Positive Chronotropic Responses Research Articles

Inhibition of the positive chronotropic response to isoproterenol by hypothermia

Inhibition of the positive chronotropic response to isoproterenol by hypothermia

Studies on histamine H2-receptor antagonistic property of FRG-8813, a novel anti-ulcer drug

The present study was conducted to investigate the histamine H2-receptor antagonistic property of FRG-8813 by using isolated guinea pig right atria, gastric cells and cerebral cortex preparations. FRG-8813 inhibited the histamine-induced positive chronotropic response of the right atria and shifted the concentration-response curve of histamine to the right with suppression of the maximal response. Although the inhibitory effect of FRG-8813 was enhanced in a time-dependent manner and long-lasting, the antagonism was reversible. The potency of FRG-8813 was 2 times and 50 times greater than those of famotidine and cimetidine, respectively. FRG-8813 decreased the histamine-induced [14C]aminopyrine accumulation in gastric cells. Schild plot analysis showed that the slopes of FRG-8813, famotidine and cimetidine were 1.56, 1.40 and 1.07, respectively, suggesting that the mode of the antagonism of FRG-8813 is also unsurmountable in gastric cells. The lack of effect on dbcAMP- and bethanechol-induced [14C]aminopyrine accumulations indicated the selectivity of FRG-8813 for histamine H2-receptor. As in the right atria, the potency of H2-antagonism was 1.5 times and 40 times greater than those of famotidine and cimetidine, respectively. In the [3H]tiotidine binding study of the cerebral cortex preparation, the Ki values showed that the affinity of FRG-8813 was 2 times and 80 times more potent than those of famotidine and cimetidine, respectively. In conclusion, FRG-8813 is an unsurmountable and selective histamine H2-receptor antagonist with 2 times greater potency than famotidine. The antagonistic activity is reversible in spite of the time-dependent increase of the antagonism.

Anti-β 1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: Mapping of epitopes in the first and second extracellular loops

G. Wallukat, A. Wollenberger, R. Morwinski and H.-K Pitschner, Anti-β-Adrenoceptor Autoantibodies with Chrono- tropic Activity from the Serum of Patients with Dilated Cardiomyopathy: Mapping of Epitopes in the First and Second Extraceltular Loops. Journal of Molecular and Cellular Cardiology (1995) 27, 397-406. In a preceding communication (Wallukat et al,, 1992, Z Kardiol 81 [Suppl. 4]: 79-83), it was reported that synthetic peptides, corresponding in amino acid sequence to either the first or the second extracellular loop of the human β-adrenoceptor, selectively suppressed the metoprolol-and bisoprolol-sensitive positive chronotropic action exerted in cultures of beating neonatal rat cardiomyocytes by the serum immunoglobulin fraction of patients with myocarditis and idiopathic dilated cardiomyopathy (DCM) and by affinity-purified autoantibodies from that fraction. These observations added to existing evidence that these antibodies were directed against the β 1-adrenoceptor and might thus contribute to the harmful chronic cardiac adrenergic drive to which patients with DCM are believed to be exposed, Specifically, they pointed to the putative first and second extracellular loops of this receptor (these loops are each identical in man and the rat) as the sites of epitopes recognized by the chronotropically active, β 1-agonistic autoantibodies. Now we report on the mapping of these epitopes with the help of two series of short synthetic overlap peptides, one series forming part of the first and the other of the second extracellular loop of the β 1-adrenoceptor. Inhibition of the positive chronotropic response of cultured rat cardiomyocytes to the anti- β 1-receptor autoantibodies (EC 50 = 0.14 ± 0.01 nM) from the serum immunoglobulin fraction of patients with DCM was taken as reflecting the neutralization of these antibodies by a particular overlap peptide. In this way the sequences S-F-F- C-E-L (residues 129-134) and A-R-R-C-Y-N-D (residues 206-212) emerged as the dominant epitopes in the first and second extracellular loops, respectively, followed with respect to neutralizing ability by the first loop sequence E-Y-G-S-F-F (residues 126-131) and the second loop sequences H-W-W-R-A-E (residues 197-202) and P-K-C-C-D-F (residues 213-218). Synthetic peptides corresponding to the sequences of the third extracellular loop of the β 1-receptor (residues 346-356) and of the second extracellular loop of the human β 2-receptor (residues 172-197) failed to neutralize the β 1-agonistic autoantibodies. Using dithiothreitol as a reducing agent a disulfide bridge between cysteine 132 in the first and cysteine 209 in the second extracellular loop was considered to be essential tbr the chronotropic action of these autoantibodies. The observed neutralizing power of some of the short synthetic peptides employed in the present study argues for their introduction as potentially valuable agents into the immunotherapy of DCM.

