effect that could be blocked by beta-adrenergic antagonists. However, 2- to 2.5-day embryonic chicken myocardial cells, although similar to 5-day heart cells with respect to the organization of myofibrils, failed to respond to EPI either by increased rates of contraction or by elevated levels of intracellular cAMP. Development of beta-adrenergic sensitivity in 2- to 2.5-day cells did not occur even after several days of growth in culture. However, addition of an extract prepared from 11-day chicken embryos to 2- to 2.5-day muscle cell cultures at any point during in vitro growth resulted in the development of sensitivity to EPI as measured by increases in both the beating frequency and cAMP levels after a 48-hr incubation in embryo extract (EE). The basal level of cAMP in cells unresponsive to EPI is 5 times that in EPI-sensitive muscle cells from older hearts (5 days). The high basal level of cAMP in these cells is reduced to a level characteristic of cells from older hearts when treated with the EE. Once sensitivity was acquired, it was retained as a stable trait of the muscle cells in culture. Furthermore, EE-treated 2- to 2.5-day cells showed less reduction of positive chronotropy in response to multiple doses of EPI than did cells prepared from 5-day hearts. Fractionation of EE on Sephadex G-200 showed that the activity was present in the large-molecule fractions. It is concluded that the development of beta-adrenergic sensitivity can be induced in unresponsive heart cells cultured from 2- to 2.5-day embryos by a factor(s) in the EE that is not adsorbed on Sephadex G-200.

Negative chronotropic effect of dibutyryl cyclic AMP on the cultured chick embryonic heart cells and the prolongation of the action potential duration.

It was shown that there were clear differences between the effects of norepinephrine and dibutyryl cyclic AMP on the cultured chick embryonic heart cells. Norepinephrine and dibutyryl cyclic AMP was applied to the cultured chick embryonic heart cells, and the changes in the beating rate and the action potential configuration were examined. Norepinephrine increased the beating rate, but dibutyryl cyclic AMP produced the significant negative chronotropic effect. Norepinephrine increased the slope of the diastolic depolarization with little affecting the duration of the action potential. In contrast, dibutyryl cyclic AMP significantly prolonged the action potential duration without changing the slope of the diastolic depolarization. Thus, it was shown that dibutyryl cyclic AMP did not always produce the positive chronotropism, and it was suggested that the negative chronotropism on the cultured chick embryonic heart cells was related to the prolongation of the action potential duration.

Effect of acetylcholine on the norepinephrine-induced positive chronotropy and increase in cyclic nucleotides of isolated rabbit sinoatrial node.

Transmural stimulation of, or application of nicotine to, the isolated rabbit sinoatrial (SA) node resulted in initial negative and late positive chronotropy. Simultaneous application of acetylcholine and norepinephrine produced a similar biphasic chronotropic effect. These procedures produced an initial increase in cyclic guanosine 3':5'-monophosphate (cyclic GMP) and a delayed elevation in cyclic adenosine 3':5'-monophosphate (cyclic AMP). The initial and late effects on rate and nucleotide levels were inhibited by pretreatment with atropine and propranolol, respectively. Pretreatment with atropine shortened the time of maximum increase in cyclic AMP level and heart rate from 3 to 1 minute after the simultaneous application of acetylcholine and norepinephrine and enhanced the positive chronotropic effect. Physostigmine prolonged the duration of the increase in cyclic GMP and negative chronotropic effect after the simultaneous application. These results suggest that when acetylocholine and norepinephrine are present simultaneously in the SA node region, the former interacts predominantly with muscarinic receptors and stimulates the cyclic GMP system, which in effect delays the cyclic AMP elevation and reduces the positive chronotropic effect of norepinephrine. However, these effects of acetylcholine cannot be explained solely on the basis of changes in the cyclic GMP level, because sodium nitroprusside produced a marked elevation of the cyclic GMP levels without decreasing the heart rate and did not affect the norepinephrine-induced increase in pacemaker rate and cyclic AMP. Sodium nitroprusside may affect cyclic GMP pools other than those susceptible to acetylcholine. These cyclic GMP pools may not exert chronotropic effects.

An adrenergic participation subserving a positive inotropism and chronotropism of prostacyclin on isolated rat atria

The effects of prostacyclin (PGI2) on the contractile frequency and on the isometric developed tension of spontaneously beating or paced isolated rat atria were explored. PGI2 enhanced frequency and contractile tension, both effects being blocked by the presence of propranolol, or following a pretreatment with 6-OHDopamine.

Electrophysiological and mechanical studies on the cardiac effects of a histamine H2 receptor antagonist, cimetidine, in the isolated guinea pig myocardium.

