Ryanodine

Ryanodine is a selective ryanodine receptor (RyR) blocker, with IC50 value of 10 nM [1].

RyR, expressed on the sarcoplasmic reticulum membranes of excitable cells, including smooth muscle myocytes, is important to the regulation of pulmonary as well as systemic vascular tone. Opening of clusters of RyRs gives rise to Ca²⁺ spark events which are particularly important for activation of the large-conductance Ca²⁺ and voltage-activated K⁺ channel in vascular smooth muscle [2].

In canine pulmonary arterial smooth muscle cells exposed to 10 mM caffeine, ryanodine at the concentration of 10 μM reversibly inhibited induced Ca²⁺ increases [2]. In addition, ryanodine (0.4, 0.8, 1.6 and 10 μmol/L) was shown to differentiate between muscles of malignant hyperthermia (MH) susceptible and normal patients in terms of in vitro contracture response [3].

In dogs, the lethal doses of ryanodine by injection were 50 ~ 300 μg/kg, which resulted in enophthalmos, followed by general spastic muscle rigidity, salivation, vomiting, and defecation. In mice, ryanodine exhibited low mammalian toxicity with intraperitoneal LD50 > 20 mg/kg, when compared with its toxicity on insects. Furthernomre, ryanodine affected the excitability and ion selectivity of K⁺ channels in insects but not in mammals [1].

References:

[1]. Ujváry I. Chapter 3 - Pest Control Agents from Natural Products. Hayes' Handbook of Pesticide Toxicology (Third Edition). 2010, 119-229.

[2]. Ostrovskaya O, Goyal R, Osman N, et al. Inhibition of ryanodine receptors by 4-(2-aminopropyl)-3,5-dichloro-N,N-dimethylaniline (FLA 365) in canine pulmonary arterial smooth muscle cells. Journal of Pharmacology and Experimental Therapeutics, 2007, 323(1): 381-390.

[3]. Hopkins P M, Ellis F R, Halsall P J. Ryanodine contracture: a potentially specific in vitro diagnostic test for malignant hyperthermia. British Journal of Anaesthesia, 1991, 66(5): 611-613.