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 mesenteric arteries and rings of aorta from rat. The concentration-effect curve of ANG II was not different in mesenteric arteries with and without endothelium. In both resistance and conductance vessels, it was shifted toward larger concentrations by losartan (3 nM) with similar apparent inhibition constant (K-B) values: 4.1 +/- 1.8 nM (n = 6) in small mesenteric arteries and 1.9 +/- 0.9 nM (n = 6) in aorta. These values 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 tissues. In small mesenteric arteries, losartan less than or equal to 30 mu M had no effect on contractile responses induced by norepinephrine (NE), serotonin, or neuropeptide Y (NPY). However, it inhibited vasoconstriction elicited by prostaglandin F-2 alpha (PGF(2 alpha)). This latter effect was also noted in the aorta. Similarly, losartan also competitively antagonized aortic contractile responses elicited by U 46619, a thromboxane A(2) analogue (TXA(2)), with a pA(2) value of 5.7. Two 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 structural requirements for this antagonistic action of losartan. We conclude that in both rat resistance and conductance vessels, ANG II induces vasoconstriction through activation of AT(1) receptors which are selectively blocked by losartan at nanomolar concentrations and that at micromolar concentrations, losartan may also block the vascular TXA(2)/PGF(2 alpha) (TP) receptor.