title: Effect of amiloride analogs on DOCA-salt-induced hypertension in rats.
abstract: 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 amiloride-sensitive Na+ 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 amiloride-sensitive cation channels at the blood-brain barrier. We also examine whether the effects of benzamil on blood pressure are mediated by a Na+ channel by comparing the effects of different amiloride analogs. Benzamil (0.15 and 0.5 microgram/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 blood-brain barrier ion transport as assessed by measurements of blood-to-brain 22Na transport and cerebral spinal fluid Na+ and K+ concentrations. Indeed, intracerebroventricular infusion of dimethyl amiloride, an amiloride analog with low affinity for Na+ 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 Na+/Ca2+ exchange in the brain.
authors.affiliation: Department of Surgery (Section of Neurosurgery), and Neurology, University of Michigan, Ann Arbor, Michigan 48109-0532, USA. rkeep@umich.edu
authors.forename: R F
authors.initials: RF
authors.lastname: Keep
authors.forename: X
authors.initials: X
authors.lastname: Si
authors.forename: P
authors.initials: P
authors.lastname: Shakui
authors.forename: S R
authors.initials: SR
authors.lastname: Ennis
authors.forename: A L
authors.initials: AL
authors.lastname: Betz
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003900:Desoxycorticosterone; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride
chemical_list: C013407:benzamil; C041470:3',4'-dichlorobenzamil; C039465:5-dimethylamiloride; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D000584:Amiloride