The purine nucleotide, ATP, can cause receptor-mediated desensitizing contractions of smooth muscle that may be modulated by pH. We investigated in the rat the effect of acidosis upon the contractile and Ca2+ responses induced by ATP upon intrapulmonary artery (PA) smooth muscle. Four successive applications of ATP (300 microM) at pH 7.4 induced desensitising contractile responses that showed progressively decreasing peak amplitudes that correlated with decreases of [Ca2+]i. Acidosis significantly reduced the peak contractile response to the first application of ATP without modifying the rate or degree of desensitisation in response to ATP and without decreasing the [Ca2+]i. Successive applications of ATP did not further reduce contractile force nor [Ca2+]i. These results demonstrated that acidosis abolishes the effect of repeat applications of ATP on pulmonary artery force and [Ca2+]i via alteration in the desensitization-resensitisation characteristics of ATP receptor. This suggest a potentially important physiological role for changes in external pH in the regulation of ATP-mediated control of the pulmonary circulation.