EFFECTS OF LOSARTAN ON CONTRACTILE RESPONSES OF CONDUCTANCE AND RESISTANCE ARTERIES FROM RATS

We investigated the selectivity of losartan as an angiotensin II (ANG II) antagonist in contractile experiments using segments of small mese nteric arteries and rings of aorta from rat. The concentration-effect curve of ANG II was not different in mesenteric arteries with and with out endothelium. In both resistance and conductance vessels, it was sh ifted toward larger concentrations by losartan (3 nM) with similar app arent inhibition constant (K-B) values: 4.1 +/- 1.8 nM (n = 6) in smal l mesenteric arteries and 1.9 +/- 0.9 nM (n = 6) in aorta. These value s agree with the known affinity of losartan for AT(1) receptors. At 1 mu M, the AT(2)-selective ligand CGP 42112A had no effect in the two t issues. In small mesenteric arteries, losartan less than or equal to 3 0 mu M had no effect on contractile responses induced by norepinephrin e (NE), serotonin, or neuropeptide Y (NPY). However, it inhibited vaso constriction elicited by prostaglandin F-2 alpha (PGF(2 alpha)). This latter effect was also noted in the aorta. Similarly, losartan also co mpetitively antagonized aortic contractile responses elicited by U 466 19, a thromboxane A(2) analogue (TXA(2)), with a pA(2) value of 5.7. T wo losartan analogues, DuP 532 and EXP 3174 (a metabolite of losartan) , less than or equal to 30 mu M, did not antagonize U 46619, showing s tructural requirements for this antagonistic action of losartan. We co nclude that in both rat resistance and conductance vessels, ANG II ind uces vasoconstriction through activation of AT(1) receptors which are selectively blocked by losartan at nanomolar concentrations and that a t micromolar concentrations, losartan may also block the vascular TXA( 2)/PGF(2 alpha) (TP) receptor.