Relaxation in different-sized rat blood vessels mediated by endothelium-derived hyperpolarizing factor: Importance of processes mediating precontractions

To clarify the mechanisms involved in relaxations mediated by endothelium-d erived hyperpolarizing factor (EDHF), acetylcholine (ACh)-induced endotheli um-dependent relaxations and hyperpolarizations were examined in the rat ao rta, the main branch of the mesenteric artery (MBMA) and the first branch o f the mesenteric aftery (FBMA). In the presence of 100 mu M N-G-nitro-L-arg inine (L-NNA) and 10 mu M indomethacin, ACh (1 nM to 100 mu M) produced no relaxation in the phenylephrine-precontracted aorta. The L-NNA-resistant re laxations by ACh in MBMA precontracted with phenylephrine were eliminated i n the presence of 1 mu M nifedipine where contractions were independent of L-type Ca2+ channel activation. In FBMA precontracted with phenylephrine, t he L-NNA-resistant relaxations were only partially inhibited by nifedipine. When vessels had been contracted with 300 nM phorbol-12,13-dibutyrate in t he presence of nifedipine, ACh-induced L-NNA-resistant relaxations were obs erved in FBMA only. Pinacidil produced relaxations in all different-sized b lood vessels, although sensitivity was inversely related to vessel size. Th e extent of the ACh hyperpolarizing responses was much smaller than that by pinacidil in the aorta. The membrane potential changes by ACh and pinacidi l were almost the same in FBMA. These results indicate that the contributio n of EDHF to endothelium-dependent relaxations increases as the vessel size decreases. This may be partly explained by precontractile processes depend ent on Ca2+ entry through L-type Ca2+ channels, because Ca2+ channel deacti vation seems to be involved as a major mechanism of EDHF-mediated vasorelax ations. However, EDHF may also generate vasorelaxations by an additional me chanism, probably a reduced Ca2+ sensitivity of contractile elements, as pr oposed for ATP-sensitive K+ channel openers.