Negative inotropic effects of tumour necrosis factor-alpha and interleukin-1beta are ameliorated by alfentanil in rat ventricular myocytes.
OBJECTIVE
Serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) increase during an inflammatory response and have been reported to induce a negative inotropic effect on the myocardium. Alfentanil, an opioid analgesic often used in the critical care of patients with sepsis, has been shown to enhance ventricular contractility. This study characterised the effects of TNF-alpha and IL-1beta on contraction and the Ca(2+) transient and investigated whether depressed ventricular function was ameliorated by alfentanil.


METHODS
Isolated rat ventricular myocytes were loaded with fura-2 and electrically stimulated at 1 Hz. Contraction and Ca(2+) transients were measured after 60, 120 and 180 min incubations in TNF-alpha (0.05 ng ml(-1)) and IL-1beta (2 ng ml(-1)). The effects of 10 microM alfentanil on contractility and Ca(2+) transients of TNF-alpha and IL-1beta treated cells were determined.


RESULTS
After 180 min of TNF-alpha and IL-1beta treatment, the amplitude of contraction, the Ca(2+) transient and sarcoplasmic reticulum (SR) Ca(2+) content were significantly reduced. Alfentanil significantly increased contraction of TNF-alpha and IL-1beta treated cells via a small increase in the Ca(2+) transient and a larger increase in myofilament Ca(2+) sensitivity, effects that were not blocked by 10 microM naloxone, a broad spectrum opioid receptor antagonist.


CONCLUSIONS
TNF-alpha and IL-1beta induce a significant negative inotropic effect on ventricular myocytes in a time dependent manner through disruption of SR Ca(2+) handling and the Ca(2+) transient. This negative inotropic effect was ameliorated by alfentanil, but this response may not be mediated via opioid receptors.
Duncan
D J
DJ
Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
Hopkins
P M
PM
Harrison
S M
SM
D015760:Alfentanil / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003864:Depression, Chemical; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D000701:Analgesics, Opioid; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D015760:Alfentanil; D009270:Naloxone