The purine ATP can cause desensitizing contractions that may play a modulatory role in a variety of pathophysiological processes such as hypoxic pulmonary vasoconstriction and pulmonary hypertension (McCormack et al. 1993).

Isometric contractions were measured, as previously described (Vandier et al. 1997) in large (ca 700 µm e.d.) and small (ca 200 µm e.d.) intrapulmonary arteries (PA) isolated from rats killed with sodium pentobarbital (60 mg kg^-1 I.P.) as approved by the Ministre Franais de l’Agriculture. Before each ATP challenge, L-NAME (10^-5 M) was added into each bath. Changes of [Ca²⁺]_i in individual arterial myocytes from large and small PA were recorded using the [Ca²⁺]_i sensitive fluorophore fura-2 and the fluorescence ratio (345/380) was calculated. Data are expressed as means ± S.E.M. and significance (P < 0.05) derived with ANOVA and Student’s unpaired t tests.

At pH 7.4, the peak amplitudes of ATP (300 µM) contractions were not significantly different between small and large PA rings and nor was the increase of [Ca²⁺]_i ratio induced by ATP in isolated cells from small or large PA. Four successive applications of ATP (40 min apart) revealed a failure to resensitize the ATP response only in large PA rings, in which the peak amplitude of the response decreased, sequentially down to 39.4 ± 8.0 % of the first peak amplitude contraction (n = 6). This failure to resensitize was also observed in single cells isolated only from large PA and, in nine cells, the [Ca²⁺]_i ratio was decreased down to 37.2 ± 5.5 % of the initial peak response. External acidosis (pH 6.8) significantly decreased the amplitude of the first ATP contraction only in large PA rings (from 38.5 ± 1.9 % K80, n = 7 to 15.3 ± 2.9 % K80, n = 6). Interestingly, acidosis induced no significant change of resting [Ca²⁺]_i ratio in isolated cells from both PA populations. In the continued presence of external acidosis, successive ATP responses were now not significantly different from the initial response both in large PA rings and in single cells from large PA. Furthermore, the amplitude of ATP contraction (% K80) in acidosis was not different between large and small PA rings.

The present study provides initial evidence of ATP receptor sensitization, which differs along the pulmonary artery tree. This phenomenon was modified with external acidosis suggesting an important physiological role of the desensitization- resensitization process in the regulation of pulmonary circulation.

This work was supported by grant from Wellcome Trust and l’Agence De l’Environnement et de la Maitrise d’Energie.