1 The effects of the nonpeptide angiotensin II receptor (AT) antagonists losartan and PD 123319 on actions of angiotensin II in the rat caudal artery and rat vas deferens preparations were investigated. 2 Angiotensin 11 (1.0 I1M) increased perfusion pressure in isolated segments of the rat caudal artery.This increase in perfusion pressure was prevented by the AT,-antagonist, losartan (0.1 JAM) but was not affected by the AT2-antagonist, PD 123319 (0.1 JAM). 3 Angiotensin II (0.1-3.01M) produced a concentration-dependent enhancement of the stimulationinduced (S-I) efflux of [3H]-noradrenaline from isolated segments of rat caudal artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline. The maximum enhancement of S-I efflux was approximately 60% with 1.O01M angiotensin II. 4 Losartan (0.01 and 0.1 AM) reduced the enhancement of S-I efflux produced by 1.0 JAM angiotensin II in the caudal artery. 5 PD 123319 (0.01 JAM) did not affect the enhancement of S-I efflux produced by angiotensin II (1.0 JAM) in the caudal artery. However, in a higher concentration (0.1 JAM), PD 123319 reduced the enhancement of S-I efflux produced by 1.O0JM angiotensin II. 6 Angiotensin II produced concentration-dependent enhancement of the purinergic twitch responses (1 pulse/60 s) in the rat vas deferens, 7 Losartan (0.03 JAM) and PD 123319 (0.03 JM) each reduced the angiotensin II-induced enhancement of the twitch responses in the rat vas deferens. 8 These findings indicate that the enhancement of sympathetic neuroeffector transmission in both the caudal artery and vas deferens of the rat involves angiotensin receptor subtype(s) sensitive to both losartan and PD 123319. In contrast, the direct vasoconstrictor effect of angiotensin II in the rat caudal artery involves activation of a receptor subtype sensitive only to losartan. Keywords: Angiotensin II; losartan; PD 123319; vasoconstriction; sympathetic neuroeffector transmission IntroductionThe renin-angiotensin system plays a central role in cardiovascular homeostasis by influencing vascular tone, extracellular fluid and electrolyte balance, and the sympathetic nervous system (Sealey & Laragh, 1989). The interactions of the renin-angiotensin system with the cardiovascular system are predominantly mediated by the octapeptide, angiotensin II. Angiotensin II influences cardiovascular function by several mechanisms, including direct constriction of resistance and capacitance vessels and direct cardiac inotropic and chronotropic activity (Sealey & Laragh, 1989). In addition, angiotensin II has been shown to facilitate noradrenergic neuroeffector transmission by enhancing stimulation-induced release of noradrenaline from sympathetic nerves, although it has also been reported to increase the rate of synthesis of noradrenaline and to inhibit neuronal uptake of the transmitter (Story & Ziogas, 1987 that, in the rabbit vas deferens, angiotensin II produces the usual enhancement of noradrenergic transmission, but that the peptide inhibits the purinergic comp...

1 Release-modulating opioid and cannabinoid (CB) receptors, b-adrenoceptors and bradykinin receptors at noradrenergic axons were studied in mouse tissues (occipito-parietal cortex, heart atria, vas deferens and spleen) preincubated with 3 H-noradrenaline. 2 Experiments using the OP 1 receptor-selective agonists DPDPE and DSLET, the OP 2 -selective agonists U50488H and U69593, the OP 3 -selective agonist DAMGO, the ORL 1 receptor-selective agonist nociceptin, and a number of selective antagonists showed that the noradrenergic axons innervating the occipito-parietal cortex possess release-inhibiting OP 3 and ORL 1 receptors, those innervating atria OP 1 , ORL 1 and possibly OP 3 receptors, and those innervating the vas deferens all four opioid receptor types. 3 Experiments using the non-selective CB agonists WIN 55,212-2 and CP 55,940 and the CB 1 -selective antagonist SR 141716A indicated that the noradrenergic axons of the vas deferens possess release-inhibiting CB 1 receptors. Presynaptic CB receptors were not found in the occipito-parietal cortex, in atria or in the spleen. 4 Experiments using the non-selective b-adrenoceptor agonist isoprenaline and the b 2 -selective agonist salbutamol, as well as subtype-selective antagonists, demonstrated the occurrence of releaseenhancing b 2 -adrenoceptors at the sympathetic axons of atria and the spleen, but demonstrated their absence in the occipito-parietal cortex and the vas deferens. 5 Experiments with bradykinin and the B 2 -selective antagonist Hoe 140 showed the operation of release-enhancing B 2 receptors at the sympathetic axons of atria, the vas deferens and the spleen, but showed their absence in the occipito-parietal cortex.6 The experiments document a number of new presynaptic receptor locations. They con®rm and extend the existence of marked tissue and species dierences in presynaptic receptors at noradrenergic neurons.

