Effects of ivermectin and midecamycin on ryanodine receptors and the Ca²⁺‐ATPase in sarcoplasmic reticulum of rabbit and rat skeletal muscle

Abstract

The ryanodine receptor (RyR) is a large conductance ion channel which allows Ca¥ release from the sarcoplasmic reticulum (SR) of skeletal muscle to initiate contraction in response to sarcolemmal depolarization (Dulhunty, 1992).The contraction is terminated when Ca¥ is pumped back into the SR by the Ca¥-Mg¥-ATPase. The functional skeletal RyR Ca¥-release channel is a homotetrameric complex of RyR monomers (Mr •560000) and four FK506-Journal of Physiology (1999), 514.2, pp. 313-326 313 Effects of ivermectin and midecamycin on ryanodine receptors and the Ca¥-ATPase in sarcoplasmic reticulum of rabbit and rat skeletal muscle 0·66-40 ìÒ) activated six of eight native, four of four control-incubated and eleven of eleven FKBP12-'stripped' RyR channels. Midecamycin (cis, 10-30 ìÒ) activated three of four single native channels, six of eight control-incubated channels and six of seven FKBP12-stripped channels. Activity declined when either drug was washed out. 3. Neither ivermectin nor midecamycin removed FKBP12 from RyRs. Western blots of terminal cisternae (TC), incubated for 15 min at 37°C with 40 ìÒ ivermectin or midecamycin, showed normal amounts of FKBP12. In contrast, no FKBP12 was detected after incubation with 40 ìÒ rapamycin. 4. Ivermectin reduced Ca¥ uptake by the SR Ca¥-Mg¥-ATPase. Ca¥ uptake by TC fell to•40% in the presence of ivermectin (10 ìÒ), both with and without 10 ìÒ Ruthenium Red. Ca¥ uptake by longitudinal SR also fell to •40% with 10 ìÒ ivermectin. Midecamycin (10 ìÒ) reduced Ca¥ uptake by TC vesicles to •76% without Ruthenium Red and to •90% with Ruthenium Red. 5. The rate of rise of extravesicular [Ca¥] increased •2-fold when 10 ìÒ ivermectin was added to TC vesicles that had been partially loaded with Ca¥ and then Ca¥ uptake blocked by 200 nÒ thapsigargin. Ivermectin also potentiated caffeine-induced Ca¥ release to •140% of control. These increases in Ca¥ release were not seen with midecamycin. 6. Ivermectin, but not midecamycin, reversibly reduced Ca¥ loading in four of six skinned rat extensor digitorum longus (EDL) fibres to •90%, and reversibly increased submaximal caffeine-induced contraction in five of eight fibres by •110% of control. Neither ivermectin nor midecamycin altered twitch or tetanic tension in intact EDL muscle fibres within 20 min of drug addition. 7. The results confirm the hypothesis that compounds with a macrocyclic lactone ring structure can directly activate RyRs. Unexpectedly, ivermectin also reduced Ca¥ uptake into the SR. These effects of ivermectin on SR Ca¥ handling may explain some effects of the macrolide drugs on mammals.

Effect of parenteral administration of ivermectin and erythromycin on abomasal emptying rate in suckling calves

“…20 Clinical signs of ivermectin toxicosis in calves were associated with an increase in serum pseudocholinesterase activity, which suggested that some of the clinical signs (salivation, difficulty in breathing, miosis, and diarrhea) may have been attributable to γ-aminobutyric acid-mediated cholinergic function. 22 Results of the study reported here should not be construed as promoting the extralabel use of ivermectin as a prokinetic agent. Alternatively, the weak prokinetic ef- fect after IV administration of ivermectin (and some or all of the adverse clinical effects after IV injection of ivermectin) may have been attributable to augmentation of smooth and skeletal muscle responsiveness to depolarization because ivermectin directly activates ryanodine receptors in skeletal muscles and decreases calcium uptake into the sarcoplasmic reticulum, thereby augmenting contraction in skeletal muscles in response to sarcolemmal depolarization.…”

The inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase by macrocyclic lactones and cyclosporin A

“…Ivermectin, an anti-helminthic agent [8], has previously been reported to be an inhibitor of ATP-dependent Ca# + uptake [13]. Ivermectin, an anti-helminthic agent [8], has previously been reported to be an inhibitor of ATP-dependent Ca# + uptake [13].…”

“…In addition, it was shown that FK-506 inhibited Ca# + -dependent ATPase activity in cardiac sarcoplasmic reticulum (SR) [12]. Furthermore it has been reported that ivermectin inhibits Ca# + uptake into skeletal muscle SR, and enhances Ca# + release via the ryanodine receptor, but not via the inositol 1,4,5-trisphosphate receptors [13].…”

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

“…In addition to nematode acetylcholine receptors, these targets also include P2X receptors of Schistosoma [32] and of mouse ( [33]) and histamine-gated chloride channels of Drosophila [34], as well as nematode [35][36][37][38] and insect [39,40] glutamate-gated chloride channels, GABA receptors from nematodes to vertebrates [41][42][43][44] and human glycine receptors [45]. There is also evidence for an action of IVM on an intracellular ligand-gated ion channel, the ryanodine receptor [46]. In most cases examined so far, the action of IVM is through an allosteric stabilization of the open state of the channel, but in the case of recombinant nematode glutamategated chloride channels and rat GABA       receptors, IVM can also act as an agonist [43].…”