Mechanism of Action and Systemic and Regional Hemodynamics of the Potassium Channel Activator BRL34915 and Its Enantiomers

BRL34915 (BRL) is a vasodilator with a novel structure. Its mechanism of action, its effects on depolarization-induced and receptor-mediated blood vessel contraction, and its hemodynamic effects were investigated. In the rat portal vein, BRL inhibited spontaneous mechanical activity [IC50 0.013 +/- 0.001 microM (mean +/- SEM) for (-)-BRL], the initial effect being a reduced frequency of contraction. At higher concentrations, the spontaneous contractions were abolished and 86Rb+ efflux was increased. These results suggest that BRL preferentially acts on the pacemaker cells, the K+ channels in other cells being activated only at higher BRL concentrations in this vessel. In experiments on the rabbit aorta, (-)-BRL shifted the KCl concentration-response curve to the right and noncompetitively inhibited responses to angiotensin II. A concentration of 3 microM (-)-BRL reduced maximal angiotensin II contractions by around 50%, higher concentrations having little further effect. This inhibition of angiotensin II contractions is notably greater than that seen with Ca2+ antagonists in this vessel. In anesthetized rabbits, (-)-BRL was a peripheral vasodilator at doses of 3-30 micrograms/kg, but it had no relevant effects on heart rate and myocardial contractile force. This suggests tissue selectivity of this compound or this mechanism of action. BRL preferentially dilated the coronary, gastrointestinal, and cerebral vessels but not those of the kidneys or skeletal muscle as measured with tracer microspheres. This profile of activity is different from that of calcium antagonists or nonspecific vasodilators like dihydralazine. All effects were stereoselective, the (-)-enantiomer being 100 to 200 times more active than the (+)-enantiomer.