Leukotriene C4 action and metabolism in the isolated perfused bullfrog heart

The effects of leukotrienes (LTs) have been widely studied in the isolated perfused mammalian heart; however, little is known about the effect or metabolism of LTs in the isolated bullfrog heart. Isolated perfused bullfrog hearts were administered randomized doses of LTC4, LTD4, or LTE4. The cardiac parameters of heart rate, developed tension, and its first derivative (dT/dt) were recorded. LTC4 was the most potent of the leukotrienes tested in eliciting positive inotropic effects. LTD4 and LTE4 were equally effective but about one order of magnitude less potent than LTC4. None of the LTs showed any chronotropic effects in this preparation. A series of [3H]LTC4 metabolism experiments were carried out using whole perfused hearts and minced bullfrog heart tissue. Isolated perfused bullfrog hearts administered [3H]LTC4 converted significant amounts to [3H]LTD4, and to a lesser degree, [3H]LTE4, during the 6-min course of collection. Both minced atrial and ventricular tissue converted [3H]LTC4 to radioactive metabolites that co-migrated with authentic LTD4 and LTE4 standards. In both tissues, the major product was [3H]LTD4, with smaller amounts of [3H]LTE4 produced. The atrium converted significantly more [3H]LTC4 to its metabolites than did the ventricle. The metabolism of [3H]LTC4 to [3H]LTD4 by both tissues was virtually abolished in the presence of serine borate. Cysteine had no effect on [3H]LTE4 production. The data in this study demonstrate that leukotrienes have the opposite inotropic effect on the heart when compared with mammals. Also in contrast to mammals, frogs metabolize LTC4 to a less potent compound and may use the LTC4 to LTD4 conversion as a mechanism of LTC4 inactivation.

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Amitriptyline functionally antagonizes cardiac H2 histamine receptors in transgenic mice and human atria

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-021-02065-7 ◽

2021 ◽

Author(s):

Joachim Neumann ◽

Maximilian Benedikt Binter ◽

Charlotte Fehse ◽

Margaréta Marušáková ◽

Maren Luise Büxel ◽

...

Keyword(s):

Antidepressant Drug ◽

Histamine Receptor ◽

Right Atrial ◽

Inotropic Effects ◽

Positive Inotropic Effects ◽

Contractile Parameters ◽

Left And Right ◽

Chronotropic Effects ◽

Perfused Hearts ◽

Right Atria

AbstractWe have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H2R-TG) mice that overexpress the human H2 histamine receptor (H2R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, was reported to act as antagonist on H2Rs. Here, we wanted to determine whether the histamine effects in H2R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H2R-TG and WT mice and human atrial preparations. Amitriptyline shifted the concentration-dependent PIE of histamine (1 nM–10 μM) to higher concentrations (rightward shift) in left atrial preparations from H2R-TG. Similarly, in isolated perfused hearts from H2R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H2R-TG mice, but not in the WT mice. However, the increases in contractility and PLB phosphorylation were attenuated by the addition of amitriptyline in perfused hearts from H2R-TG. In isolated electrically stimulated human atria, the PIE of histamine that was applied in increasing concentrations from 1 nM to 10 μM was reduced by 10-μM amitriptyline. In summary, we present functional evidence that amitriptyline also acts as an antagonist of contractility at H2Rs in H2R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.

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Monoamines and the isolated auricle of sepia officinalis: are there β-like receptors in the heart of a cephalopod?

Journal of Experimental Biology ◽

10.1242/jeb.202.9.1067 ◽

1999 ◽

Vol 202 (9) ◽

pp. 1067-1079

Author(s):

B. Versen ◽

S. Gokorsch ◽

A. Fiedler ◽

R. Schipp

Keyword(s):

Sepia Officinalis ◽

Receptor System ◽

Ventricular Performance ◽

Inotropic Effects ◽

Noradrenergic Innervation ◽

Positive Inotropic Effects ◽

Chronotropic Effects ◽

Hplc Analyses

Pharmacological examinations of isolated auricles from Sepia officinalis were carried out to analyze the putative role of the monoaminergic transmitter/receptor system in the control of auricle function. In conjunction with histofluorescence studies and HPLC analyses, evidence of a double excitatory serotonergic and noradrenergic innervation of the auricles was obtained. Serotonin-induced positive chronotropic and inotropic effects were blocked by mianserin (5-HT1 and 5-HT2) but not by cyproheptadine (5-HT2). It is assumed that the auricular serotonin (5-HT) receptor represents a 5-HT1-like subtype and is not identical to the ventricular 5-HT receptor. Noradrenaline, adrenaline and dopamine evoked mainly positive chronotropic reactions and less prominent positive inotropic reactions. The potency range (pD2 frequency: noradrenaline 6.65 >> adrenaline 5.69 > dopamine 5.34; pD2 amplitude: noradrenaline 6.09 (greater than or equal to) adrenaline 5.91 > dopamine 5.33) indicates out that noradrenaline might be the effective neurotransmitter in vivo. The α -mimetics clonidine (α 2) and phenylephrine (α 1) induced positive chronotropic and inotropic effects, while the β-mimetics albuterol (β2>β1) and dobutamine (β1) revealed only positive inotropic reactions. The β-agonist isoprenaline mimicked the positive chronotropic effects of noradrenaline and induced the strongest positive inotropic effects of all the agonists tested. Urapidil (α 1) or phentolamine (α 1 and α 2) blocked only the positive chronotropic effects of noradrenaline and isoprenaline. The positive inotropic effects of isoprenaline could be blocked by the adenylate cyclase inhibitors MDL-12,330A or SQ-22, 536, which had no effect on the chronotropic effects of isoprenaline. These results suggest that two catecholaminergic receptors are present in the auricles of Sepia officinalis: an α -like adrenoreceptor mediating mainly chronotropic effects, and a β-like receptor which appears to mediate inotropic effects by activating the cyclic AMP pathway. These results suggest that the auricles exert a regulatory effect on ventricular performance.

