ENDOTHELIN-DEPENDENT TONE LIMITS ACETYLCHOLINE-INDUCED DILATION OF RESISTANCE CORONARY VESSELS AFTER BLOCKADE OF NO FORMATION IN CONSCIOUS DOGS

Nitric oxide (NO) impairs endothelin (ET) formation and/or action in i solated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance c oronary vessels in conscious dogs. In conscious instrumented dogs, gra ded intracoronary (IC) doses of acetylcholine (ACh) were delivered bef ore IC administration of N-omega-nitro-L-arginine methyl ester (L-NAME ), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB recepto r blocker. Before L-NAME, ACh (100 ng . kg(-1) . min(-1)) increased co ronary blood flow (CBF) by 43+/-4% from 47+/-6 mL . min(-1). After L-N AME, ACh failed to increase CBF (-3+/-2% from 50+/-7 mL . min(-1)). CB F responses to ACh were partially restored (+10+/-2% from 50+/-7 mL . min(-1), P<0.01) after the addition of bosentan. Bosentan alone (witho ut L-NAME) did not alter CBF responses to ACh. Blockade of ETA (Ro 61- 1790) but not ETB (Ro 46-8443) receptors partially restored CBF respon ses to ACh after L-NAME. Myocardial immunoreactive ET levels in the pe rfusion territories of the circumflex and left anterior descending cor onary arteries did not differ. ETA-dependent tone magnified the inhibi tory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO rele ase has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.