Positive inotropic effects of low concentrations of leukotrienes C4 and D4 in rat heart

We examined the effects of leukotrienes (LT) B4, C4, D4, and E4 (0.010-2.5 ng/ml) on contractile and coronary function in isolated rat hearts. Concentration-dependent effects were examined either by the cumulative addition of LTs or by addition of specific concentrations to individual preparations. Neither LTB4 nor LTE4 produced myocardial or coronary effects at any concentration, irrespective of addition protocol. At 0.010 ng/ml, both LTC4 and LTD4 produced an increase in force that was associated with a 30% elevation in coronary pressure. Further cumulative addition of either leukotriene resulted in a negative inotropic effect and a further increase in coronary pressure. In contrast, following single additions of LTC4 or LTD4 (0.01-0.50 ng/ml) a positive inotropic effect and an increased coronary pressure were observed. LTC4 or LTD4 at 0.5 ng/ml produced a negative inotropic effect in hearts pretreated with 0.01 ng/ml of LTD4 or LTC4, respectively. Reversal of this addition protocol resulted in a negative inotropic effect of either 0.01 ng/ml LTD4 or LTC4. Verapamil and nifedipine significantly attenuated the positive inotropic and coronary constricting effect of 0.5 ng/ml LTC4 and LTD4. The addition of either LT following BAY K 8644 resulted in a negative inotropic effect, in contrast to the positive inotropic influence seen with leukotriene alone. Our results demonstrate a positive inotropic effect of low concentrations of LTC4 and LTD4 concomitant with coronary artery constriction, a phenomenon determined by leukotriene addition protocols and suggestive of LTC4/LTD4 receptor interaction. The effects of calcium channel antagonists and BAY K 8644 on the inotropic response suggest a leukotriene-mediated activation of the calcium channel resulting in increased intracellular calcium concentrations.

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Negative and Positive Inotropic Effects of Propofol via L-type Calcium Channels and the Sodium-Calcium Exchanger in Rat Cardiac Trabeculae

Anesthesiology ◽

10.1097/00000542-200211000-00019 ◽

2002 ◽

Vol 97 (5) ◽

pp. 1146-1155 ◽

Cited By ~ 8

Author(s):

Wouter de Ruijter ◽

Ger J. M. Stienen ◽

Jan van Klarenbosch ◽

Jacob J. de Lange

Keyword(s):

Calcium Channel ◽

Calcium Concentration ◽

Positive Inotropic Effect ◽

Calcium Influx ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Sodium Calcium Exchanger ◽

Inotropic Effects ◽

Reverse Mode ◽

Sodium Calcium

Background Conflicting opinions are present in the literature regarding the origin of the negative inotropic effect of propofol on the myocardium. This study aims to resolve these discrepancies by investigating the inotropic effects of propofol the L-type calcium channels and the sodium-calcium exchanger (NCX). Methods The effect of 20 microg/ml propofol on force development was determined in rat cardiac trabeculae at different pacing frequencies and different extracellular calcium concentrations. Postrest potentiation, sodium withdrawal during quiescence, and the NCX inhibitor KB-R7943 were used to study changes in the activity of the reverse mode of the NCX by propofol. Results The effect of propofol on steady state peak force depended on pacing frequency and calcium concentration. A negative inotropic effect was observed at pacing frequencies greater than 0.5 Hz, but a positive inotropic effect was observed at 0.1 Hz and low calcium, which cannot be explained by an effect on the L-type calcium channel. Propofol enhanced postrest potentiation in a calcium-dependent manner. Sodium withdrawal during quiescence and the use of the specific NCX inhibitor KB-R7943 provided evidence for an enhancement of calcium influx by propofol the reverse mode of the NCX. Conclusions The effects of propofol on the myocardium depend on pacing frequency and calcium concentration. The positive inotropic effect of propofol is associated with increased calcium influx the reverse mode of the NCX. The authors conclude that the net inotropic effect of propofol is the result of its counteracting influence on the functioning of the L-type calcium channel and the NCX.

