Direct activation of Ca 2+ channels by palmitoyl carnitine, a putative endogenous ligand

1 Palmitoyl carnitine, a lipid metabolite which accumulates in cytoplasmic membranes during ischaemia, has been shown to resemble the Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ ‐dependent, nor were they modified by calcium‐antagonists. Other detergents did not have selective interactions with Ca 2+ channels. 4 Palmitoyl carnitine inhibited [ 3 H]‐nitrendipine, [ 3 H]‐verapamil and [ 3 H]‐diltiazem binding to rat cortical membranes with IC 50 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 IC 50 value for [ 3 H]‐verapamil binding at 37°C (42 ± 5 μmol l −1 ). Palmitoyl carnitine interacted selectively with the Ca 2+ channel, in that effects on ligand binding to α‐adrenoceptors, β‐adrenoceptors and 5‐HT 1A 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 Ca 2+ channels and may therefore be considered as an endogenous modulator of channel function. The site of action differs from that of other agents.