Diltiazem, a
1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous
cardiovascular diseases.
TA-3090, a newly synthetized
1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with
diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled
catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of
TA-3090 (n = 16) or
diltiazem (n = 15) (15, 50, 200, and 400 micrograms/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both
TA-3090 and
diltiazem elicit slight peripheral and coronary
vasodilator properties at low doses (15 and 50 micrograms/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between
TA-3090 and
diltiazem indicates that both drugs elicit coronary
vasodilator selectivity and
TA-3090 has a prolonged duration of action compared with that of
diltiazem. A straightforward relationship is demonstrated between
vasodilator properties and plasma levels of either
TA-3090 or
diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with
TA-3090. Changes of heart rate were not correlated with plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)