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Pharmacological and physiological assessment of serotonin formation and degradation in isolated preparations from mouse and human hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00350.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. H1087-H1097 ◽

Cited By ~ 5

Author(s):

Ulrich Gergs ◽

Franziska Jung ◽

Igor B. Buchwalow ◽

Britt Hofmann ◽

Andreas Simm ◽

...

Keyword(s):

Acid Decarboxylase ◽

Monoamine Transporters ◽

Metabolizing Enzymes ◽

Inotropic Effects ◽

Amino Acid Decarboxylase ◽

Mammalian Heart ◽

Physiological Assessment ◽

Positive Inotropic Effects ◽

Chronotropic Effects ◽

5 Ht Uptake

Using transgenic (TG) mice that overexpress the human serotonin (5-HT)4a receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT4a receptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias. NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT.

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Contractile effects of cardiac neuropeptides in isolated canine atrial and ventricular muscles

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.4.h1082 ◽

1989 ◽

Vol 257 (4) ◽

pp. H1082-H1087 ◽

Cited By ~ 1

Author(s):

D. F. Rigel ◽

I. L. Grupp ◽

A. Balasubramaniam ◽

G. Grupp

Keyword(s):

Isometric Force ◽

Contractile Force ◽

Adrenergic Blockade ◽

Canine Heart ◽

Inotropic Action ◽

Inotropic Effects ◽

Calcitonin Gene ◽

Positive Inotropic Effects ◽

The Right ◽

Ventricular Trabeculae

Contractile effects of the cardiac neuropeptides vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), and neurotensin (NT) were compared with those of l-isoproterenol (ISO) in isolated canine atrial and ventricular trabeculae muscles stimulated to contract at 1 Hz. In ventricular muscles, ISO, VIP, and PHI augmented developed isometric force by approximately 100%. VIP and PHI were three times and 1/10, respectively, as potent as ISO. VIP also exhibited positive inotropic effects in atrial trabeculae. The contractile responses to VIP were unchanged after beta-adrenergic blockade with nadolol at a concentration (10 microM) that shifted the ISO dose-response curve two to three orders of magnitude to the right. In atrial and ventricular trabeculae, NPY (1 microM) attenuated contractile force by 36 +/- 8 and 30 +/- 4%, respectively. Each peptide also caused comparable increases or decreases in the rate of development of force and the rate of relaxation. CGRP and NT caused no significant changes in developed force in either atrial or ventricular muscles in concentrations up to 1 microM. Our results indicate a potential positive inotropic action of endogenous VIP and PHI and a cardiodepressant effect of endogenous NPY in the canine heart.

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Failure of dibutyryl and 8-bromo-cyclic gmp to mimic the antagonistic action of carbachol on the positive inotropic effects of sympathomimetic amines in the canine isolated ventricular myocardium

The Japanese Journal of Pharmacology ◽

10.1254/jjp.29.423 ◽

1979 ◽

Vol 29 (3) ◽

pp. 423-433 ◽

Cited By ~ 14

Author(s):

Masaso Endoh ◽

Tetsuo Shimizu

Keyword(s):

Cyclic Gmp ◽

Ventricular Myocardium ◽

Antagonistic Action ◽

Inotropic Effects ◽

Sympathomimetic Amines ◽

Positive Inotropic Effects

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Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart

Journal of Endocrinology ◽

10.1677/joe.0.1690177 ◽

2001 ◽

Vol 169 (1) ◽

pp. 177-183 ◽

Cited By ~ 64

Author(s):

K Terui ◽

A Higashiyama ◽

N Horiba ◽

KI Furukawa ◽

S Motomura ◽

...

Keyword(s):

Rat Heart ◽

Isolated Rat Heart ◽

Coronary Vasodilation ◽

Duration Of Action ◽

Inotropic Effects ◽

Vasodilator Effect ◽

Cardiac Effects ◽

Positive Inotropic Effects ◽

Isolated Rat

Corticotropin-releasing factor (CRF) has a coronary vasodilator effect and a positive inotropic effect on the isolated rat heart. Recently, expression of CRF receptor type 2 (CRF-R2) has been demonstrated in the heart. In addition, urocortin (Ucn), a new member of the CRF family, has been reported to have much greater affinity for CRF-R2 than CRF. It is suggested that the cardiac effects of Ucn may be more potent than those of CRF. We compared the effect of Ucn with that of CRF on isolated rat heart. The effects of Ucn were then analyzed to determine whether these effects were mediated by CRF receptors and/or any other mediators under the following conditions: perfusion buffer containing (1) alpha-helical CRF 9-41, (2) indomethacin, (3) N(G)-nitro-l -arginine methylester and (4) propranolol. Ucn exhibited a greater effect with a longer duration of action than CRF. Indomethacin significantly attenuated the vasodilator effects of Ucn (P<0.05). CRF receptor antagonist diminished both coronary vasodilation and the positive inotropic effects of Ucn (P<0.05). These results suggest that the cardiac effects of Ucn may be mediated by a CRF receptor, and prostaglandins may be involved in the vasodilator effect.

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