Sodium channel blockers are vasodilator as well as natriuretic and diuretic agents

Amiloride (100-400 micrograms) injected intra-arterially into the dog forelimb perfused at constant flow produced a prompt but transient dose-dependent decrease in perfusion pressure. Intravenous injection lowered systemic arterial pressure, but effects were small and transient except in doses exceeding 10 mg. We tested 11 analogues of amiloride, 3 other diuretics, and a hypotensive imidazopyrazine for vasodilator activity in the dog forelimb and found one analogue, 6-iodo-amiloride, with twice the activity of amiloride. Intravenous injection of 3 mg of 6-iodo-amiloride promptly decreased systemic arterial pressure and forelimb perfusion pressure 65 and 47 mm Hg respectively. The decreases with 3 mg of amiloride were only 5 and 23 mm Hg respectively. Intravenous infusion of 17 to 77 mg of 6-iodo-amiloride produced diuresis, natriuresis, and antikaliuresis and, with the higher doses, hypotension. The latter occurred promptly on starting the infusion and was sustained for the duration of the infusion. Wistar rats responded to an intravenous infusion of 0.38 mg/100 g in 11 minutes in the same manner. In the spontaneously hypertensive rat, this same dose produced a large, sustained antihypertensive effect with little change in the urinary parameters. These studies indicate that 6-iodo-amiloride is a vasodilator and a vasodepressor as well as natriuretic and diuretic in the normal dog and rat and that it produces a sustained, large fall in blood pressure, independently of urinary effects, in the spontaneously hypertensive rat. These results suggest that 6-iodo-amiloride and other sodium channel blockers might be useful as vasodilatory antihypertensive agents, particularly in those types of hypertension characterized by increased vascular smooth muscle cell permeability to sodium.