Acute and chronic effects of losartan (DuP 753) on blood pressure and vascular reactivity in normotensive rats.
The effects of in vivo treatment with the nonpeptide subtype 1 angiotensin II receptor antagonist, losartan, on blood pressure and vascular reactivity in normotensive male Sprague-Dawley rats were studied. Initial acute experiments demonstrated that blood pressure was significantly decreased six hours following a single injection of losartan (10 mg/kg, sc), but returned to control levels by 24 hours post-injection. Pressor responses to angiotensin II (0.1 ug/kg, iv) in these rats were significantly attenuated 2 and 24 hours following losartan injection. For chronic studies, rats were injected once daily for 21 days with either the same dose of losartan or saline vehicle. Blood pressure and pressor responses to angiotensin II were assessed at the end of the 21 day treatment period. A significant decrease in blood pressure was observed in chronic losartan treated rats 6 hours after the last injection on day 21; however, as in the acute studies, blood pressure had returned to control values by 24 hours post-injection. Although blood pressure had returned to normal, pressor responses to angiotensin II were significantly attenuated in chronic losartan treated rats 24 hours after the last injection. Following the in vivo studies, aortae and tail arteries were removed for experiments on vascular reactivity. Acute and chronic losartan treatment had no effect on KCl and norepinephrine reactivity. Endothelial-dependent and independent relaxation responses were also unaltered. A significant decrease in the maximal contractile response to angiotensin II was observed in aorta from acute and chronic losartan treated rats. Electrical stimulation-induced responses were unaltered in tail arteries from rats acutely treated with losartan but were potentiated in rats chronically treated with losartan. Exogenously applied angiotensin II, in concentrations which did not elicit contractile responses, potentiated electrical stimulation-induced responses of tail arteries from control rats but did not influence responses in arteries from acute and chronic losartan treated rats. These results demonstrate that losartan has significant blood pressure lowering effects in normotensive rats. Interestingly, although blood pressure returns to normal by 24 hours post-injection, pressor responses to angiotensin II remain attenuated in acute and chronic losartan treated rats. Finally, losartan treatment results in specific alterations in vascular reactivity associated with the actions of angiotensin II.
Soltis
E E
EE
Division of Pharmacology and Experimental Therapeutics College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Jewell
A L
AL
Dwoskin
L P
LP
Cassis
L A
LA
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004558:Electric Stimulation; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan