The effect of repeated intravenous and oral doses of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester) on plasma renin activity and plasma catecholamine levels in conscious dogs

Abstract

The responses of plasma renin activity (PRA) and plasma catecholamine levels to molsidomine, administered both intravenously and orally, were investigated in conscious trained dogs. Intravenous administration of molsidomine at increasing dosage up to 0.4 mg/kg with a constant dose interval of 4 hours did not lead to a sustained increase in PRA. By contrast, a significant increase in PRA was still present after 4 hours on administration of 0.4 mg/kg molsidomine by the oral route. This longer-lasting increase in PRA following oral administration is discussed in relation to the conversion of molsidomine to an active metabolite in the liver. A reduction of dose interval to 3 hours or less led to a marked cumulative increase in PRA. It appears that substances acting via venous pooling lead to persistent activation of the renin angiotensin aldosterone system (RAA system), which counteracts its primary therapeutic effect. A slight increase in plasma noradrenaline levels was observed in response to repeated oral administration of 0.4 mg/kg molsidomine at a dose interval of 2 hours, indicating participation of the sympathetic nervous system in the counterregulatory process.