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Theophylline is a drug commonly used to treat asthma due to its anti-inflammatory and bronchodilatory properties. Testosterone (TES) has been suggested to reduce the severity of asthma symptoms. This condition affects boys more than girls in childhood, and this ratio reverses at puberty. We reported that guinea pig tracheal tissue chronic exposure to TES increases the expression of β₂-adrenoreceptors and enhances salbutamol-induced K⁺ currents (IK⁺). Herein, we investigated whether the upregulation of K⁺ channels can enhance the relaxation response to methylxanthines, including theophylline. Chronic incubation of guinea pig tracheas with TES (40 nM, 48 h) enhanced the relaxation induced by caffeine, isobutylmethylxanthine, and theophylline, an effect that was abolished by tetraethylammonium. In tracheal myocytes, chronic incubation with TES increased theophylline-induced IK⁺; flutamide reversed this effect. The increase in IK⁺ was blocked by 4-aminopyridine by ~82%, whereas iberiotoxin reduced IK⁺ by ~17%. Immunofluorescence studies showed that chronic TES exposure increased the expression of K_V1.2 and K_V1.5 in airway smooth muscle (ASM). In conclusion, chronic exposure to TES in guinea pig ASM promotes upregulation of K_V1.2 and K_V1.5 and enhances theophylline relaxation response. Therefore, gender should be considered when prescribing methylxanthines, as teenage boys and males are likely to respond better than females.