Evidence for the involvement of different receptor subtypes in the pre‐ and postjunctional actions of angiotensin II at rat sympathetic neuroeffector sites

Abstract

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...

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

“…The significantly greater basal luminal perfusion pressure observed in the present study in caudal artery preparations from SH rats compared to that in preparations from WKY rats is consistent with findings with the mesenteric vasculature (Lais & Brody, 1978; tions of angiotensin II in rabbit renal artery (Zhang et al, 1994), rat portal vein, rabbit aorta and pulmonary artery (Rhaleb et al, 1991). Likewise, we previously described blockade by losartan of the vasoconstrictor response to angiotensin II in the caudal artery of Sprague-Dawley rats (Cox et al, 1995 Prejuncdonal anglotensin 11 receptors in SH rats sponse. In preparations from both strains of rats, the maximal enhancement of S-I [3H]-noradrenaline efflux and of the vasoconstrictor response occurred with a concentration of 1 gM and a further increase in concentration to 3 gM produced less enhancement.…”

“…We have recently found that the enhancement of transmitter noradrenaline release by angiotensin II in the caudal artery of Sprague-Dawley rats is blocked by both losartan and PD 123319 (Cox et al, 1995). 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).…”

“…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.…”

“…Angiotensin II-mediated effects such as vascular smooth muscle contraction (Cox et al, 1995), aldosterone release (Wong et al, 1990a) and the regulation of fluid and electrolyte balance (Barbella et al, 1993) are all blocked by losartan and unaffected by AT2 receptor antagonists. Hence, the major physiological actions of angiotensin II appear to involve the AT1 receptor subtype and a functional role of the AT2 receptor remains to be determined.…”

“…Thus, two populations of AT, sites on mesangial cells were shown to bind losartan and PD 123319 with different relative affinities Madhun et al, 1993). The sites for which losartan had the higher affinity were classified ATlA and those for which PD 123319 had the higher affinity were termed ATIB .Angiotensin II-mediated effects such as vascular smooth muscle contraction (Cox et al, 1995), aldosterone release (Wong et al, 1990a) and the regulation of fluid and electrolyte balance (Barbella et al, 1993) are all blocked by losartan and unaffected by AT2 receptor antagonists. Hence, the major physiological actions of angiotensin II appear to involve the AT1 receptor subtype and a functional role of the AT2 receptor remains to be determined.…”