κ And δ opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons

C. Ventura, H. Spurgeon, E. G. Lakatta, C. Guarnieri, M. C. Capogrossi

Research output: Contribution to journalArticle

Abstract

We investigated the effects of μ, δ, and κ opioid receptor stimulation on the contractile properties and cytosolic Ca2+ (Ca(i)) of adult rat left ventricular myocytes. Cells were field-stimulated at 1 Hz in 1.5 mM bathing Ca2+ at 23°C. The μ-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10-5 M) had no effect on the twitch. The δ-agonists methionine enkephalin and leucine enkephalin (10-10 to 10-6 M) and the κ-agonist (trans-(dl)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclo-hexyl]-benzeneacetamide) methanesulfonate hydrate (U-50,488H; 10-7 to 2x10-5 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 δ- and κ-receptor stimulation were antagonized by naloxone and (-)-N-(3-furylmethyl)-α-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 Ca(i) 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 δ and κ 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 Ca(i) or caused Ca(i) oscillations and eventually abolished the caffeine-triggered Ca(i) 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, δ and κ but not μ opioids have a negative inotropic action due to a decreased Ca(i) transient. The decreased twitch amplitude due to κ-receptor stimulation is preceded by a transient increase in contractility, and it occurs despite an enhanced myofilament responsiveness to Ca2+. The effects of δ and κ opioids appear coupled to phosphatidylinositol turnover and, at least in part, may be due to sarcoplasmic reticulum Ca2+ depletion. Ca2+ release and depletion of an intracellular store site occur in both myocytes and neurons and may represent a general mechanism for the effects of opioids.

Original languageEnglish (US)
Pages (from-to)66-81
Number of pages16
JournalCirculation research
Volume70
Issue number1
DOIs
StatePublished - Jan 1 1992
Externally publishedYes

Keywords

  • calcium
  • cardiac myocytes
  • inositol 1,4,5-trisphosphate
  • myocardial contraction
  • neurons
  • opioid peptides

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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