1 The interaction between a 2 -autoreceptors and receptors for angiotensin (AT 1 ) and bradykinin (B 2 ) was studied in mouse isolated atria. The preparations were labelled with [ 3 H]-noradrenaline and then superfused with desipramine-containing medium and stimulated electrically. 2 Angiotensin II (10 711 ± 10 77 M), angiotensin III (10 710 ± 10 76 M) and bradykinin (10 711 ± 10 77 M) enhanced the evoked over¯ow of tritium when preparations were stimulated with conditions that led to marked a 2 -autoinhibition (120 pulses at 3 Hz), but not when stimulated with conditions that led to little a 2 -autoinhibition (20 pulses at 50 Hz). 3 Blockade of a-adrenoceptors by phentolamine (1 or 10 mM) reduced or abolished the e ect of angiotensin II and bradykinin on the over¯ow response to 120 pulses at 3 Hz. 6 The experiments show that (i) a marked prejunctional facilitatory e ect of angiotensin and bradykinin in mouse isolated atria requires prejunctional a 2 -autoinhibition; (ii) in the absence of a 2 -autoinhibition, activation of other prejunctional G i/o protein-coupled reeptors, namely opioid and neuropeptide Y receptors, restores a marked e ect of angiotensin II and bradykinin; and (iii) the facilitatory e ect of terbutaline is not dependent upon the degree of a 2 -autoinhibition. The ®ndings indicate that the major part of the release-enhancing e ect elicited through prejunctional G q/11 protein-coupled receptors is due to disruption of an ongoing, a 2 -autoreceptor-triggered G i/o protein mediated inhibition.

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...

1 The e ect of angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1 ± 7) on the electrically induced release of noradrenaline was studied in preparations of mouse atria, spleen, hippocampus, occipito-parietal cortex and hypothalamus preincubated with [ 3 H]-noradrenaline. The prejunctional angiotensin receptor type was investigated using the non-selective receptor antagonist saralasin (AT 1 /AT 2 ) and the AT 1 and AT 2 selective receptor antagonists losartan and PD 123319, respectively. 2 In atrial and splenic preparations, angiotensin II (0.01 nM ± 0.1 mM) and angiotensin III (0.01 and 0.1 nM ± 1 mM) increased the stimulation-induced over¯ow of tritium in a concentration-dependent manner. Angiotensin IV, only at high concentrations (1 and 10 mM), enhanced tritium over¯ow in the atria, while angiotensin-(1 ± 7) (0.1 nM ± 10 mM) was without e ect in both preparations. 3 In preparations of hippocampus, occipito-parietal cortex and hypothalamus, none of the angiotensin peptides altered the evoked over¯ow of tritium. 4 In atrial and splenic preparations, saralasin (0.1 mM) and losartan (0.1 and 1 mM), but not PD 123319 (0.1 mM), shifted the concentration-response curves of angiotensin II and angiotensin III to the right. 5 In conclusion, in mouse atria and spleen, angiotensin II and angiotensin III facilitate the action potential induced release of noradrenaline via a prejunctional AT 1 receptor. Only high concentrations of angiotensin IV are e ective in the atria and angiotensin-(1 ± 7) is without e ect in both preparations. In mouse brain areas, angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1 ± 7) do not modulate the release of noradrenaline.