Arachidonic acid enhances contraction and intracellular Ca2+ transients in individual rat ventricular myocytes

Abstract

Modulation of intracellular free Ca2+ concentration ([Ca2+]i) by inotropic stimuli alters contractility in cardiac muscle. Arachidonic acid (AA), a precursor for eicosanoid formation, is released in response to receptor activation and myocardial ischemia and has been demonstrated to alter K+ and Ca2+ channel activity. We investigated the effects of AA on contractility by simultaneously measuring [Ca2+]i and shortening in single field-stimulated rat ventricular myocytes. [Ca2+]i transients were measured using fura 2, and myocyte shortening was assessed using video edge detection. AA stimulated a doubling in the amplitude of the [Ca2+]i transient and a twofold increase in myocyte shortening. In addition, AA stimulated a 30% increase in the time to 50% diastolic [Ca2+]i and a 35% increase in the time to 50% relengthening. These effects of AA were mediated by AA itself (56 +/- 5%) and by cyclooxygenase metabolites. Pretreatment with the protein kinase C inhibitors staurosporine and chelerythrine nearly abolished (> 90% inhibition) these AA-induced effects. Inhibition of voltagegated K+ channels with 4-aminopyridine mimicked the effects of AA. Addition of AA to the 4-aminopyridine-treated myocyte had no additional effect on parameters of contractile function. These data indicate that AA alters the amplitude and duration of Ca2- transients and myocyte shortening via protein kinase C-dependent inhibition of voltage-gated K+ channels. Release of AA by phospholipases in response to receptor activation by endogenous mediators or pathological stimuli may be involved in mediating inotropic responses in cardiac muscle.

The cyclooxygenase-2 product prostaglandin E2 modulates cardiac contractile function in adult rat ventricular cardiomyocytes

“…This cardiac potentiating property of PGE 2 is consistent with those elicited by PGE 2 or its precursor arachidonic acid reported at the whole animal or multicellular myocardial levels [6,9,11]. The PGE 2 -elicited positive cardiac contractile response is expected to counter-balance the vasoconstrictive action of PGE 2 on main arteries such as aorta to facilitate cardiac energy expenditure and ventricular performance [3,12].…”

“…Arachidonic acid, the precursor for eicosanoid formation, is released in response to receptor activation and pathological stimuli such as my-ocardial ischemia. It has been demonstrated that release of arachidonic acid in response to receptor activation or pathological stimuli elicits a positive cardiac inotropic response probably through modulation of membrane K + and Ca 2+ channel activity [5,6]. Although the precise mechanism(s) behind the positive cardiac inotropic actions of arachidonic acid and inflammatory cytokines (such as tumor necrosis factor-␣) is largely undefined, it may be speculated that the COX product PGE 2 plays a major role over other prostaglandins in mediating the cardiac function induced by arachidonic acid and inflammatory cytokines [7].…”

Inhibition of L-type Ca2+ channel current and negative inotropy induced by arachidonic acid in adult rat ventricular myocytes

“…This could result from different lipid composition in the cell membrane between adult and neonatal cardiomyocytes. By contrast, one study (10) in ARVM showed that AA (Ͼ10 M) enhanced CS and Ca 2ϩ transients, which were suggested to be mediated by cyclooxygenase metabolites via PKC-dependent inhibition of K ϩ channels. It is unclear whether this discrepancy could be explained by differences in experimental conditions; e.g., only cells that responded to AA were selected for study (10).…”

“…Am J Physiol Cell Physiol 293: C1594-C1604, 2007. First published September 5, 2007; doi: 10.1152/ajpcell.00284.2007.-We have previously shown an increase in arachidonic acid (AA) release in response to proinflammatory cytokines in adult rat ventricular myocytes (ARVM). AA is known to alter channel activities; however, its effects on cardiac L-type Ca 2ϩ channel current (ICa,L) and excitationcontraction coupling remain unclear.…”

“…AA has been shown to enhance cell shortening (CS) and the Ca 2ϩ transient in ARVM (10) or to reduce CS in adult guinea pig ventricular myocytes (36). It also has been reported that AA mediates a biphasic effect of TNF-␣ on contraction and the Ca 2ϩ transient in ARVM (1).…”