Test of a criterion for selecting intracranial doses of angiotensin receptor blockers.
Investigators using intracerebroventricular (ICV) injections of competitive antagonists of angiotensin II (Ang II) to study thirst usually select doses sufficient to block drinking to IV Ang II. We questioned whether this test truly indicates the dose needed under physiological conditions when Ang II-induced hypertension, which inhibits thirst, is not present. Rats were prepared with chronic venous and ICV cannulas, plus femoral arterial cannulas in those used to measure arterial pressure. Captopril (100 mg/kg SC) was given before all experiments to block endogenous Ang II production. The test dose of Ang II, 50 ng/kg/min IV for 1 hr, increased water intake and arterial pressure. We selected an ICV dose of saralasin (Sar1Ala8Ang II), 4 micrograms bolus and 4 micrograms/hr for 75 min, that did not stimulate drinking itself and completely blocked drinking to IV Ang II. This dose of saralasin only partially (45%) reduced drinking to the same dose of Ang II IV when arterial pressure was lowered by giving the vasodilator diazoxide (15 mg/kg IV). Diazoxide itself did not stimulate drinking. These results support our concern that the criterion normally used to select ICV doses of Ang II antagonists probably underestimates the amount needed to inhibit angiotensinergic drinking in hypovolemic or hypotensive animals.
Evered
M D
MD
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Siddiqui
S H
SH
Kenyon
P J
PJ
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D011945:Receptors, Angiotensin / Q000502:physiology*; D012504:Saralasin / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D014665:Vasodilator Agents; D012504:Saralasin; D003981:Diazoxide