Stimulation of AT2 receptor exerts beneficial effects in stroke-prone rats: focus on renal damage.
OBJECTIVE
Angiotensin II acts through two major receptors: AT1-R and AT2-R. It is known that the stimulation of AT1-R mediates vasoconstriction, cell proliferation and fibrosis, aldosterone release and inflammatory response but, although the stimulation of AT2-R is thought to promote vasodilation and anti-inflammatory effects, its real in-vivo functions are still unclear. The aim of this study was to investigate the effects of specific and selective AT2-R stimulation on the pathological events occurring in spontaneously hypertensive stroke-prone rats (SHRSPs).


RESULTS
SHRSPs who were fed a high-salt diet underwent long-term treatment with vehicle or compound 21 (C21), a nonpeptide selective AT2-R agonist, at doses of 0.75, 5 and 10 mg/kg per day. The vehicle-treated rats developed brain abnormalities detectable by magnetic resonance imaging after 42.5 +/- 7.5 days, and died 43 +/- 9.5 days after the start of the dietary treatment. The highest C21 dose delayed the occurrence of brain damage (P < 0.001 vs. vehicle-treated SHRSPs) and prolonged survival (P < 0.001) without affecting blood pressure. These beneficial effects of C21 were abolished by the administration of PD123319, an AT2-R antagonist. C21 treatment preserved renal structure by preventing inflammatory cell infiltration, collagen accumulation, and the neo-expression of vimentin; it also prevented the increased plasma renin activity and accumulation of urinary acute-phase proteins observed in the vehicle-treated rats.


CONCLUSIONS
Specific and selective AT2-R stimulation has beneficial effects on the pathological events occurring in SHRSPs. These data indicate a new avenue for the pharmacological treatment of diseases in which modulation of the renin-angiotensin system is required.
Gelosa
Paolo
P
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Pignieri
Alice
A
Fändriks
Lars
L
de Gasparo
Marc
M
Hallberg
Anders
A
Banfi
Cristina
C
Castiglioni
Laura
L
Turolo
Lucia
L
Guerrini
Uliano
U
Tremoli
Elena
E
Sironi
Luigi
L
D000322:Adrenergic Agonists / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008136:Longevity / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D011507:Proteinuria / Q000188:drug therapy / Q000652:urine; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000322:Adrenergic Agonists; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C073402:PD 123319; D012965:Sodium Chloride