Effects of extraneuronal uptake inhibitors on the positive chronotropic response to isoprenaline and on the accumulation of isoprenaline in perfused rat heart after inhibition of catechol-O-methyl transferase.

Abstract

Experiments were carried out in isolated perfused rat hearts. The presence of tropolone (100 mumol/l), an inhibitor of catechol-O-methyl transferase (COMT), significantly potentiated the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/l). Two uptake2 inhibitors, 3-O-methylisoprenaline (100 mumol/l) and normetanephrine (100 mumol/l), induced a positive chronotropic response, but corticosterone (100 mumol/l) and hydrocortisone (100 mumol/l) had no such effect. 3-O-methylisoprenaline (100 mumol/l) and normetanephrine (100 mumol/l) enhanced the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/l). Corticosterone (100 mumol/l) potentiated the positive chronotropic response to isoprenaline (0.1 and 1 nmol/l). Hydrocortisone (30 mumol/l) enhanced the response to 0.1 nmol/l isoprenaline but did not affect the positive chronotropic responses to 1, 3 or 10 nmol/l isoprenaline. The addition of uptake2 inhibitors (3-O-methylisoprenaline, 100 mumol/l; normetanephrine, 100 mumol/l; corticosterone, 100 mumol/l) to the perfusion medium significantly reduced the positive chronotropic response to the perfusion with isoprenaline (3 nmol/l) and tropolone (100 mumol/l). The accumulation of 3H-isoprenaline in the heart perfused with 3H-isoprenaline (1, 10 and 100 nmol/l) was significantly increased by the presence of tropolone (100 mumol/l): the accumulation for 1, 10 and 100 nmol/l of 3H-isoprenaline was 5.07, 47.0 and 500 pmol/g, respectively. The high accumulation observed during perfusion with 3H-isoprenaline (3 nmol/l) and tropolone (100 mumol/l) was significantly decreased by the addition of an uptake2 inhibitor, 3-O-methylisoprenaline (100 mumol/l), normetanephrine (100 mumol/l) or corticosterone (100 mumol/l), but not by hydrocortisone (30 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)