Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia

Abstract

In pigs, the serotonin-2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 0.8 mg/kg, induced "psychotic" behaviour (e.g., grimacing, backward locomotion, blank stare) and a muscular syndrome, which is known as malignant hyperthermia (MH) in pigs and humans. This syndrome is characterized by generalized skeletal muscle rigidity, leading to an increase in body temperature, marked acidosis, hyperkaliaemia, cyanosis and elevation of lactate, carbon dioxide and the muscle enzyme creatine kinase (CK) in plasma. In pigs which were selectively bred for susceptibility to MH induction by known triggering agents, such as halothane, the administration of DOI was fatal in 3 out of 5 animals. In genetically susceptible pigs, MH was also induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 0.5-1.8 mg/kg, and D-lysergic acid diethylamide (LSD), 60-110 micrograms/kg. Furthermore, 5-MeO-DMT and LSD induced head shakes in the animals, which had not been observed after DOI and could not be blocked by 5-HT2-antagonists, ketanserin (0.5-5 mg/kg) and ritanserin (1-2.5 mg/kg). The psychotomimetic effects of 5-MeO-DMT could be blocked by ketanserin or ritanserin, which, depending on the dose, also reduced or totally prevented the hyperthermia and metabolic changes induced by 5-MeO-DMT in pigs. Administration of 5-MeO-DMT, 1.8 mg/kg, was fatal in 4 of 5 MH-susceptible pigs, whereas pigs injected with this dosage after pretreatment with ketanserin (0.5-5 mg/kg) or ritanserin (1-2.5 mg/kg) did not die. In pigs from MH-resistant littermates, administration of 5-MeO-DMT was not fatal. Comparison of metabolic changes in susceptible and non-susceptible pigs suggested that the marked increase in plasma potassium, which arises principally from damaged muscle cells, is primarily responsible for the fatal effect of DOI and 5-MeO-DMT in genetically susceptible individuals. In MH-susceptible pigs, which were anesthetized, relaxed and artificially ventilated, 5-MeO-DMT did not induce hyperthermia, thus substantiating that the marked hyperthermia observed in conscious pigs was a result of muscle activation and not due to effects on thermoregulation or blood pressure. The results indicate that hallucinogenic drugs with 5-HT2 agonistic effects trigger a life-threatening syndrome, MH, in genetically susceptible pigs. 5-HT2 antagonists, such as ketanserin or ritanserin, are capable of counteracting the fatality of this syndrome.

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia

“…These findings, however, do not exclude an additional involvement of enhanced synthesis of IPs by activation of receptors which are G-protein-linked or coupled to tyrosine kinases (Berridge, 1993;Foster, 1994). As shown by the present data, 5-HT seems not to be critically involved in the enhancement of IPs at least in the halothane-induced MH crisis, whereas in MH triggered by a 5-HT2 receptor agonist this mechanism may play an important role (L6scher et al 1990a;Wappler et al 1996). Possibly, already moderate increases of IPs induced by 5-HT2A receptor agonists may be sufficient to induce contractures of skeletal muscle as found in MHS pigs (LOscher et al 1990a) or in muscle specimens of MH susceptible patients (Wappler et al 1996) because of a hypersensitive response of MHS skeletal muscle to IP3 induced release of calcium (Lopez et al 1995).…”

Thyroid status affects 5-HT2Areceptor modulation of breathing before, during, and following exposure of hamsters to acute intermittent hypoxia

“…Several other studies have shown similar results in that stimulation of 5-HT 2A receptors by specific agonists cause hyperthermia in laboratory animals (3,32,37). Currie et al (13) evaluated the role of neuropeptide Y (NPY) on 5-HT receptors in relation to food intake and energy metabolism in rats.…”

Maligne Hyperthermie

“…Ein weiterer Mechanismus könnte im Zusammenhang mit dem ᭤ Serotoninrezeptorsystem gesehen werden, da einige Serotoninrezeptorsubtypen, u. a. der ᭤ Serotonin-2-Rezeptor, an den Inositolphosphatstoffwechsel gekoppelt sind [2], und nach Applikation eines Serotonin-2-Rezeptoragonisten bei MH-Disposition signifikant früher eine Muskelkontraktur am isolierten Skelettmuskelpräparat registriert werden kann [41]. Darüber hinaus konnte nach Gabe von Serotonin-2-Rezeptoragonisten bei Schweinen eine MH-Episode ausgelöst [20] bzw. durch Prämedikation mit einem Serotonin-2-Rezeptorantagonisten die Entwicklung einer Halothan-induzierten MH-Krise verhindert werden.…”