Flavodilol: a new antihypertensive agent that preferentially depletes peripheral biogenic amines

Flavodilol, ((+/-)-7-[2-hydroxy-3-(propylamine)-propoxy]flavone maleate), a new orally effective antihypertensive agent, extensively depleted catecholamines and serotonin in heart tissue of normotensive and spontaneously hypertensive rats (SHR). Dose-response studies demonstrated that greater than or equal to 75% depletion of cardiac norepinephrine (NE) was accompanied by marked blood pressure decline in SHR. In contrast, whole brain biogenic amine levels were decreased only by 15-20% after acute or chronic treatment with antihypertensive doses (35-75 mg/kg). Adrenal epinephrine (EPI) stores were unaffected by acute treatment, although chronic treatment for 18 days with an antihypertensive dose of 75 mg/kg flavodilol decreased EPI by 70%. Acute treatment also decreased serotonin content of spleen by 70-80%. In dogs, a cumulative oral dose of 40 mg/kg decreased catecholamines by greater than or equal to 50% in aorta and heart muscle. Although hypothalamic catecholamine stores appeared to be more susceptible to depletion by flavodilol than catecholamines in other brain regions, these changes did not appear functionally related to blood pressure decreases since analogs of flavodilol without antihypertensive properties produced equivalent or greater depletion of hypothalamic catecholamine stores. In vitro flavodilol promoted spontaneous and potassium-evoked release of dopamine from isolated striatal nerve endings (0.3 microM) and blocked uptake of NE by hypothalamus and hippocampal nerve endings (1 microM), suggesting that biogenic amine depletion in vivo may be caused by an interference with storage and release mechanisms. Despite structural features reminiscent of beta-adrenergic antagonists, flavodilol had low affinity for beta-receptors. Neither was there any inhibition of tyrosine hydroxylase. These findings suggest that the antihypertensive activity of flavodilol results, at least in part, from depletion of sympathetic stores of NE in heart and vascular tissues that moderate adrenergic transmission, thereby decreasing heart rate (HR) and prevailing vascular tone.