Influence of flosequinan on autonomic tone in congestive heart failure: Implications for the mechanism of the positive chronotropic effect and survival influence of long-term vasodilator administration

The vasodilator flosequinan has been shown to be effective in the management of symptoms of congestive heart failure but has been found to influence survival adversely when administered in selected doses. A moderate positive chronotropic response accompanies long-term administration of this agent, which may be associated with an activation of the neurohormonal axis that itself may contribute to the reported increase in mortality. This investigation used the technique of spectral analysis of heart rate variability to examine the autonomic response to long-term flosequinan administration in 39 patients enrolled in a double-blind placebo-controlled trial of this vasodilator to determine whether autonomic mechanisms account for the observed changes in heart rate. Although heart rate significantly increased in the flosequinan-treated patients, parasympathetic tone increased and sympathetic drive decreased compared with placebo, as reflected by high- and low-frequency heart rate variabilities, respectively. It is concluded that (1) autonomic inputs to the myocardium that would be expected to produce increases in heart rate do not result from long-term flosequinan administration; (2) accordingly, a direct positive chronotropic effect must account for the heart rate changes observed with this vasodilator; and (3) the increased mortality associated with the administration of this agent in the doses examined does not appear to result from reflex changes in autonomic tone and must result from other properties of this vasodilator.

Mechanosensitive fibroblasts in the sino-atrial node region of rat heart: interaction with cardiomyocytes and possible role.

The positive chronotropic response of the heart to stretch of the right atrium is one of the major mechanisms adjusting the heart rate to variations in venous return on a beat-by-beat basis. The precise pathway of this mechano-electric feedback and its cellular basis are uncertain. In this study, a possible contribution of mechanosensitive fibroblasts, abundant in the sino-atrial node region, was investigated using a mathematical model of the electrical interaction of a mechanosensitive fibroblast and a sino-atrial pacemaker cell. Electrophysiological evidence for a bio-electrical interaction of mechanosensitive fibroblasts with surrounding cardiomyocytes has been studied in (i) the isolated spontaneously beating atrium of rat hearts, and (ii) cell cultures of the neonatal rat heart. These investigations were performed using (i) double-barrelled floating microelectrodes for intracellular potential registrations, and (ii) the double whole cell patch-clamp technique. It was shown that cardiac fibroblasts and surrounding cardiomyocytes can be either electrically well isolated from each other, or coupled both capacitively and electrotonically. The electrophysiological data obtained were incorporated into the OXSOFT HEART program. Assuming that equivalent coupling may occur between mechanosensitive fibroblasts and sino-atrial pacemaker cells, a heterologous cell pair consisting of one fibroblast and one sino-atrial node myocyte connected by ten to thirty single gap junctional channels with a conductance of 30 pS was modelled. The model of the electrotonic interaction of these cells showed that stretch of the fibroblast during atrial diastole, simulating increased atrial wall tension during atrial filling, can raise the spontaneous depolarization rate of the pacemaker cell in a stretch-dependent manner by up to 24%. These results show that cardiac mechanosensitive fibroblasts could form a cellular basis for the positive chronotropic response of the heart to stretch of the right atrium.

Calcium sensitization as a positive inotropic mechanism in diseased rat and human heart.

The two isomers of the positive inotropic compound EMD 53998, (+)EMD 57033 and (-)EMD 57439, possess selective calcium sensitizing and phosphodiesterase (PDE) inhibitory properties, respectively. We measured the pharmacological responses to both enantiomers in isolated rat cardiac and vascular tissues and in muscles from severely failing human hearts. We also measured positive inotropic and chronotropic responses to EMD 57033 in cardiac tissues from rats with thyroid dysfunction, diabetes, or hypertension. Both compounds increased force of contraction in isolated rat cardiac tissues, although the ventricular response to EMD 57439 was only approximately 10% that of calcium chloride. Forskolin pretreatment potentiated responses to both compounds in atria but only to EMD 57439 in ventricles. Hyperthyroidism increased ventricular responses to EMD 57033 relative to calcium chloride; hypothyroidism and diabetes decreased these responses. Ventricular responses were unchanged in hypertensive rats. Both enantiomers produced positive inotropy in human isolated right atrial trabeculae, although the maximal increases were only 14% (EMD 57033) and 26% (EMD 57439) that of calcium chloride. In rat thoracic aortic rings, both enantiomers produced relaxation; the responses due to EMD 57033 were endothelium dependent. Thus, calcium sensitization produces positive inotropy and vascular relaxation in rats. Positive chronotropic responses to EMD 57033 are most likely due to PDE inhibition. The limited inotropic response in severely failing human myocardium, together with possible vasorelaxation, may provide cardiac support in heart failure without an excessive increase in cardiac O2 demand.

