MULTIPLE PREJUNCTIONAL ACTIONS OF ANGIOTENSIN-II ON NORADRENERGIC TRANSMISSION IN THE CAUDAL ARTERY OF THE RAT

1 Angiotensin II produced concentration-dependent enhancement of both stimulation-induced (S-I) efflux of [H-3]-noradrenaline and stimulatio n-evoked vasoconstrictor responses in isolated preparations of rat cau dal artery in which the noradrenergic transmitter stores had been labe lled with [H-3]-noradrenaline. The threshold concentrations of angiote nsin II for enhancement of S-T efflux (between 0.03 and 0.1 mu M) and of the stimulation-evoked vasoconstrictor responses (about 0.3 mu M) w ere 10 - 1000 times higher than those that have been found for several other vascular preparations. 2 The ATI angiotensin II receptor antago nist losartan (0.01 and 0.1 mu M), reduced or abolished the enhancemen t of S-I efflux by 1 and 3 mu M angiotensin II and the enhancement of vasoconstrictor responses by 1 mu M angiotensin II. Surprisingly, the combination of 0.01 mu M losartan and 0.1 mu M angiotensin II enhanced S-I efflux to a much greater extent than did 0.1 mu M angiotensin II alone. Moreover, the combination of 0.01 mu M losartan and 0.1 mu M an giotensin II enhanced stimulation-evoked vasoconstrictor responses, in contrast to the lack of effect of 0.1 mu M angiotensin II alone. 3 In a concentration of 0.01 mu M, the angiotensin II AT(2) receptor antag onist PD 123319 did not affect the enhancement of either S-I efflux or vasoconstrictor responses by angiotensin II. However, in a higher con centration (0.1 mu M), PD 123319 antagonized the enhancement of both t he S-I efflux and vasoconstrictor responses by angiotensin II. 4 In co ncentrations of 0.01 and 0.1 mu M, PD 123319 prevented the marked enha ncement of both S-I efflux and stimulation-evoked vasoconstrictor resp onses produced by the combination of 0.1 mu M angiotensin II and 0.01 mu M losartan. 5 The potentiation by losartan (0.01 mu M) of the facil itatory effect of 0.1 mu M angiotensin II on S-I efflux and on stimula tion-evoked vasoconstriction was still observed in the presence of eit her the cyclo-oxygenase inhibitor indomethacin (3 mu M), or the nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAM E, 100 mu M). 6 The findings confirm our previous suggestion that, in the rat caudal artery, angiotensin II receptors similar to the AT(1B) subtype subserve enhancement of transmitter noradrenaline release. 7 T he synergistic prejunctional interaction of 0.01 mu M losartan and 0.1 mu M angiotensin II may be due to either the unmasking by losartan of a latent population of angiotensin II receptors also subserving facil itation of transmitter noradrenaline release, or alternatively, losart an may block an inhibitory action of angiotensin II on transmitter nor adrenaline release which normally opposes its facilitatory effect.