Abstract: Airway Hyperresponsiveness (AHR) is the main feature of asthma which also exists in Chronic Obstructive Pulmonary Disease (COPD). However the mechanism of AHR is uncertain due to the complexity stimuli action used for measuring AHR. The mechanism of competitive antagonism blockade, which is measured as concentration ratio-1 (CR-1) is far simpler than that of agonists and depends only on drug delivery to the receptor sites and receptor affinity. Therefore, in this study we have examined the histamine (H1) receptor blockade by chlorpheniramine on isolated tracheal chains of a model of COPD compared to control guinea pigs. Experimental models of COPD was induced in guinea pigs by exposing animals to cigarette smoke for three months. The responses of tracheal chains of COPD and control animals (for each group n=7) to cumulative concentrations of histamine (H) in the absence and presence of 10 nM chlorpheniramine were measured and the effective concentrations of H causing 50% of maximum response (EC50 H) were obtained. The chlorpheniramine blockade (CR-1) was calculated by: (post chlorpheniramine EC50 H/EC50 H)-1. In addition, the contractility of tracheal chains due to 50 μM histamine concentration and hematocrit were also measured. The tracheal responses of COPD guinea pigs were significantly higher than those of control animals to histamine (EC50 H for COPD and control animals were 19±2.45 and 34.28±2.06 μM, respectively, p<0.001). The histamine (H1) receptor blockade by chlorpheniramine (CR-1) was also significantly higher in trachea of COPD compared to that of control animals (2.62±0.51 vs 0.44±0.06, p<0.001). There were significant correlations between tracheal response to EC50 H and (CR-1) (r=-0.564, p<0.05).The hematocrit in COPD animal was significantly higher than control animals (p<0.001). However there were not significantly difference in contractility response of tracheal chains between COPD and control animals. The enhanced histamine (H1) receptor blockade increased tracheal response to histamine in tracheal chains of COPD animals and significant correlation between these two phenomenan may indicate that increased drug delivery to the receptors could be a determinant factor for bronchial responsiveness to stimuli in COPD.