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Inotropic effects of ETB receptor stimulation and their modulation by endocardial endothelium, NO, and prostaglandins

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00563.2003 ◽

2004 ◽

Vol 287 (3) ◽

pp. H1194-H1199 ◽

Cited By ~ 18

Author(s):

Adelino F. Leite-Moreira ◽

Carmen Brás-Silva

Keyword(s):

Vascular Tone ◽

Positive Inotropic Effect ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Papillary Muscles ◽

Active Tension ◽

Receptor Stimulation ◽

Inotropic Effects ◽

Etb Receptor ◽

Endocardial Endothelium

Endothelin (ET)-1 acts on ETA and ETB receptors. The latter include ETB1 (endothelial) and ETB2 (muscular) subtypes, which mediate opposite effects on vascular tone. This study investigated, in rabbit papillary muscles ( n = 84), the myocardial effects of ETB stimulation. ET-1 (10−9 M) was given in the absence or presence of BQ-123 (ETA antagonist). The effects of IRL-1620 (ETB1 agonist, 10−10–10−6 M) or sarafotoxin S6c (ETB agonist, 10−10–10−6 M) were evaluated in muscles with intact or damaged endocardial endothelium (EE); intact EE, in the presence of NG-nitro-l-arginine (l-NNA); and intact EE, in the presence of indomethacin (Indo). Sarafotoxin S6c effects were also studied in the presence of BQ-788 (ETB2 antagonist). ET-1 alone increased 64 ± 18% active tension (AT) but decreased it by 4 ± 2% in the presence of BQ-123. In muscles with intact EE, sarafotoxin S6c alone did not significantly alter myocardial performance. Sarafotoxin S6c (10−6 M) increased, however, AT by 120 ± 27% when EE was damaged and by 39 ± 8% or 23 ± 6% in the presence of l-NNA or Indo, respectively. In the presence of BQ-788, sarafotoxin S6c decreased AT (21 ± 3% at 10−6 M) in muscles with intact EE, an effect that was abolished when EE was damaged. IRL-1620 also decreased AT (22 ± 3% at 10−6 M) in muscles with intact EE, an effect that was abolished when EE was damaged or in the presence of l-NNA or Indo. In conclusion, the ETB-mediated negative inotropic effect is presumably due to ETB1 stimulation, requires an intact EE, and is mediated by NO and prostaglandins, whereas the ETB-mediated positive inotropic effect, observed when EE was damaged or NO and prostaglandins synthesis inhibited, is presumably due to ETB2 stimulation.

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Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.1.h119 ◽

1997 ◽

Vol 273 (1) ◽

pp. H119-H127 ◽

Cited By ~ 6

Author(s):

Y. Zhu ◽

H. T. Yang ◽

M. Endoh

Keyword(s):

Receptor Antagonist ◽

Positive Inotropic Effect ◽

Dominant Role ◽

Negative Inotropic Effect ◽

Camp Level ◽

Inotropic Effect ◽

Inotropic Effects ◽

Eta Receptor ◽

Etb Receptor ◽

Eta Receptor Antagonist

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

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Transient inotropic effects of low extracellular sodium in perfused rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.3.h712 ◽

1990 ◽

Vol 259 (3) ◽

pp. H712-H719 ◽

Cited By ~ 2

Author(s):

F. Kolar ◽

W. C. Cole ◽

B. Ostadal ◽

N. S. Dhalla

Keyword(s):

Rat Heart ◽

Positive Inotropic Effect ◽

Minor Role ◽

Inotropic Response ◽

Inotropic Effects ◽

Low Concentrations ◽

Rat Hearts ◽

Rapid Loading ◽

Perfused Rat Hearts ◽

Extracellular Sodium

The inotropic effects of low concentrations of extracellular Na+ (35-110 mM) were studied using Langendorff-perfused rat hearts. Low Na+ induced an initial positive inotropic response proportional to the decrease of transsarcolemmal Na+ gradient. At 35 mM Na+, this effect was followed by a secondary fall in contractility and rise of resting force (RF) and then by a delayed positive inotropic effect and recovery of RF. The magnitude of these low Na(+)-induced transient changes was dependent on the extracellular Ca2+ concentration and was altered by amiloride (6 x 10(-4) and 2.5 x 10(-3) M), ouabain (5 x 10(-5) and 5 x 10(-4) M), ryanodine (2 x 10(-8), 1 x 10(-7) and 1 x 10(-6) M), and sodium azide (1 x 10(-3) and 5 x 10(-3) M) but not by verapamil (2 x 10(-8) and 1 x 10(-7) M) or vanadate (4 x 10(-6) M). The data indicate the initial positive inotropic response of the rat heart to low Na+ may be due to rapid loading of myocytes with Ca2+ through the Na(+)-Ca2+ exchange mechanism. The secondary depression of contractility and the rise of RF appear to be the consequence of the short-lived intracellular Ca2+ overload. Furthermore, the recovery of contractions and the delayed positive inotropic response may be the result of the intracellular redistribution of excessive Ca2+ into the sarcoplasmic reticulum with mitochondria and increased transsarcolemmal Ca2+ efflux apparently playing a more minor role.

