Effect of angiotensin II antagonism on canine renal sympathetic nerve function.
The objective of this study was to examine effects of nonpeptide angiotensin II (Ang II) receptor antagonists on renal vasoconstrictor responses to renal nerve stimulation (RNS) and intrarenal injection of norepinephrine in pentobarbital-anesthetized dogs. The subtype 1-selective Ang II receptor antagonists, DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt) and EXP3174 (2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole-5-carboxylic acid) given intra-arterially to the kidney caused dose-dependent reductions of renal vasoconstrictor responses to RNS but not to norepinephrine. In contrast, the subtype 2-selective Ang II receptor specific ligand, PD 123177 (1-[(4-amino-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), did not alter the renal vasoconstrictor responses to RNS, norepinephrine, and Ang II in doses of 10-100 micrograms/kg/min i.a. Captopril also reduced the renal vasoconstrictor responses to RNS but not to norepinephrine. However, saralasin did not alter the renal vasoconstrictor responses to RNS and norepinephrine, although it was as effective as DuP 753 and EXP3174 in blocking the renal vasoconstrictor response to Ang II. These results suggest that endogenous Ang II enhances renal adrenergic function at the prejunctional site in anesthetized dogs. Analogous to the Ang II receptor in vascular smooth muscle, the prejunctional Ang II receptor appears to be of subtype 1. Mechanisms accounting for the absence of the inhibition of Ang II-mediated renal adrenergic response by saralasin remain to be determined.
Wong
P C
PC
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Hart
S D
SD
Timmermans
P B
PB
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000294:innervation*; D019808:Losartan; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012504:Saralasin / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; D002216:Captopril; C066026:losartan carboxylic acid; D012504:Saralasin; D019808:Losartan; D009638:Norepinephrine