The effects of cimetidine, a new histamine H2 receptor antagonist, were studied electrophysiologically and mechanically in the isolated guinea pig myocardium. Cimetidine did not modify the electrical activity of the sinoatrial pacemaker cells at the concentrations up to 10-4 M, but depressed the pacemaker potential at the higher concentration, 3×10-4 M. Increase in the slope of the pacemaker potential produced by histamine was completely inhibited by cimetidine, indicating that the histamine receptor for the positive chronotropism is of H2-type. Cimetidine did not depress the maximum rate of rise of the atrial and ventricular action potentials ; thus, unlike most of the H1 receptor antagonists, cimetidine does not have quinidine like actions. The shape of the action potential was not modified significantly. Slow electrical and mechanical activities produced by histamine in the right ventricular myocardium whose fast Na+ channels were blocked by elevated external potassium were partially blocked by either cimetidine or diphenhydramine, supporting the view that both types of receptors are present in the right ventricle. Histamine-induced mechanical activity in the depolarized right atrium was inhibited by cimetidine, but that in the left atrium was not inhibited ; these results support the view that the histamine receptor in the left atrium is of H1-type and suggest that the histamine receptor for the positive inotropism in the right atrium is of H2-type. In addition, some results were shown suggesting the possibility that cimetidine might have some agonist-like action in the myocardium.

INFLUENCE OF FENTANYL ON THE CHRONOTROPIC RESPONSE OF ISOLATED RABBIT ATRIA TO CHOLINERGIC AND ADRENERGIC STIMULATION

Effects of fentanyl and morphine on chronotropic responses to transmural stimulation applied to the S-A node were studied in isolated rabbit atria. The stimulation caused a frequency-dependent negative chronotropism followed by positive chronotropism, the former abolished by atropine and the latter suppressed by propranolol. The former response at 5 and 20/sec was attenuated in a dose-dependent manner by fentanyl and morphine. Potency ratio of fentanyl to morphine was approx. 50-100. The inhibitory effect of fentanyl and morphine on the response to stimulation of cholinergic nerves was partially prevented or reversed by both naloxone and levallorphan, and also partially reversed by repeated washing of the preparations. Antagonism by naloxone was appreciably greater than that of levallorphan. The negative chronotropic response to transmural stimulation was reduced by levallorphan but not by naloxone. Dose-chronotropic response curves of acetylcholine were unaffected by treatment with fentanyl and morphine. High concentrations of fentanyl and morphine attenuated the response to stimulation of adrenergic nerves, while dose-chronotropic response curves of noradrenaline were not influenced by these narcotics. Naloxone was ineffective in preventing or reversing the effect of fentanyl and morphine. It is therefore concluded that fentanyl and morphine activate opiate receptors located in cholinergic nerve terminals innervating the S-A node, thereby interfering with the release of acetylcholine. Further, it appears that high concentrations of fentanyl and morphine interfere with the release of noradrenaline from postganglionic adrenergic nerve terminals in rabbit atria; however, this action is not related to opiate receptors.

Pharmacological analysis of sympathetic function in the embryonic chick heart

Sympathetic nerve cells enter the embryonic chick heart on the fifth day in ovo, but it is uncertain when these nerves become functional. Using pharmacological probes known to affect the embryonic circulation, sympathetic nerve function was examined at various stages of development. Exogenous norepinephrine elicited cardioacceleration in the hearts of embryos with intact extraembryonic circulation both before (stage 20-24) and after (stage 28-32) sympathetic innervation of the heart, and this acceleration could be inhibited by propranolol and practolol. In contrast, ganglionic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) elicited cardioacceleration only after stages 27-28 (i.e., after sympathetic innervation), producing a 25-30% increase in heart rate over the predrug levels of 148.7 +/- 1.8 beats/min. DMPP-elicited positive chronotropy was reduced by beta-receptor antagonists, hexamethonium, guanethidine (GuE), and tetrodotoxin. In preparations of the embryonic thorax in which the innervated heart was separated from brain and adrenal influences, DMPP elicited a GuE-sensitive cardioacceleration. It is concluded that during chick embryonic development, no more than a 1-day interval exists between the appearance of sympathetic nerves in the heart and the onset of neuronal function in that organ.

A correlative study on the changes of cardiac dynamics and myocardial energy liberation in blood-let dogs.

Blood-letting of 450 to 1,000 ml with or without saline infusion was performed in dogs. In some dogs, right atrial pacing was carried out during blood-letting. Heart rate and isometric time-tension index were measured as the indicators of chronotropism and inotropism, respectively. After 60 min of blood-letting, dogs were sacrificed and mitochondria were isolated from the left ventricular myocardium. Mitochondrial respiration was measured polarographically and respiratory control index was calculated. As blood-letting advanced, the hearts revealed negative chronotropism with negative inotropism. Mitochondrial respiration was suppressed. When heart rate was forced to increase with atrial pacing, the hearts showed positive chronotropism with negative inotropism. Respiratory control index of mitochondria was deteriorated, showing uncoupling of oxidative phosphorylation. In consideration with our previous study on the ischemic heart, it is concluded that uncoupling of oxidative phosphorylation appeared in hypoxic myocardium when cardiac dynamics shifted to positive chronotropism with negative inotropism, though suppression of mitochondrial respiration was revealed when cardiac dynamics altered to negative chronotropism with negative inotropism.

A correlative study of the experimental cardiac dynamics and myocardial energy metabolism.

Relationship between cardiac dynamics and myocardial energy metabolism was studied using dogs treated by isoproterenol, dinitrophenol, propranolol or amobarbital. Isoproterenol changed cardiac dynamic state to positive chronotropism with positive inotropism and myocardial energy liberation to uncoupling of oxidative phosphorylation. Dinitrophenol inducing uncoupling of oxidative phosphorylation, revealed also positive chronotropic and positive inotropic state. Propranolol changed cardiac dynamic state to negative chronotropism with negative inotropism, and myocardial energy liberation to suppression of oxidation. Amobarbital inducing inhibition of intracellular terminal oxidation, revealed also negative chronotropic and negative intropic state. From the above-mentioned results, it might be clear that the positive chronotropism with positive inotropism appears to be relating to the uncoupling of oxidative phosphorylation, as well as the negative chronotropism with negative inotropism to the suppression of mitochondrial respiration.

Primary effect of glucagon on positive chronotropism

Chronotropic and inotropic effects of glucagon were compared with those of norepinephrine using the excised SA node and the papillary muscle preparations cross-circulated with a donor dog. Glucagon was administered i.v. to the donor dog at doses of 1 to 30 μg/kg, which caused a marked chronotropic but less marked inotropic effect. Cardiohemodynamic response to glucagon of anesthetized dogs was simulated by an acceleration induced by atrial pacing. It was concluded that glucagon is more effective on chronotropism than on inotropism, and that its cardiohemodynamic effects are mainly ascribed to the increased heart rate.

Complete cardiac denervation without transplantation: a simple and reliable technique

ARTICLESComplete cardiac denervation without transplantation: a simple and reliable techniqueW. P. Geis, C. J. Tatooles, M. P. Kaye, and W. C. RandallW. P. Geis, C. J. Tatooles, M. P. Kaye, and W. C. RandallPublished Online:01 Feb 1971https://doi.org/10.1152/jappl.1971.30.2.289MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByDenervation supersensitivity in the canine heart: Catecholamine-enhanced positive chronotropy without altered arrhythmogenicityAmerican Heart Journal, Vol. 103, No. 3Intrapericardial denervation of the heartJournal of Surgical Research, Vol. 29, No. 2Intrinsic innervation of the canine heart. Effects on conduction in the atrium, atrioventricular node, and proximal bundle branch.Circulation Research, Vol. 47, No. 1Horseradish peroxidase localization of cardiac vagal preganglionic somataBrain Research, Vol. 182, No. 1Cholinergic sensitivity of the denervated cannine heart.Circulation Research, Vol. 41, No. 5The intrinsic innervation of the canine heart: a functional study.Circulation Research, Vol. 40, No. 1Prevention of exercise-induced cardiac hypertrophy in rats by chemical sympathectomy (guanethidine treatment)Neuroscience, Vol. 1, No. 6Cardiac dysrhythmias in the conscious dog after surgically induced autonomic imbalanceThe American Journal of Cardiology, Vol. 38, No. 2Myocardial Performance after Excision of the Extrinsic Cardiac Nerves in the DogCirculation Research, Vol. 34, No. 4One stage cardiac denervation without transplantationJournal of Surgical Research, Vol. 15, No. 5 More from this issue > Volume 30Issue 2February 1971Pages 289-293 Copyright & PermissionsCopyright © 1971 the American Physiological Societyhttps://doi.org/10.1152/jappl.1971.30.2.289PubMed5539897History Published online 1 February 1971 Published in print 1 February 1971 Metrics

Effects of hemicholinium and bretylium on the release of autonomic transmitters in the isolated sino-atrial node.

1. In the isolated, spontaneously beating, sino-atrial node of the rabbit selective electrical excitation of intranodal autonomic nerve fibres results in a biphasic chronotropic response. This chronotropic response (negative followed by positive chronotropism) is due to the release of the autonomic transmitters (acetylcholine and noradrenaline, respectively) from intranodal nerve fibres.2. In the presence of 2 x 10(-4) g/ml hemicholinium, the negative chronotropic (cholinergic) response is abolished while the positive chronotropic (adrenergic) response is unaltered.3. In the presence of 5 x 10(-6) g/ml bretylium, the positive chronotropic response is abolished while the negative chronotropic response is little affected.4. After blockade of the negative chronotropic response by hemicholinium, bretylium abolishes the remaining positive chronotropic response. The effect of bretylium is not altered in the presence of hemicholinium.5. Considering currently accepted mechanisms of action for hemicholinium and bretylium, the results of these experiments do not lend support to the cholinergic link hypothesis of adrenergic neuro-effector transmission.

Supersensitivity of the chronically denervated feline heart.

Supersensitivity of the chronically denervated feline heart.