Enkephalins increase cyclic adenosine monophosphate content, calcium uptake, and contractile state in cultured chick embryo heart cells.

Laurent, Stephans; Marsh, James D.; Smith, Thomas W.

doi:10.1172/jci112455

Cited by 27 publications

(12 citation statements)

References 35 publications

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“…In a subsequent report, the same authors related this result to an increase in cell Ca'4 loading mediated by an enhancement in adenylate cyclase activity and cAMP levels. 35 In contrast, in a similar preparation, others have described that opioid receptor stimulation decreases cAMP, increases cGMP, and markedly inhibits the effect of norepinephrine to stimulate cAMP and reduce cGMP. 89 In rat brain homogenate, morphinelike substances were reported to inhibit hormonally stimulated cAMP formation without affecting its basal production,65 and a similar action on adenylate cyclase activity and cAMP levels has been reported in other neuronal cell types.64 '66 In unstimulated cardiac myocytes, an increase in cAMP would be expected to enhance SR Ca'+ uptake67, 68 (Tables 1 and 2).…”

Section: Release Of Sr Ca' By Ip3mentioning

confidence: 95%

Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons.

Ventura

Spurgeon

Lakatta

et al. 1992

Circulation Research

167

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We investigated the effects of mu, delta, and kappa opioid receptor stimulation on the contractile properties and cytosolic Ca2+ (Cai) of adult rat left ventricular myocytes. Cells were field-stimulated at 1 Hz in 1.5 mM bathing Ca2+ at 23 degrees C. The mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10(-5) M) had no effect on the twitch. The delta-agonists methionine enkephalin and leucine enkephalin (10(-10) to 10(-6) M) and the kappa-agonist (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-hexyl]- benzeneacetamide)methanesulfonate hydrate (U-50,488H; 10(-7) to 2 x 10(-5) M) had a concentration-dependent negative inotropic action. The sustained decrease in twitch amplitude due to U-50,488H was preceded by a transient increase in contraction. The effects of delta- and kappa-receptor stimulation were antagonized by naloxone and (-)-N-(3-furyl-methyl)-alpha-normetazocine methanesulfonate, respectively. In myocytes loaded with the Ca2+ probe indo-1, the effects of leucine enkephalin (10(-8) M) and U-50,488H (10(-5) M) on the twitch were associated with similar directional changes in the Cai transient. Myofilament responsiveness to Ca2+ was assessed by the relation between twitch amplitude and systolic indo-1 transient. Leucine enkephalin (10(-8) M) had no effect, whereas U-50,488H (10(-5) M) increased myofilament responsiveness to Ca2+. We subsequently tested the hypothesis that delta and kappa opioid receptor stimulation may cause sarcoplasmic reticulum Ca2+ depletion. The sarcoplasmic reticulum Ca2+ content in myocytes and in a caffeine-sensitive intracellular Ca2+ store in neurons was probed in the absence of electrical stimulation via the rapid addition of a high concentration of caffeine from a patch pipette above the cell. U-50,488H and leucine enkephalin slowly increased Cai or caused Cai oscillations and eventually abolished the caffeine-triggered Cai transient. These effects occurred in both myocytes and neuroblastoma-2a cells. In cardiac myocyte suspensions U-50,488H and leucine enkephalin both caused a rapid and sustained increase in inositol 1,4,5-trisphosphate. Thus, delta and kappa but not mu opioids have a negative inotropic action due to a decreased Cai transient. The decreased twitch amplitude due to kappa-receptor stimulation is preceded by a transient increase in contractility, and it occurs despite an enhanced myofilament responsiveness to Ca2+. The effects of delta and kappa opioids appear coupled to phosphatidylinositol turnover and, at least in part, may be due to sarcoplasmic reticulum Ca2+ depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Release Of Sr Ca' By Ip3mentioning

confidence: 95%

Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons.

