Korean J Physiol Pharmacol.  2022 Mar;26(2):125-133. 10.4196/kjpp.2022.26.2.125.

Carbon monoxide releasing molecule-2 suppresses stretchactivated atrial natriuretic peptide secretion by activating largeconductance calcium-activated potassium channels

• Li W
• Lee SH
• Kim SH

• KMID: 2526731
• DOI: http://doi.org/10.4196/kjpp.2022.26.2.125

Abstract

Carbon monoxide (CO) is a known gaseous bioactive substance found across a wide array of body systems. The administration of low concentrations of CO has been found to exert an anti-inflammatory, anti-apoptotic, anti-hypertensive, and vaso-dilatory effect. To date, however, it has remained unknown whether CO influences atrial natriuretic peptide (ANP) secretion. This study explores the effect of CO on ANP secretion and its associated signaling pathway using isolated beating rat atria. Atrial perfusate was collected for 10 min for use as a control, after which high atrial stretch was induced by increasing the height of the outflow catheter. Carbon monoxide releasing molecule-2 (CORM-2; 10, 50, 100 µM) and hemin (HO-1 inducer; 0.1, 1, 50 µM), but not CORM-3 (10, 50, 100 µM), decreased high stretch-induced ANP secretion. However, zinc porphyrin (HO-1 inhibitor) did not affect ANP secretion. The order of potency for the suppression of ANP secretion was found to be hemin > CORM-2 >> CORM-3. The suppression of ANP secretion by CORM-2 was attenuated by pretreatment with 5-hydroxydecanoic acid, paxilline, and 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one, but not by diltiazem, wortmannin, LY-294002, or NG-nitroL-arginine methyl ester. Hypoxic conditions attenuated the suppressive effect of CORM-2 on ANP secretion. In sum, these results suggest that CORM-2 suppresses ANP secretion via mitochondrial K _ATP channels and large conductance Ca ²⁺ -activated K⁺ channels.

Keyword

ANP; BK _Ca channel; