REDUCED ENDOTHELIUM-DEPENDENT VASODILATION BY ACETYLCHOLINE AND BRADYKININ IN ISOLATED NITROGLYCERIN-TOLERANT BLOOD-VESSELS

1. Rings of porcine pulmonary arteries were mounted in tissue organ baths and incubated in physiological solution. The rings were allowed to equilibrate for >1 hr under a resting tension of 1.0 g. The presence of endothelium was confirmed by 10(-6) M acetylcholine (ACh)-induced relaxation (60-80%) of 10(-6) M norepinephrine (NE) contraction. 2. Relaxation response generated by nitroglycerin (NTG) (10(-9)-10(-5) M), ACh (10(-9)-10(-5) M), bradykinin (BK) (10(-13)-10(-6) M) and nitric oxide (NO) after NE (10(-6) M) contraction was compared before and after 1 hr treatment of NTG (5 x 10(-4) M). Then tissues were pretreated with N-G-monomethyl-L-arginine (LNMMA) (10(-4) M) each before and after NTG treatment respectively, and ACh-induced relaxation was compared. 3. After 1 hr treatment with 5 x 10(-4) M NTG, the relaxation response of NTG at concentrations > 10(-7) M was attenuated significantly. This indicates that 1 hr treatment with 5 x 10(-4) M NTG induces NTG tolerance in isolated porcine pulmonary arterial rings. 4. The relaxation response of ACh at concentrations > 10(-7) M was attenuated significantly after NTG tolerance induction. 5. Relaxation response of BK at concentrations > 10(-10) M was attenuated significantly after NTG tolerance induction. 6. NTG tolerance had no effect on NO-induced vascular smooth muscle relaxation. 7. The relaxation response of ACh pretreated with LNMMA at concentrations higher than 10(-7) M was attenuated after NTG tolerance. 8. These results demonstrate that ACh releases an endothelium-derived relaxing factor (EDRF) or several EDRFs other than NO which is (are) affected by NTG tolerance.