Changes in the responsiveness to endothelin-1 in isolated atria from diabetic rats.

This study investigates the influence of diabetes on the cardiac responsiveness to endothelin-1. The effects of endothelin-1 on rate and force of contraction were examined in isolated right and left atria, respectively, obtained from either streptozotocin (65 mg/kg)-treated rats (diabetic) or vehicle (0.02 M citric acid)-treated rats (control). The positive chronotropic and inotropic effects of endothelin-1 did not change in atria from diabetic rats at 2 and 4 weeks, but were reduced at 8 and 12 weeks. The positive chronotropic response to noradrenaline, but not to sympathetic nerve stimulation, was also reduced in 12-week diabetic rats. Endothelin-1 caused a decrease in the positive chronotropic and inotropic responses to sympathetic nerve stimulation and to noradrenaline; these inhibitory effects of endothelin-1 were not altered in 2-, 4-, 8- or 12-week diabetic rats. The study demonstrates that atrial responses to endothelin-1 and to noradrenaline are reduced by streptozotocin-induced diabetes, but the alteration depends on the duration of diabetes.

Cardiomyocyte-like cells differentiated in vitro from embryonic carcinoma cells P19 are characterized by functional expression of adrenoceptors and Ca2+ channels.

P19 embryonal carcinoma cells were differentiated via embryolike aggregates (embryoid bodies) into spontaneously beating myocytes. During the whole process of differentiation the functional expression of cardiac-specific receptors and ionic channels was characterized by measuring the chronotropic reactivity, action potentials, and ionic currents in response to various cardioactive drugs. Positive chronotropic effects obtained at different maximal effective concentrations of adrenoceptor-mediated agonists indicated differential adrenoceptor expression during the in vitro development of cardiomyocyte-like cells. No cardiac-specific response was obtained with the muscarinic cholinoceptor agonist carbachol. Single beating cells were enzymatically isolated and investigated by the patch-clamp technique. Pacemaker action potentials similar to those of embryonal cardiomyocytes exhibited amplitudes ranging from 50 to 85 mV. The action potentials were synchronous to the mechanical contractions and, comparable to the chronotropic effects, were modulated by BayK 8644, isradipine, and adrenaline. The functional expression of L-type Ca2+ channels was demonstrated by the Ca2+ channel blockers isradipine, nisoldipine, gallopamil, and diltiazem causing negative chronotropic responses, as well as by the Ca2+ channel activator BayK 8644 causing positive chronotropic responses. These effects gradually increased with time of differentiation. The expression of L-type Ca2+ channels and of nicotinic acetylcholine receptors was confirmed in voltage-clamp experiments. The study demonstrates that P19 embryonal carcinoma cells can be induced to differentiate into cardiomyocyte-like cells comparable to embryonal and neonatal heart cells lacking the muscarinic cholinoceptor response only.

Circulatory Failure Caused by a Fungicide Containing Iminoctadine and a Surfactant: A Pharmacological Analysis in Rats

The fungicide Befran (BFR), containing iminoctadine as an active ingredient and polyoxyethylene alkylether (POEAE) as a surfactant, has been known to cause circulatory failure in human acute oral poisoning. We investigated separately the effects of iminoctadine, POEAE, and BFR on heart rate and blood pressure of rats and also on isolated atria and aortas. In isolated rat atria, iminoctadine produced positive chronotropic and inotropic responses. In contrast, POEAE produced negative chronotropic and inotropic responses. BFR produced no effects at low concentrations, but significant negative chronotropic and inotropic responses at high concentrations. In isolated rat aortas, iminoctadine produced remarkable vasodilative responses, but POEAE produced vasoconstrictive responses. BFR produced both vasodilative and vasoconstrictive responses. When intravenously administered to anesthetized rats, iminoctadine produced hypotension and tachycardia in a dose-dependent manner. POEAE produced significant hypotension and slight bradycardia. BFR, at low doses, produced hypotension without elevation of heart rate. At high doses, it produced significant hypotension and tachycardia. From these results, it can be concluded that severe hypotension induced by BFR is due mainly to the vasodilative effect of iminoctadine and partly to the cardio-suppressive effect of POEAE.