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Responses of contractile function to ruthenium red in rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.6.h1413 ◽

1988 ◽

Vol 255 (6) ◽

pp. H1413-H1420 ◽

Cited By ~ 1

Author(s):

M. P. Gupta ◽

I. R. Innes ◽

N. S. Dhalla

Keyword(s):

Rat Heart ◽

Contractile Function ◽

Negative Inotropic Effect ◽

Ruthenium Red ◽

Inotropic Effect ◽

Inotropic Effects ◽

Rat Hearts ◽

Positive Inotropic Effects ◽

High Concentrations

Isolated rat hearts exhibited a biphasic contractile response to varying concentrations of ruthenium red. A negative inotropic effect was observed with concentrations of 0.025–0.5 microM, whereas a reversal of these initial changes toward control or even exceeding the predrug values was obtained as ruthenium red concentration was increased to 2.5 or 5.0 microM. High concentrations (12.5–25.0 microM) of ruthenium red caused a sustained contracture. In contrast, isolated frog hearts exhibited only a sustained negative inotropic effect at 0.25–12.5 microM ruthenium red. In studies with rat heart, both negative and positive inotropic effects of 2.5 microM ruthenium red were blocked either by increasing the concentration of Ca2+ (from 1.25 to 5.0 mM) or by decreasing the concentration of Na+ (from 140 to 35 mM) in the perfusion medium. The contracture induced by 12.5 microM ruthenium red was markedly inhibited when Ca2+ in the medium was lowered. The positive inotropic effect and contracture due to ruthenium red were also blocked by 1 microM of verapamil and 1.5 mM of amiloride; however, these interventions did not prevent the initial negative inotropic effect of ruthenium red. These experiments suggest the role of extracellular Ca2+ in the dose- and time-dependent effects of ruthenium red on contractile function of the rat heart. Furthermore, the positive inotropic response to ruthenium red may be related to its actions on the Na+-dependent Ca2+ movements in the cardiac cell.

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Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of β2-adrenoceptor agonists in guinea pig right papillary muscles

AJP Cell Physiology ◽

10.1152/ajpcell.00231.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. C106-C117 ◽

Cited By ~ 6

Author(s):

Fabien A. Faucher ◽

François E. Gannier ◽

Jacques M. Lignon ◽

Pierre Cosnay ◽

Claire O. Malécot

Keyword(s):

Guinea Pig ◽

Positive Inotropic Effect ◽

Negative Inotropic Effect ◽

Inotropic Effect ◽

Papillary Muscles ◽

Guinea Pig Heart ◽

Inotropic Effects ◽

Inotropic State ◽

No Release ◽

High Concentrations

Although β2-adrenoceptors represent 15–25% of β-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of β2-adrenoceptor partial agonists in right papillary muscles. Salbutamol induced a small but significant concentration-dependent negative inotropic effect (NIE, −5% at 60 nM) followed by a moderate positive inotropic effect (+36% at 6 μM) due to activation of β1-adrenoceptors. In the presence of 4 μM atenolol, the concentration-dependent NIE (−12% at 6 μM) was biphasic, best described by a double logistic equation with respective EC50 values of 3 and ∼420 nM, and was insensitive to SR59230A. In muscles from pertussis toxin-treated guinea pigs, the salbutamol-induced positive inotropic effect was sensitive to low concentrations of ICI-118551 in an unusual manner. Experiments in reserpinized animals revealed the importance of the phosphorylation-dephosphorylation processes. PKA inhibition reduced and suppressed the effects obtained at low and high concentrations, respectively, indicating that its activation was a prerequisite to the NIE. The effect occurring at nanomolar concentrations depended upon PKA/phosphatidylinositol 3-kinase/cytosolic phospholipase A2 (cPLA2) activations leading to nitric oxide (NO) release via the arachidonic acid/cyclooxygenase pathway. NO release via PKA-dependent phosphorylation of the receptor was responsible for the inotropic effect observed at submicromolar concentrations, which is negatively controlled by cPLA2. The possibility that these effects are due to an equilibrium between different affinity states of the receptor (Gs/Gi coupled and Gi independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that β2-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state.

