Suppression of β-adrenergic responsiveness of L-type Ca²⁺ current by IL-1β in rat ventricular myocytes

Abstract

The possible mechanism by which interleukin-1β (IL-1β) affects β-adrenergic responsiveness of L-type Ca2+ current ( I Ca,L) was examined in adult rat ventricular myocytes by use of whole cell patch-clamp techniques. In the presence of isoproterenol (Iso), exposure for 3 min to IL-1β suppressed the Iso-activated I Ca,L. In the presence of IL-1β, the response of I Ca,L to Iso was decreased, and the EC50 for Iso stimulation was increased. However, IL-1β had no effect on [3H]CGP-12177 binding, displacement of [3H]CGP-12177 binding by Iso, or on basal and Iso-enhanced cAMP content. When I Ca,L was activated by extracellular application of forskolin or 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, or by intracellular dialysis with cAMP, IL-1β had little effect on I Ca,L. In contrast, in the presence of cAMP, IL-1β still suppressed the Iso-enhanced I Ca,L. These results show that the IL-1β-induced decrease in β-adrenergic responsiveness of I Ca,L does not result from inhibition of β-adrenoceptor binding, adenylyl cyclase activity, or cAMP-mediated pathways, suggesting a cAMP-independent mechanism.

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

“…Recent studies have highlighted the involvement of IL-1 signaling in heart disease (13). IL-1 has been shown to induce impairment in β-adrenergic responsiveness and contractility, both in vitro and in vivo (16,32). Single or repeated injections of recombinant murine IL-1β induce systolic dysfunction and impaired contractile reserve in absence of structural changes (16,33).…”

Disease–drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation

“…23,24 In general, in vitro introduction of inflammatory mediators (e.g., interleukines, tumor necrosis factor-a and interferon-a) has resulted in reduced responsiveness, affinitym and/or density of b-adrenergic receptors. [25][26][27][28][29] These in vitro observations may also be attributed to an overexpression of NO secondary to inflammation or introduction of other pro-inflammatory mediators. 30 Our AA rats showed almost threefold greater nitrate concentration than controls.…”

Cytokine-Induced Modulation of Cardiac Function

“…In isolated mammalian myocytes, within minutes of exposure to cytokines such as TNF-␣, IL-1␤, and IL-6, there is an inhibition of catecholamine-stimulated contractility, 71,75 cAMP generation, 71 and I Ca augmentation. 75,76 The mechanism for this defect in ␤-AR signal transduction is not clear, although one study 76 suggested a mechanism unrelated to alterations in ␤-AR binding, adenylyl cyclase (AC) activity, or cAMP. Finally, in another isolated myocyte study, IL-2 was shown to reduce cell contraction and Ca 2ϩ transients via the cardiac opioid receptor, a mechanism dependent on pertussis toxinsensitive G protein and phospholipase C. 62 Further studies are needed to determine the mechanistic role of these signal transduction pathways.…”