Increased sensitivity of neonatal mouse myocardia to autonomic transmitters

Chronotropic and inotropic responses to noradrenaline and acetylcholine were examined in isolated right atrial and ventricular preparations from neonatal and adult mice. 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. 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. 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.

Role of α 1-adrenoceptor subtypes which mediate positive chronotropy in neonatal rat cardiac myocytes

We investigated the involvement of α 1-adrenoceptor subtypes in the positive chronotropic response to norepinephrine (NE) in neonatal rat cardiac myocytes at day 3 of culture. The cardiac myocytes at day 3 of culture exhibited a dose-dependent positive chronotropic response to NE in the presence of propranolol, a β-adrenoceptor antagonist. The positive chronotropic responses to NE were completely antagonized by the α 1-adrenoceptor antagonist prazosin. The NE-induced positive chronotropic response was inhibited 68% by the α 1B-adrenoceptor antagonist, chloroethylclonidine (CEC), but partially (41%) so by the α 1A-adrenoceptor antagonist, WB4101. In the membrane fraction derived from cardiac myocytes at day 3 of culture, pretreatment with CEC decreased the Bmax of the α 1-adrenoceptor to 22% of the control value. The NE-induced positive chronotropic response was inhibited 62 and 77% by the voltage-gated Ca 2+ channel blocker such as nifedipine and verapamil, respectively. These findings indicate (1) that cultured neonatal rat cardiac myocytes possess both α 1-adrenoceptor subtypes, i.e., α 1A and α 1B, (2) that the predominant α 1-adrenoceptor subtypes mediating NE-induced positive chronotropy in neonatal rat cardiac myocytes at day 3 of culture are α 1B-subtypes, and (3) that NE-induced positive chronotropy may be caused via voltage-gated Ca 2+ channel activation.

Histamine H2-Receptor Antagonism of T-593: Studies on Positive Chronotropic Responses in Guinea Pig Atria

Histamine H2-antagonistic properties of the novel H2-antagonist T-593, (+-)-N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-N'-[2- [[[5-(methylamino)methyl-2-furyl]methyl]thio]ethyl]-N"- (methylsulfonyl) guanidine were investigated on the histamine-induced positive chronotropic responses in isolated guinea pig right atria. T-593 at 3 x 10(-7)-3 x 10(-6) M suppressed the maximal responses of the histamine concentration-response curves in a concentration-dependent fashion, indicating that T-593 is an unsurmountable antagonist. The pD'2 values were 5.50 for T-593 and 5.61 for famotidine; and the IC50 values at 1 x 10(-5) M histamine were 1.05 x 10(-6) M for T-593, 1.59 x 10(-6) M for ranitidine and 1.67 x 10(-7) M for famotidine. T-593 is a racemic compound composed of two enantiomers, (-)-T-593 and (+)-T-593. The histamine H2-antagonistic activity of (-)-T-593 was 1.5-fold more potent than that of racemic T-593, but (+)-T-593 scarcely inhibited the histamine-induced positive chronotropic response. Histamine H2-antagonism by racemic T-593 was mainly attributed to (-)-T-593. Isoproterenol-induced positive chronotropic responses were not affected by T-593 even at 3 x 10(-5) M. Pretreatment of ranitidine for 10 min prior to application of T-593 protected H2-receptors from unsurmountable antagonism by T-593. Reversibility of H2-antagonism was determined every 1 hr after a 30-min treatment of H2-antagonists. T-593 inhibited the positive chronotropic responses for over 6 hr in contrast to fast recovery from inhibition by ranitidine or famotidine. This result showed that T-593 is a slowly dissociable, long-acting histamine H2-antagonist.

Pinacidil attenuates positive inotropic but not chronotropic responses to norepinephrine in isolated dog atrial and ventricular preparations.

We investigated whether pinacidil, a K+ATP channel opener like acetylcholine and adenosine, attenuated the positive chronotropic and inotropic responses to norepinephrine in isolated, blood-perfused dog atrial and ventricular preparations. Pinacidil (0.01-0.3 mumol) decreased atrial and ventricular contractile force to a much greater extent than sinus rate in a dose-related manner. Pinacidil dose-dependently attenuated increases in atrial and ventricular forces induced by norepinephrine but not increases in sinus rate. Pinacidil similarly attenuated the positive atrial and ventricular inotropic responses to Bay k 8644 and CaCl2. The pinacidil doses producing a fifty percent decrease (ED50) of the atrial and ventricular contractile force were not significantly different from the respective pinacidil doses producing a fifty percent inhibition (ID50) of the positive inotropic responses to norepinephrine, Bay k 8644 and CaCl2. Ouabain (5 and 15 nmol) did not affect the decreases in atrial and ventricular contractile force in response to pinacidil. These results suggest that the K+ATP-channel activator pinacidil, unlike acetylcholine or adenosine, functionally attenuates increases in ventricular and atrial contractile force in the responses to norepinephrine and other cardiotonics due to shortening of the action potential duration induced by K+ATP-channel activation in the dog heart.

