Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.
Oral administration of the angiotensin II receptor subtype 1 (AT1) antagonist DuP 753 causes long-lasting lowering of mean arterial pressure in spontaneously hypertensive rats. We examined whether the antihypertensive action of DuP 753 is a result of inhibition of brain angiotensin II. In normal spontaneously hypertensive rats, we found that intracerebroventricular DuP 753 (10 micrograms) blocked the pressor action of intracerebroventricular angiotensin II (100 ng); however, intracerebroventricular DuP 753 (10 micrograms) had no effect on the pressor response to 300 ng/kg angiotensin II administered intravenously (48 +/- 3 mm Hg in the presence of intracerebroventricular DuP 753 versus 49 +/- 4 mm Hg in its absence). In both normal and furosemide-treated spontaneously hypertensive rats (low Na+ diet plus furosemide), intracerebroventricular DuP 753 alone at 10 or 100 micrograms caused transient but significant pressor responses; however, no significant reduction in pressure (versus controls) was observed over the next 48 hours. In contrast to its central effects, we found that oral DuP 753 (10 or 30 mg/kg) in normal spontaneously hypertensive rats resulted in sustained mean arterial pressure decreases of up to -74 mm Hg. These data suggest that, although the pressor effect of brain angiotensin II is mediated by the AT1 receptor, blockade of these receptors does not lower blood pressure in spontaneously hypertensive rats. In the spontaneously hypertensive rat, DuP 753 depresses blood pressure by blockade of peripheral, not central, AT1 receptors.
DePasquale
M J
MJ
Department of General Pharmacology, Pfizer Inc., Groton, Conn. 06340.
Fossa
A A
AA
Holt
W F
WF
Mangiapane
M L
ML
D000284:Administration, Oral; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology*; D007276:Injections, Intraventricular; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan