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. 2000 Mar;129(6):1095-102.
doi: 10.1038/sj.bjp.0703167.

Enhancement of noradrenaline release by angiotensin II and bradykinin in mouse atria: evidence for cross-talk between G(q/11) protein- and G(i/o) protein-coupled receptors

Affiliations

Enhancement of noradrenaline release by angiotensin II and bradykinin in mouse atria: evidence for cross-talk between G(q/11) protein- and G(i/o) protein-coupled receptors

S L Cox et al. Br J Pharmacol. 2000 Mar.

Abstract

1. The interaction between alpha(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(-11) - 10(-7) M), angiotensin III (10(-10) - 10(-6) M) and bradykinin (10(-11) - 10(-7) M) enhanced the evoked overflow of tritium when preparations were stimulated with conditions that led to marked alpha(2)-autoinhibition (120 pulses at 3 Hz), but not when stimulated with conditions that led to little alpha(2)-autoinhibition (20 pulses at 50 Hz). 3. Blockade of alpha-adrenoceptors by phentolamine (1 or 10 microM) reduced or abolished the effect of angiotensin II and bradykinin on the overflow response to 120 pulses at 3 Hz. 4. Addition of the delta-opioid agonist [D-Ser(2)]-leucine enkephalin-Thr (DSLET, 0.1 microM), or of neuropeptide Y (0.1 microM), together with phentolamine, restored the effect of angiotensin II and bradykinin. 5. The beta-adrenoceptor agonist terbutaline (10(-9) - 10(-4) M) enhanced the evoked overflow of tritium irrespective of the degree of autoinhibition. 6. The experiments show that (i) a marked prejunctional facilitatory effect of angiotensin and bradykinin in mouse isolated atria requires prejunctional alpha(2)-autoinhibition; (ii) in the absence of alpha(2)-autoinhibition, activation of other prejunctional G(i/o) protein-coupled receptors, namely opioid and neuropeptide Y receptors, restores a marked effect of angiotensin II and bradykinin; and (iii) the facilitatory effect of terbutaline is not dependent upon the degree of alpha(2)-autoinhibition. The findings indicate that the major part of the release-enhancing effect elicited through prejunctional G(q/11) protein-coupled receptors is due to disruption of an ongoing, alpha(2)-autoreceptor-triggered G(i/o) protein mediated inhibition.

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Figures

Figure 1
Figure 1
Effect of angiotensin II, angiotensin III (left panel) and bradykinin (right panel) on the overflow of tritium, evoked by stimulation trains leading either to marked or to little autoinhibition. The preparations were stimulated for 6 periods (S1–S6) by either 120 p at 3 Hz (marked autoinhibiton) or 20 p at 50 Hz (little autoinhibition). Angiotensin II, angiotensin III and bradykinin were introduced into the PSS in increasing concentrations, 12 min before S2–S6. The symbols represent the mean percentage increase, calculated from Sn/S1 values and corrected for changes observed in control experiments in the absence of the angiotensins and bradykinin. The vertical lines represent the s.e.mean from 4–30 preparations. Most of the experiments with angiotensin II and angiotensin III, 120 p at 3 Hz, are from Cox et al. (1999).
Figure 2
Figure 2
Effect of angiotensin II (left panel) and bradykinin (right panel) on the overflow of tritium, evoked by stimulation trains leading to marked autoinhibition, in the absence and presence of phentolamine. The preparations were stimulated for 6 periods (S1–S6) by 120 p at 3 Hz. Angiotensin II and bradykinin were introduced into the PSS either alone or in the presence of phentolamine (Phent, 1 or 10 μM), which was present throughout superfusion. In some experiments, losartan (0.1 μM) or Hoe 140 (0.01 μM) was also present throughout superfusion. Angiotensin II and bradykinin were introduced in increasing concentrations, 12 min before S2–S6. The symbols represent the mean percentage increase, calculated from Sn/S1 values and corrected for changes observed in control experiments in the absence of angiotensin II and bradykinin. The vertical lines represent the s.e.mean from 4–30 preparations. The curves showing the effect in the absence of phentolamine are from Figure 1.
Figure 3
Figure 3
Effect of angiotensin II (left panel) and bradykinin (right panel) on the overflow of tritium, evoked by stimulation trains leading to marked autoinhibition, in the absence and presence of phentolamine: influence of a reduction of S1 overflow values. The preparations were stimulated for six periods (S1–S6). Angiotensin II and bradykinin were introduced into the PSS either alone or in the presence of phentolamine (Phent, 1 μM), which was present throughout superfusion. Angiotensin II and bradykinin were introduced into the PSS in increasing concentrations, 12 min before S2–S6. Left panel: preparations were stimulated with either 36 or 60 p (instead of the usual 120 p) at 3 Hz. Right panel: preparations were stimulated with 120 p at 3 Hz; the PSS contained either 0.65 or 1.3 mM (instead of the usual 2.5 mM) Ca2+. The symbols represent the mean percentage increase, calculated from Sn/S1 values and corrected for changes observed in control experiments in the absence of angiotensin II and bradykinin. The vertical lines represent the s.e.mean from 4–14 preparations.
Figure 4
Figure 4
Effect of angiotensin II and bradykinin on the overflow of tritium, evoked by stimulation trains leading to marked autoinhibition, in the absence and presence of phentolamine: interaction with DSLET and NPY. The preparations were stimulated for three periods (S1–S3) by 120 p at 3 Hz. Angiotensin II and bradykinin were introduced into the PSS either alone, or in the presence of phentolamine (Phent, 1 μM), or in the presence of Phent plus DSLET (0.1 μM) or NPY (0.1 μM). Phent, when given alone, was present from the beginning of superfusion. The combinations of Phent plus DSLET or NPY were present from t=30 min. Angiotensin II and bradykinin were introduced 12 min before S3. The columns represent the mean percentage increase, calculated from S3/S1 values and corrected for changes observed in control experiments in the absence of angiotensin II or bradykinin. The vertical lines represent the s.e.mean from 5–15 preparations. * Indicates a significant difference (P<0.05). All increases were significant (P<0.05) as compared to control experiments without angiotensin II and bradykinin (not shown).
Figure 5
Figure 5
Effect of terbutaline on the evoked overflow of tritium. The preparations were stimulated for six periods (S1–S6) by either 120 p at 3 Hz or 20 p at 50 Hz. Terbutaline was introduced into the PSS either alone or in the presence of phentolamine (Phent, 1 μM), which was present throughout superfusion. Terbutaline was introduced in increasing concentrations, 12 min before S2–S6. The symbols represent the mean percentage increase, calculated from Sn/S1 values and corrected for changes observed in control experiments in the absence of terbutaline. The vertical lines represent the s.e.mean from 4–10 preparations.

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