Selective inhibition by bradycardic agents, zatebradine and E4080, of the positive chronotropic responses to catecholamines

Selective inhibition by bradycardic agents, zatebradine and E4080, of the positive chronotropic responses to catecholamines

Selective inhibition by E4080, a novel bradycardic agent, of positive chronotropic responses to norepinephrine in isolated dog hearts

E4080, a novel bradycardic agent acts on various ionic currents including the hyperpolarization-activated inward current ( I f), L-type Ca 2+ current ( I Ca) and ATP-sensitive K + (K ATP +) current in mammalian heart and vascular tissues. We thus investigated the chronotropic and inotropic effects of E4080 and its interaction with the positive cardiac responses to norepinephrine, 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 in the isolated, blood-perfused dog right atria and left ventricles. E4080 (0.01–1 μmol) decreased the sinus rate and atrial and ventricular contractile forces in a dose-related manner. Glibenclamide (3 μmol) partly blocked the decrease in atrial force but not the decreases in sinus rate and ventricular force induced by E4080. Atropine (10 nmol) did not affect the negative cardiac responses to E4080. E4080 )0.01−1 μmol) inhibited the positive chronotropic responses to norepinephrine and IBMX dose dependently, but did not inhibit the positive inotropic ones in isolated atria. E4080 affected neither positive chronotropic nor inotropic responses to Bay k 8644. These results suggest that (1) the activation of K ATP + channels by E4080 is partly related to the decrease in atrial force but not the decreases in sinus rate and ventricular force, and (2) the selective inhibition of E4080 of the cyclic AMP-dependent positive chronotropic responses but not inotropic ones is probably due to the inhibition of I f rather than other properties, e.g., activation of K ATP + channels and inhibition of I Ca in the dog heart.

Heart Muscle Cells Acutely Infected with Trypanosoma cruzi: Characterization of Electrophysiology and Neurotransmitter Responses

Primary cell cultures of mouse ventricular myocardium were infected with Trypanosoma cruzi , to study the consequences of T. cruzi-muscle cell interaction on the rate of spontaneous contractions, on the responses to norepinephrine, and on action potential parameters. Single cells or small cell groups infected cultures were subjected to pharmacological and electrophysiological experiments. In concentrations ranging from 1 nM to 100 μM norepinephrine exerted positive or negative chronotropic effects mediated by α-adrenergic receptors. A significant number of infected cells (25%) did not respond to the agonist. Two days after infection the cultures exhibited a higher frequency of spontaneous contractions (20%), paralleled by an increase in firing rate and a decrease in the action potential duration without significant changes in maximum diastolic potential and action potential amplitude. A decrease in α-adrenergic receptor-mediated positive chronotropic response to norepinephrine was also observed in 2-day infected cells. Cells made to phagocyte ferritin particles showed an increase in the rate of spontaneous contractions, but no changes in the positive chronotropic response to norepinephrine. In conclusion, these observations show that during acute infection with T. cruzi, there are alterations in automaticity and in the chronotropic responses to norepinephrine, whose mechanisms are related to the process of parasite endocytosis by the cardiac cells.

Inhibition by ω‐conotoxin GVIA of the chronotropic responses to sympathetic and parasympathetic nerve stimulation in the isolated, blood‐perfused atrium of the dog

1. We investigated the effects of omega-conotoxin GVIA (omega-CgTX), a blocker of N-type voltage-operated calcium channels, on the chronotropic response to stimulation of the intracardiac sympathetic and parasympathetic nerves in the isolated, blood-perfused right atrium of the dog. 2. omega-CgTX (0.3-3 nmol) itself did not affect the sinus rate significantly, but it inhibited the negative followed by positive chronotropic response to simultaneous stimulation of sympathetic and parasympathetic nerves in a dose-dependent manner. 3. omega-CgTX at higher doses (1-3 nmol) inhibited the positive response to sympathetic stimulation more strongly than the negative response to parasympathetic stimulation. omega-CgTX (3 nmol) abolished the positive chronotropic response to sympathetic nerve stimulation in the atrium treated with atropine, but did not abolish the negative response to selective parasympathetic stimulation. Neither the chronotropic response to noradrenaline nor the response to acetylcholine was affected by omega-CgTX. 4. These results indicate that omega-CgTX inhibits not only the response to sympathetic stimulation but also the response to parasympathetic stimulation in the dog heart and it inhibits the positive chronotropic response to sympathetic stimulation more strongly than the negative chronotropic response to parasympathetic stimulation.

