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 [ 3 H]‐noradrenaline and stimulation‐evoked vasoconstrictor responses in isolated preparations of rat caudal artery in which the noradrenergic transmitter stores had been labelled with [ 3 H]‐noradrenaline. The threshold concentrations of angiotensin II for enhancement of S‐I efflux (between 0.03 and 0.1 μ m ) and of the stimulation‐evoked vasoconstrictor responses (about 0.3 μ m ) were 10–1000 times higher than those that have been found for several other vascular preparations. 2 The AT 1 angiotensin II receptor antagonist losartan (0.01 and 0.1 μ m ), reduced or abolished the enhancement of S‐I efflux by 1 and 3 μ m angiotensin II and the enhancement of vasoconstrictor responses by 1 μ m angiotensin II. Surprisingly, the combination of 0.01 μ losartan and 0.1 μ m angiotensin II enhanced S‐I efflux to a much greater extent than did 0.1 μ m angiotensin II alone. Moreover, the combination of 0.01 μ m losartan and 0.1 μ m angiotensin II enhanced stimulation‐evoked vasoconstrictor responses, in contrast to the lack of effect of 0.1 μ m angiotensin II alone. 3 In a concentration of 0.01 μ m , the angiotensin II AT 2 receptor antagonist PD 123319 did not affect the enhancement of either S‐I efflux or vasoconstrictor responses by angiotensin II. However, in a higher concentration (0.1 μ m ), PD 123319 antagonized the enhancement of both the S‐I efflux and vasoconstrictor responses by angiotensin II. 4 In concentrations of 0.01 and 0.1 μ m , PD 123319 prevented the marked enhancement of both S‐I efflux and stimulation‐evoked vasoconstrictor responses produced by the combination of 0.1 μ m angiotensin II and 0.01 μ m losartan. 5 The potentiation by losartan (0.01 μ m ) of the facilitatory effect of 0.1 μ m angiotensin II on S‐I efflux and on stimulation‐evoked vasoconstriction was still observed in the presence of either the cyclo‐oxygenase inhibitor indomethacin (3 μ m ), or the nitric oxide synthase inhibitor N ω ‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μ 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 The synergistic prejunctional interaction of 0.01 μ m losartan and 0.1 μ m angiotensin II may be due to either the unmasking by losartan of a latent population of angiotensin II receptors also subserving facilitation of transmitter noradrenaline release, or alternatively, losartan may block an inhibitory action of angiotensin II on transmitter noradrenaline release which normally opposes its facilitatory effect.