Effect of nitrate tolerance and dipyridamole on the response to SIN1 in the human isolated saphenous vein

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Abstract
The relaxant effects of nitroglycerin (NTG) and SIN1 on human vena saphena magna were studied in vitro. Nitrate tolerance was produced after incubation of the preparation with nitroglycerin (NTG 10 μM for 10 minutes). Vessels precontracted by serotonin (0.25 (μM) and made tolerant to NTG exhibited a slight but significant shift (p < 0.01) to the right of the dose-response curve to SIN, (EC50 increased from 1.12 ± 0.21 μM to 2.74 ± 0.32 μM). The maximal relaxation was unaltered. On the contrary, there was a marked attenuation of the maximal relaxation to NTG in the nitrate-tolerant preparation (maximal relaxation decreased from 73 ± 2% to 35 ± 1%). Dipyridamole, a phosphodiesterase (PDe) inhibitor, significantly potentiated the responses to SIN1 on control rings (EC50 = 57.1 ± 1.8 nM), and on NTG-tolerant rings it reversed the responsiveness to SIN1 (EC50 = 88.9 ± 9.2 nM), which suggests that nitrate tolerance may be partially due to an increase in PDe activity. In conclusion we have demonstrated a slight cross-tolerance between SIN1 and NTG on human vena saphena magna. Nevertheless, after induction of in vitro NTG tolerance, the attentuation of responses to SIN1 is much less pronounced that the alteration of NTG relaxations.