Adrenoceptor-mediated cardiac and vascular responses in genetically growth hormone-deficient rats

This study has measured cardiovascular parameters, pharmacological responses to α and β-adrenoceptor agonists, and cardiac β-adrenoceptor characteristics in growth hormone (GH)-deficient (dwarf) Lewis rats, normal Lewis rats and dwarf rats treated with GH (2mg/kg/day for 28 days). Dwarf rats showed a decreased mean blood pressure and heart rate but an increased ventricular weight relative to body weight when compared with age-matched normal Lewis rats. Positive chronotropic responses in vivo to the non-selective β-adrenoceptor agonist, isoprenaline, were unchanged in dwarf rats. The selective β 1-adrenoceptor agonist, noradrenaline, was less potent in isolated right atria from dwarf rats although maximal responses were unchanged. Basal force of contraction was greater in isolated cardiac muscles from dwarf rats than from normal rats. Maximal positive inotropic responses to both calcium chloride and noradrenaline were reduced in left atria but increased in left ventricular papillary muscles from dwarf rats. Responses to the α 1-adrenoceptor agonist, phenylephrine, were markedly increased in isolated cardiac tissues from dwarf rats. Maximal contractile responses of isolated thoracic aortic rings from dwarf rats to KCl (100 mM) and the α-adrenoceptor agonist, noradrenaline, were markedly reduced compared to responses in normal rats. Left ventricular β-adrenoceptor density measured by 125I-cyanopindolol binding was significantly increased in dwarf rats. Administration of GH (2 mg/kg/day for 28 days) reversed the altered responses in dwarf rats. We conclude that GH: (a) is required for the development of normal contractile capability of cardiac and vascular tissues; (b) regulates both β-adrenoceptors and α- and β-adrenoceptor-mediated responses; (c) differentially regulates atrial and ventricular responsiveness.

Positive chronotropic and inotropic responses to BRL 37344, a β 3-adrenoceptor agonist in isolated, blood-perfused dog atria

We investigated the chronotropic and inotropic responses to BRL 37344 (a β 3-adrenoceptor agonist) and isoproterenol in isolated, blood-perfused dog atria. BRL 37344 (0.1–30 nmol) or isoproterenol (0.001–0.3 nmol) increased the sinus rate and contractile force dose dependently. BRL 37344 was 290 times less potent than isoproterenol to increase sinus rate and 140 times less potent to increase atrial force. Both propranolol and bisoprolol similarly inhibited the positive chronotropic and inotropic responses to BRL 37344 and isoproterenol dose dependently. ICI 118,551 (0.1 and 1 nmol) did not significantly affect the positive cardiac responses to BRL 37344 or isoproterenol. Neither imipramine nor tetrodotoxin significantly affected the positive cardiac responses to BRL 37344. These results suggest that the positive chronotropic and inotropic responses to BRL 37344 are mediated mainly by β 1-adrenoceptors in the dog heart. It is unlikely that β 3-adrenoceptors, as previously reported in adipose tissue or gastrointestinal smooth muscle, mediate chronotropic and inotropic responses in the normal dog heart.

Positive chronotropic and inotropic responses to lysophosphatidylcholine are mediated by norepinephrine released from myocardial sympathetic nerve terminals

1. 1. The effects of beta-adrenoceptor blockade and reserpinization on the positive chronotropic and inotropic responses to lysophosphatidylcholine (LPC) were examined in isolated atrial and ventricular preparations from rat hearts. 2. 2. The positive responses to 10 −4 M LPC were about 40–55% of those to 10 −5 M norepinephrine (NE) in each preparation. 3. 3. The responses to LPC in the presence of propranolol or in the reserpinized preparations were significantly smaller than the corresponding values obtained in control preparations, and were about 10–25% of those to NE. 4. 4. It was concluded that positive chronotropic and inotropic responses to LPC are at least partially mediated by release of NE from myocardial sympathetic nerve terminals.