Korean J Physiol Pharmacol.  2017 Nov;21(6):667-674. 10.4196/kjpp.2017.21.6.667.

Comparative effects of angiotensin II and angiotensin-(4-8) on blood pressure and ANP secretion in rats

• Phuong HT
• Yu L
• Park BM
• Kim SH

• KMID: 2395262
• DOI: http://doi.org/10.4196/kjpp.2017.21.6.667

Abstract

Angiotensin II (Ang II) is metabolized from N-terminal by aminopeptidases and from C-terminal by Ang converting enzyme (ACE) to generate several truncated angiotensin peptides (Angs). The truncated Angs have different biological effects but it remains unknown whether Ang-(4-8) is an active peptide. The present study was to investigate the effects of Ang-(4-8) on hemodynamics and atrial natriuretic peptide (ANP) secretion using isolated beating rat atria. Atrial stretch caused increases in atrial contractility by 60% and in ANP secretion by 70%. Ang-(4-8) (0.01, 0.1, and 1 µM) suppressed high stretch-induced ANP secretion in a dose-dependent manner. Ang-(4-8) (0.1 µM)-induced suppression of ANP secretion was attenuated by the pretreatment with an antagonist of Ang type 1 receptor (AT₁R) but not by an antagonist of ATâ‚‚R or ATâ‚„R. Ang-(4-8)-induced suppression of ANP secretion was attenuated by the pretreatment with inhibitor of phospholipase (PLC), inositol triphosphate (IP₃) receptor, or nonspecific protein kinase C (PKC). The potency of Ang-(4-8) to inhibit ANP secretion was similar to Ang II. However, Ang-(4-8) 10 µM caused an increased mean arterial pressure which was similar to that by 1 nM Ang II. Therefore, we suggest that Ang-(4-8) suppresses high stretch-induced ANP secretion through the AT₁R and PLC/IP₃/PKC pathway. Ang-(4-8) is a biologically active peptide which functions as an inhibition mechanism of ANP secretion and an increment of blood pressure.

Keyword

Angiotensin-(4-8); Angiotensin II; Angiotensin type 1 receptor; Atrial natriuretic peptide; Heart; Signal pathway

MeSH Terms

Aminopeptidases
Angiotensin II*
Angiotensins*
Animals
Arterial Pressure
Atrial Natriuretic Factor*
Blood Pressure*
Heart
Hemodynamics
Inositol
Peptides
Phospholipases
Protein Kinase C
Rats*
Receptor, Angiotensin, Type 1
Signal Transduction
Aminopeptidases
Angiotensin II
Angiotensins
Atrial Natriuretic Factor
Inositol
Peptides
Phospholipases
Protein Kinase C
Receptor, Angiotensin, Type 1

Figure

• 

  Fig. 1 Effects of angiotensin-(4-8) on atrial parameters. (A) Effects of different doses of angiotensin-(4-8) [Ang-(4-8)] (0.01, 0.1, 1.0 µM) on pulse pressure (a) and ANP secretion (b) as a function of time in isolated perfused beating atria. Atrial perfusate was collected at 2-min intervals for 50 min. Closed triangle (▲) indicates the time to increase the height of outflow catheter and to expose to Ang-(4-8). (B) Relative percent changes in pulse pressure (a) and ANP secretion (b) by different doses of Ang-(4-8) in high atrial stretch condition. Values are the mean±SEM (n=10-15). *vs. control group, p<0.05, **p<0.01; #vs. 0.01 µM Ang-(4-8) group, p<0.05; #vs. 1 µM Ang-(4-8), p<0.05.

• 

  Fig. 2 Modification of effects of Ang-(4-8) on atrial parameters by receptor antagonists. Modification of effects of Ang-(4-8) (0.1 µM) on pulse pressure (A), ECF translocation (B), ANP secretion (C) and ANP concentration (D) in the presence of angiotensin receptor antagonist. Atria were pretreated with losartan (Los, 1 µM, n=10), PD123319 (1 µM, n=10), LVV-H7 (LVV, 1 µM, n=10) or vehicle (Veh, n=15) at 10 min before sample collection. After a 10 min control collection period, the height of outflow catheter was increased and Ang-(4-8) (0.1 µM) or vehicle (n=8 for each antagonist) was simultaneously perfused for 40 min. Values are the mean±SEM. *vs. each vehicle group, p<0.05, **p<0.01.

• 

  Fig. 3 Modification of effects of Ang-(4-8) on atrial parameters by signaling inhibitors. Modification of effects of Ang-(4-8) (0.1 µM) on pulse pressure (A), ECF translocation (B), ANP secretion (C) and ANP concentration (D) in the presence of downstream signaling pathway inhibitors. Atria were perfused with PLC inhibitor [U73122, 10 µM, n=10; edelfosine (Edelfo), 1 µM, n=10], IP3 receptor inhibitor (2APB, 1 µM, n=10) or PKC inhibitor [staurosporine (Stauro), 1 µM, n=10] at 10 min before sample collection. After a 10 min control collection period, the height of outflow catheter was increased and Ang-(4-8) or vehicle was simultaneously perfused for 40 min. To rule out self-effects of inhibitors, atria were perfused with inhibitor alone (n=8 for each inhibitor). Values are the mean±SEM. *vs. each vehicle group, p<0.05, **p<0.01.

• 

  Fig. 4 Comparison of effects of Ang II and Ang-(4-8) on atrial parameters. Comparison of effects of Ang II (0.01, 0.1 µM, n=8) and Ang-(4-8) (0.01, 0.1 µM, n=10) on pulse pressure (A), ECF translocation (B), ANP secretion (C), and ANP concentration (D). Values are expressed as percent change compared to control value. Values are the mean±SEM. *vs. each vehicle group, p<0.05, **p<0.01; #vs. Ang II group, p<0.05.

• 

  Fig. 5 Comparison of effects of Ang II and Ang-(4-8) on hemodynamics. (A) Representative tracing of change in arterial pressure by Ang II and Ang-(4-8) in anesthetized rats. (B) Comparison of changes in mean arterial pressure and heart rate by Ang-(4-8) (n=5) and Ang II (n=5). Values are expressed as percent change compared to control value. Values are the mean±SEM. **vs. Ang-(4-8) group, p<0.01.

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