Acute renal excretory actions of losartan in spontaneously hypertensive rats: role of AT2 receptors, prostaglandins, kinins and nitric oxide.
OBJECTIVE
The effects of losartan on blood pressure and on renal function have mainly been attributed to AT1 receptor blockade. Experimental evidence suggests that these effects could also be related to the actions of angiotensin II through AT2 receptors or to vasodilatory systems. The present study was therefore designed to investigate the manner in which the acute effects of losartan on renal excretory function are affected during simultaneous administration of an AT2 receptor antagonist, a kinin B2 receptor antagonist, a cyclo-oxygenase inhibitor or a nitric oxide synthesis inhibitor.


METHODS
The AT2 receptor antagonist PD 123319 (10 mg/kg), the bradykinin B2 receptor antagonist Hoe 140 (30 mu g/kg), the cyclo-oxygenase inhibitor meclofenamate (5 mg/kg) and the nitric oxide synthesis inhibitor NG-monomethyl-L-arginine (1 mu g/kg per min) were administered separately with acute intravenous losartan (1 mg/kg) to spontaneously hypertensive rats and the effects on mean arterial pressure and renal excretory function were assessed.


RESULTS
Losartan reduced mean arterial pressure by 11.1 +/- 5.7 mmHg and increased the glomerular filtration rate, urine flow and sodium excretion rate. The decrease in mean arterial pressure was blocked in the presence of NG-monomethyl-L-arginine but not during concurrent administration of PD 123319, Hoe 140 or meclofenamate. The increase in glomerular filtration rate induced by losartan was blunted by Hoe 140, meclofenamate and NG-monomethyl-L-arginine. Co-administration of PD 123319, Hoe 140 or meclofenamate, but not of NG-monomethyl-L-arginine, partially blunted the diuresis and natriuresis induced by losartan.


CONCLUSIONS
Nitric oxide participates in the antihypertensive action of losartan. Kinins, prostaglandins and nitric oxide appear to be involved in the effects of losartan on the glomerular filtration rate. The increases in urine flow and sodium excretion rate induced by losartan depend partially on AT2 receptors, kinins and prostaglandins.
Department of Physiology, University Complutense, Madrid, Spain.
R
R
Munoz-Garcia
R
R
Maeso
E
E
Rodrigo
J
J
Navarro
L M
LM
Ruilope
M C
MC
Casal
V
V
Cachofeiro
V
V
Lahera
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007705:Kinins / Q000378:metabolism*; D019808:Losartan; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012964:Sodium / Q000652:urine; D013777:Tetrazoles / Q000008:administration & dosage*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007705:Kinins; D011453:Prostaglandins; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C073402:PD 123319; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D008469:Meclofenamic Acid; C065679:icatibant; D012964:Sodium; D019808:Losartan; D001920:Bradykinin