Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand

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Abstract
1 Palmitoyl carnitine, a lipid metabolite which accumulates in cytoplasmic membranes during ischaemia, has been shown to resemble the Ca2+ channel activator, Bay K 8644, in K+-depolarized smooth muscle. Palmitoyl carnitine caused concentration-dependent (1–1000 μmol l−1) augmentations in the sensitivity to Ca2+ of K+-depolarized taenia preparations from the guinea-pig caecum. The (±)-isomer was equieffective with the (–)-isomer, whereas carnitine was ineffective and palmitic acid relaxed the tissues. The shift to the left of Ca2+ concentration-response curves induced by palmitoyl carnitine (100 μmol l−1) was additive with that of Bay K 8644 (1 μmol l−1). 2 The interactions of palmitoyl carnitine with the different classes of calcium-antagonist were similar to those seen with Bay K 8644. Schild plots of the calcium-antagonist effects of nifedipine were shifted to the right following preincubation of the taenia with palmitoyl carnitine (30–300 μmol l−1). The inhibitory effects of verapamil were especially sensitive to palmitoyl carnitine (100 μmol l−1). Whereas the potency of diltiazem as a calcium-antagonist was reduced by palmitoyl carnitine (100 μmol l−1), the inhibitory effects of the lipophilic class III calcium-antagonists, cinnarizine and flunarizine, were entirely resistant to palmitoyl carnitine (100 μmol l−1). 3 Although palmitoyl carnitine has detergent properties in high concentrations and lyses red blood cells, these effects were not Ca2+-dependent, nor were they modified by calcium-antagonists. Other detergents did not have selective interactions with Ca2+ channels. 4 Palmitoyl carnitine inhibited [3H]-nitrendipine, [3H]-verapamil and [3H]-diltiazem binding to rat cortical membranes with IC50 values (μmol l−1) of 120 ± 1, 95 ± 17 and 120 ± 15 μmol l−1 respectively. The inhibition showed little temperature-dependence, in contrast to that of Bay K 8644, except for a small reduction in the IC50 value for [3H]-verapamil binding at 37°C (42 ± 5 μmol l−1). Palmitoyl carnitine interacted selectively with the Ca2+ channel, in that effects on ligand binding to α-adrenoceptors, β-adrenoceptors and 5-HT1A receptors occurred only at 5–10 fold higher concentrations. 5 It is concluded that palmitoyl carnitine, at concentrations which have previously been shown to occur in the cytoplasm during myocardial ischaemia, may interact directly with Ca2+ channels and may therefore be considered as an endogenous modulator of channel function. The site of action differs from that of other agents.

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