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Positive inotropic effects of acetylcholine and BAY K 8644 in embryonic chick ventricle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1987.252.4.h807 ◽

1987 ◽

Vol 252 (4) ◽

pp. H807-H815 ◽

Cited By ~ 1

Author(s):

Y. Tsuji ◽

T. Tajima ◽

J. Yuen ◽

A. J. Pappano

Keyword(s):

Action Potentials ◽

Positive Inotropic Effect ◽

Bay K 8644 ◽

Inotropic Effect ◽

Phosphoinositide Metabolism ◽

Ca Channel ◽

Embryonic Chick ◽

Muscarinic Agonists ◽

Cholinergic Agonists ◽

Inotropic Effects

BAY K 8644 augmented Ca2+-dependent action potentials and evoked a positive inotropic effect in embryonic chick ventricle. These effects are consistent with the properties of this Ca channel "agonist" whose actions are independent of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphorylation. At low to intermediate concentrations (10(-8) to 10(-6) M), the cholinergic agonists acetylcholine, carbachol, and oxotremorine inhibit Ca2+-dependent action potentials and contractions in embryonic ventricle only in the presence of drugs that cause cAMP accumulation. The prediction that low to intermediate concentrations of these cholinergic agonists should not inhibit the effects of BAY K 8644 on Ca2+-dependent action potentials and contractions was borne out experimentally. This result is consistent with the cAMP hypothesis for muscarinic inhibition. It is noteworthy that all cholinergic agonists tested evoked a positive inotropic effect at high concentrations (greater than 10(-6) M) in the presence or absence of BAY K 8644. The positive inotropic effect was initiated by muscarinic receptors for it was blocked by atropine and was independent of endogenous catecholamines, since it occurred in the presence of propranolol. It is speculated that the positive inotropic effect of muscarinic agonists in embryonic heart muscle is related to stimulation of phosphoinositide metabolism.

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Interaction of Halothane with α- and β-Adrenoceptor Stimulations in Rat Myocardium

Anesthesiology ◽

10.1097/00000542-199701000-00019 ◽

1997 ◽

Vol 86 (1) ◽

pp. 147-159 ◽

Cited By ~ 21

Author(s):

Jean-Luc Hanouz ◽

Bruno MD Riou ◽

Laurent Massias ◽

Yves Lecarpentier ◽

Pierre Coriat

Keyword(s):

Positive Inotropic Effect ◽

Negative Inotropic Effect ◽

Left Ventricular ◽

Inotropic Effect ◽

Papillary Muscles ◽

Inotropic Effects ◽

Beta Adrenoceptor ◽

Low Load ◽

Positive Inotropic Effects

Background Halothane induces negative inotropic and lusitropic effects in myocardium. It has been suggested that halothane potentiates beta-adrenoceptor stimulation. However, its effects on the inotropic response to alpha-adrenoceptor stimulation and its effects on the lusitropic effects of alpha- and beta-adrenoceptor stimulation are unknown. Methods The effects of halothane (0.5 and 1 minimum alveolar concentration [MAC]) on the inotropic responses induced by phenylephrine (10(-8) to 10(-4) M) and isoproterenol (10(-8) to 10(-4) M) were studied in rat left ventricular papillary muscles in vitro (in Krebs-Henseleit solution at 29 degrees C, pH 7.40, with 0.5 mM calcium and stimulation frequency at 12 pulses/min). The lusitropic effects were studied in isotonic (R1) and isometric (R2) conditions. Results One MAC halothane induced a negative inotropic effect (54 +/- 3%, P < 0.05), increased R1 (109 +/- 3%, P < 0.05), and decreased R2 (88 +/- 2%, P < 0.05). In control groups, phenylephrine (137 +/- 7%, P > 0.05) and isoproterenol (162 +/- 6%, P < 0.05) induced a positive inotropic effect. Halothane did not significantly modify the positive inotropic effect of calcium, suggesting that it did not modify the inotropic reserve of papillary muscles. In contrast, 1 MAC halothane enhanced the positive inotropic effects of phenylephrine (237 +/- 19%, P < 0.05) and isoproterenol (205 +/- 11%, P < 0.05). Halothane did not modify the lusitropic effect of phenylephrine under high or low load. In contrast, 1 MAC halothane impaired the positive lusitropic effect of isoproterenol under low load (P < 0.05), whereas it did not modify the positive lusitropic effect of isoproterenol under high load. Conclusions At clinically relevant concentrations, halothane potentiated the positive inotropic effects of both alpha- and beta-adrenoceptor stimulation. Furthermore, halothane alters the positive lusitropic-effect of beta-adrenoceptor stimulation under low load.

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