EFFECTS OF 1-PYRROLIDINYLMETHYL-2-NAPHTHOL ON CONTRACTILE-FORCE AND IONIC CURRENT IN CARDIAC AND VASCULAR SMOOTH MYOCYTES

Ionic mechanisms of the cardiovascular actions of 1-pyrrolidinylmethyl -2-naphthol hydrochloride (TPY-beta) were examined. Intravenous infusi on of TPY-beta produced hypotension and bradycardia in a dose-dependen t manner. TPY-beta (30 mu M) produced biphasic change in contractile f orce in isolated rat atria, i.e., an initial decrease and a gradual in crease. In electrophysiological studies of rat ventricular myocytes, T PY-beta dose-dependently suppressed the amplitude of L-type Ca2+ inwar d current (I-Ca,I-L), but it did not modify the time constants for I-C a,I-L inactivation and the overall shape of the current-voltage relati onship of I-Ca,I-L. The EC50 value for TPY-beta-mediated inhibition of I-Ca,I-L is 10.6 +/- 1.0 mu M. TPY-beta (50 mu M) mildly suppressed t he amplitude of Na+ current. TPY-beta (50 mu M) effectively suppressed the amplitude of transient outward current (I-TO). The time course fo r inactivation of I-TO was changed to a biexponential process after th e application of TPY-beta. TPY-beta (50 mu M) also mildly suppressed t he amplitude of inwardly rectifying current. in addition, the effect o f TPY-beta on Ba2+ inward current (I-Ba) was examined in A7r5 vascular smooth muscle cells. TPY-beta dose-dependently inhibited I-Ba. The EC 50 value for the inhibitory effect of TPY-beta is 3.4 +/- 0.6 mu M. Th e results indicate that the suppressive effects of TPY-beta involve a direct depressant action on heart cells and vascular smooth muscle cel ls. Thus, direct inhibition of voltage-dependent L-type Ca2+ channel i s involved in the TPY-beta-mediated vasodilatory action. In addition, the inhibitory effect of TPY-beta on cardiac contractility through the blockade of L-type Ca2+ channels can be prevented by TPY-beta-mediate d inhibition of I-TO. Drug Dev. Res. 44:87-96, 1998. (C) 1998 Wiley-Li ss, Inc.