Ventura

Spurgeon

Lakatta

et al. 1992

Circulation Research

167

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“…Determination of 45 Ca influx during this initial phase of its uptake in the presence of various agents permitted assessment of their effects on the activity of the calcium channel or Na ϩ /Ca 2ϩ exchange (24,25). For all data comparing the effect of different agents on 45 Ca influx, one-way ANOVA (14,15).…”

Section: Methodsmentioning

confidence: 99%

A New Cyclic AMP-independent, Gs-mediated Stimulatory Mechanism via the Adenosine A2a Receptor in the Intact Cardiac Cell

Liang

Morley

1996

Journal of Biological Chemistry

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The objectives of this study were to investigate the mechanism underlying the adenosine A 2a receptor (A 2a R)-mediated positive inotropic response and to define its contractile function using chick embryo ventricular cells as a model. Activation of the A 2a R caused a marked stimulation of calcium entry and cell contractility, which were blocked by verapamil or nifedipine. The effects elicited by maximal concentrations of the A 2a R agonist 2-[4-(2-carboxyethyl)phenylethylamino]-5-Nethylcarboxamidoadenosine and the ␤-adrenergic agonist isoproterenol were additive, indicating that the two receptors do not share a common stimulatory mechanism. The cAMP antagonist (R p )-adenosine cyclic 3:5-monophosphorothioate was ineffective in inhibiting the A 2a R-mediated stimulation of contractility or the L-type calcium channel, while it completely abolished the isoproterenol effects. Activation of the A 2a R had no effect on Na Multiple pathways mediate stimulation of cardiac cell contractility. The classical and best characterized pathway is that mediated by the ␤-adrenergic receptor, giving rise to an increase in cAMP with subsequent calcium entry and increase in myocyte contractility (1-4). The ␣-adrenergic receptor-mediated augmentation of cardiac contractility involves stimulation by inositol phosphates and protein kinase C that is cyclic AMPindependent (5-8). Adenosine exerts pronounced contractile effects in the heart. In the cardiac ventricular cell, adenosine attenuates the increase in the force of contraction elicited by ␤-adrenergic agonist, known as the anti-adrenergic effect, while adenosine by itself has no direct effect on the basal level of contractility. The anti-adrenergic effect is mediated by the inhibitory A 1 subtype of the adenosine receptor (for review, see Refs. 9 -13). Using fetal chick embryo ventricular cells as a model, prior studies demonstrated the presence of a high affinity adenosine A 2a receptor capable of mediating positive inotropic response when the A 1 receptor is blocked (14, 15). The marked positive inotropic response mediated by the A 2a receptor suggests a significant physiological or pathophysiological role of this receptor in the cardiac cell. Since the inhibitory A 1 receptor coexists with the stimulatory A 2a receptor and since the A 1 receptor mediates the anti-adrenergic effect of adenosine, the question arises regarding specifically the function of the A 2a receptor in modulating the basal as well as the ␤-adrenergic stimulated contractile states. Furthermore, the mechanism underlying the A 2a receptor-mediated positive inotropic response is not known. Although activation of the A 2a receptor can be coupled to stimulation of cAMP accumulation, it is not known whether cAMP mediates the increase in myocyte contractility.The objectives of this study, using cultured fetal ventricular cells as a model system, were to investigate the mechanism underlying the adenosine A 2a receptor-mediated positive inotropic response and to study the contractile function subserved by the A 2a r...

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“…There are studies showing that DOR agonist depressed cardiac function in Bio 14.6 hamster (3), while others demonstrated the escalation of cardiac contractility (9, 22). There is also a report showing that both DOR agonists and antagonists have negative inotropism (23).…”

Section: Discussionmentioning

confidence: 99%

Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling

Nguyen¹,

Guillory

et al. 2012

Peptides

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Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Methods Rats were injected with DOR-agonist DPDPE (100 μg/kg) with or without 10-min pretreatment with either β-adrenergic receptor (β-AR) blocker propranolol (2 mg/kg) or CGRP-receptor (CGRPR) blocker CGRP8-37 (300 μg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Results Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after DPDPE infusion. At 5-min DPDPE induced a 36±18% (p<0.001) increase of the LVFS, which continues to increase to 51±24% (p<0.0001) by 10 min, and 68±19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5 min and 11±6% (p<0.001) by 15 min post DPDPE infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17±8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post DPDPE administration, respectively. There was a modest (9±9%, p=0.03) decrease in SBP that was not apparent until 20 min post DPDPE infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol, CGRP8-37, or combined propranolol+CGRP8-37. Furthermore, in whole animal and cardiomyocyte cell culture preparations, DPDPE induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP8-37. Conclusion DOR agonists augment myocardial contraction through enhanced β-AR and CGRPR co-signaling.

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Enkephalins increase cyclic adenosine monophosphate content, calcium uptake, and contractile state in cultured chick embryo heart cells.

Cited by 27 publications

References 35 publications

Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons.

Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons.

A New Cyclic AMP-independent, Gs-mediated Stimulatory Mechanism via the Adenosine A2a Receptor in the Intact Cardiac Cell

Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling

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