RECEPTOR-MEDIATED EFFECTS OF ENDOTHELIN ON THE L-TYPE CA++ CURRENT INVENTRICULAR CARDIOMYOCYTES

The purpose of this study was to establish whether specific receptor s ubtypes are responsible for mediating the effects of endothelin-1 (ET- 1) and endothelin-3 (ET-3) on the L-type calcium current (I-Ca using a number of receptor-selective antagonists, including PD155080 (ETA, BQ -733, RES-701 and IRL-1038 (ETB and the ETA/ETB, receptor-non-selectiv e antagonist PD145065. Ventricular cardiomyocytes were isolated from a dult New Zealand White rabbits using Langendorff perfusion with collag enase. I-Ca was recorded using a whole-cell patch-champ technique. ET- 1 decreased, whereas ET-3 increased, I-Ca at equimolar concentrations of 10 nM. The decrease in I-Ca produced by ET-1 was completely blocked by PD155080 and PD145065 (1 and 10 mu M); however, I-Ca was increased upon washout of PD155080. Although the decrease in I,, produced by ET -1 was partially blocked by BQ-788 (1 and 10 mu M), ET-1 in combinatio n with either RES-701 (1 and 10 mu M) or IRL-1038 (1 mu M) produced a decrease in I,, similar to that produced by ET-1 alone. The increase i n I-Ca by ET-3 was completely abolished by either BQ-788 or IRL-1038 ( 1 mu M). These data indicate that the decrease in I-Ca produced by ET- 1 in rabbit ventricular cardiomyocytes is mediated by the ETB receptor subtype, because PD155080 completely inhibited this response. The ETB receptor-selective antagonists RES-701 and IRL-1038 did not alter the decrease in current produced by ET-1, although the response was parti ally sensitive to BQ-783, which may lack receptor-subtype selectivity in these cells. In contrast, the increase in I-Ca produced by ET-3 was mediated by the ETB receptor subtype, because BQ-788 and IRL-1038 abo lished this response.