Receptor subtypes mediating spinal cardiovascular effects of angiotensin II in rat using losartan and PD 123319.
It has previously been shown in this laboratory that intrathecal administration of 10 microg of angiotensin II produces an increase in arterial pressure and heart rate. As two receptor subtypes of angiotensin II, termed AT1 and AT2, have been identified in central nervous tissue this study examines the effects of selective antagonists on the pressor and cardioacceleratory responses to intrathecal administration of 10 microg of angiotensin II to the ninth thoracic spinal cord. The two non-peptide antagonists were losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H)-tetrazol-5-yl)biph enyl-4-yl)methyl]imidazole), which is selective for the angiotensin AT1 receptor, and PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenyacetyl)-4, 5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid, ditrifluoroacetate, dihydrate), which is selective for the angiotensin AT2 receptor. Intravenous administration of losartan blocked both pressor and cardioacceleratory effects of angiotensin II. Intrathecal administration of losartan blocked only the pressor effects, raising the possibility that block of the heart rate response was in the periphery. Intrathecal administration of PD 123319 blocked the pressor effect of angiotensin II but had no effect on the cardioacceleratory response. However, by itself the antagonist produced a transient increase in arterial pressure and a slower increase in heart rate. The data support the involvement of the angiotensin AT1 receptor in mediating the effects of exogenously administered angiotensin II but also indicate a possible role of angiotensin AT2 receptors at the spinal level.
Park
P D
PD
Department of Psychiatry, Allan Memorial Institute, Montreal, Canada.
Henry
J L
JL
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D007275:Injections, Intravenous; D007278:Injections, Spinal; D019808:Losartan; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; C073402:PD 123319; D019808:Losartan