AHEART June 45/6

Keep, Richard F., Xiaochen Si, Parvin Shakui, Steven R. Ennis, and A. Lorris Betz. Effect of amiloride analogs on DOCA-salt-induced hypertension in rats. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H2215–H2220, 1999.—Intracerebroventricular infusions of an amiloride analog, benzamil, reduce blood pressure in several rat models of hypertension. This effect has been attributed to an inhibition of amiloridesensitive Na1 channels in the brain. This study examines whether intracerebroventricular benzamil would prevent the onset of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats and whether this effect correlates with an inhibition of ion transport through the known amiloridesensitive cation channels at the blood-brain barrier. We also examine whether the effects of benzamil on blood pressure are mediated by a Na1 channel by comparing the effects of different amiloride analogs. Benzamil (0.15 and 0.5 μg/h icv) did significantly attenuate the increase in blood pressure induced by DOCA treatment. This antihypertensive effect, however, was not associated with an alteration in a bloodbrain barrier ion transport as assessed by measurements of blood-to-brain 22Na transport and cerebral spinal fluid Na1 and K1 concentrations. Indeed, intracerebroventricular infusion of dimethyl amiloride, an amiloride analog with low affinity for Na1 channels, also attenuated the increase in blood pressure induced by DOCA-salt treatment. Comparisons of the effects of benzamil, dimethyl amiloride, and 3,4-dichlorobenzamil, another amiloride analog, suggest that these antihypertensive effects are mediated by an inhibition of Na1/Ca21 exchange in the brain.