Chávez J, Segura P, Vargas MH, Arreola JL, Flores-Soto E, Montaño LM. Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release. Am J Physiol Lung Cell Mol Physiol 292: L915-L923, 2007. First published December 8, 2006; doi:10.1152/ajplung.00253.2005.-Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca 2ϩ measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, -conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of ϳ50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M 2-or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca 2ϩ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX-and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the stimulation of M 2 receptors; and 3) after this transient salbutamol-induced relaxation, a paradoxical contraction ensues due to the subsequent release of substance P. albuterol;  2-adrenoceptor agonist; parathion; paraoxon; tachykinins; physostigmine; airway smooth muscle PARATHION IS ONE OF THE MAIN representatives of organophosphates, a family of compounds synthesized since the 1940s and still widely used all around the world in agriculture and veterinary medicine as insecticides and antihelmintics (12). To achieve biological activity, parathion must be biotransformed in the liver and other tissues into paraoxon. The latter metabolite has a very strong inhibitory capacity on acetylcholinesterase (AChE) activity (27, 36), leading to an increase in ACh...