Multiple prejunctional actions of angiotensin II on noradrenergic transmission in the caudal artery of the rat

Abstract

1 Angiotensin II produced concentration-dependent enhancement of both stimulation-induced (S-I) efflux of [3H]-noradrenaline and stimulation-evoked vasoconstrictor responses in isolated preparations of rat caudal artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline.The threshold concentrations of angiotensin II for enhancement of S-I efflux (between 0.03 and 0.1 gM) and of the stimulation-evoked vasoconstrictor responses (about 0.3 gM) were 10-1000 times higher than those that have been found for several other vascular preparations.2 The AT, angiotensin II receptor antagonist losartan (0.01 and 0.1 gM), reduced or abolished the enhancement of S-I efflux by 1 and 3 gM angiotensin II and the enhancement of vasoconstrictor responses by 1 pM angiotensin II. Surprisingly, the combination of 0.01 Mm losartan and 0.1 Mm angiotensin II enhanced S-I efflux to a much greater extent than did 0.1 gM angiotensin II alone. Moreover, the combination of 0.01 Mm losartan and 0.1 gM angiotensin II enhanced stimulation-evoked vasoconstrictor responses, in contrast to the lack of effect of 0.1 gM angiotensin II alone. 3 In a concentration of 0.01 gM, the angiotensin II AT2 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 Mm), 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 gM, PD 123319 prevented the marked enhancement of both S-I efflux and stimulation-evoked vasoconstrictor responses produced by the combination of 0.1 gM angiotensin II and 0.01 gM losartan. 5The potentiation by losartan (0.01 gM) of the facilitatory effect of 0.1 gM angiotensin II on S-I efflux and on stimulation-evoked vasoconstriction was still observed in the presence of either the cyclooxygenase inhibitor indomethacin (3 pM), or the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME, 100 gM). 6 The findings confirm our previous suggestion that, in the rat caudal artery, angiotensin II receptors similar to the ATIB subtype subserve enhancement of transmitter noradrenaline release. 7 The synergistic prejunctional interaction of 0.01 gM losartan and 0.1 ,Mm 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. Keywords: Angiotensin II; angiotensin II receptors; losartan; PD 123319; rat caudal artery; noradrenergic transmission Introduction Angiotensin II, the primary effector hormone of the reninangiotensin system, has a wide range of physiological actions directed at target organs in the cardiovascular system. These include vasoconstriction of peripheral blood vessels and facilitation of noradrenerg...

Angiotensin II receptors involved in the enhancement of noradrenergic transmission in the caudal artery of the spontaneously hypertensive rat

“…Thus, we suggested that the prejunctional receptor subserving the enhancement of transmitter noradrenaline release in this tissue had characteristics similar to the ATIB binding site described by Zhou et al (1993). In contrast, the receptor subtype subserving the direct vasoconstrictor actions of angiotensin II in the rat caudal artery was found to be sensitive to losartan but not PD 123319 (Cox et al, 1995), which is consistent with results from other studies (Rhaleb et al, 1991).In our studies with isolated caudal artery preparations from a normotensive (Sprague-Dawley) strain of rat, we found that, compared to published findings in other tissues, angiotensin II had a relatively low potency in respect of its ability to enhance stimulation-induced (S-I) [3H]-noradrenaline efflux (Cox et al, 1996). In addition, a striking and unexpected finding of those studies was that the enhancement of S-I [3H]-noradrenaline efflux and of the associated vasoconstrictor responses produced by angiotensin II, in a concentration just above threshold (0.1 /iM), was greatly increased in the presence of 0.01 gM losartan.…”

“…[3H]-noradrenaline present in the perfusate/superfusate collection was separated chromatographically from its tritiated metabolites and measured by liquid scintillation counting (Cox et al, 1996). noradrenaline were determined, again, as previously described (Cox et al, 1996), the second period of stimulation in each case being expressed as a percentage of the corresponding value for the first period of stimulation (% R2/R1 and % S2/S1, respectively).…”

“…noradrenaline were determined, again, as previously described (Cox et al, 1996), the second period of stimulation in each case being expressed as a percentage of the corresponding value for the first period of stimulation (% R2/R1 and % S2/S1, respectively).…”

“…Furthermore, when, in addition to losartan, the AT2 receptor antagonist PD 123319 was also present in the artery perfusion/superfusion solution in low concentrations (0.01 or 0.1 Mm), angiotensin II (0.1 jIM) failed to enhance the S-I efflux. We suggested that the synergistic interaction between losartan and angiotensin II was due either to the unmasking by losartan of a latent population of angiotensin II receptors, possibly of the AT2 subtype which also subserve facilitation of noradrenaline release, or alternatively, to the blockade by losartan of an inhibitory action of angiotensin II on transmitter release, possibly involving ATIA receptors which normally opposes its facilitatory action (Cox et al, 1996 (Cox et al, 1996).…”

“…[3H]-noradrenaline present in the perfusate/superfusate collection was separated chromatographically from its tritiated metabolites and measured by liquid scintillation counting (Cox et al, 1996). …”