Haemodynamic effects of dual blockade of the renin-angiotensin system in spontaneously hypertensive rats: influence of salt.
OBJECTIVE
To elucidate the mechanisms responsible for the adverse renal effects induced by dual blockade of the renin-angiotensin system (RAS) and the role of salt therein.


METHODS
The effects of enalapril, losartan and their combination on blood pressure, renal haemodynamics, renal function and RAS were investigated over a wide range of doses in spontaneously hypertensive rats fed either a low-sodium or a high-sodium diet.


RESULTS
In rats fed the low-sodium diet, the losartan-enalapril combination induced the same dose-dependent haemodynamic and hormonal changes as did three- to 10-fold greater doses of enalapril or losartan alone. When a strong decrease (> 50%) in blood pressure was achieved (with 10 mg/kg enalapril plus 10 mg/kg losartan, 100 mg/kg enalapril or 100 mg/kg losartan), a massive renal vasoplegia occurred and renal insufficiency developed. In addition, because of the huge release of renin, angiotensinogen concentrations were reduced, leading to a decrease in intrarenal angiotensins. In rats fed the high-sodium diet, those treated with the enalapril 30 mg/kg plus losartan 30 mg/kg combination, despite complete functional RAS blockade, exhibited smaller decreases in blood pressure and renal resistance, lesser release of renin and angiotensinogen consumption, and a normal renal function. These effects were similar to those produced by 100 mg/kg of enalapril or losartan in rats fed the high-salt diet, or by 10 mg/kg of enalapril or of losartan in rats fed the low-salt diet.


CONCLUSIONS
Dual RAS blockade could be either beneficial, when sodium intake is unrestricted, or dangerous, when sodium intake is restricted.
Richer-Giudicelli
Christine
C
Département de Pharmacologie, Faculté de Médecine, Paris-Sud-INSERM 00-01, 94276 Le Kremlin-Bicêtre Cédex, France. christine.giudicelli@kb.u-psud.fr
Domergue
Valérie
V
Gonzalez
Marie-Françoise
MF
Messadi
Erij
E
Azizi
Michel
M
Giudicelli
Jean-François
JF
Ménard
Joël
J
D000758:Anesthesia; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D003243:Consciousness; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000502:physiology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D017673:Sodium Chloride, Dietary; D004656:Enalapril; D019808:Losartan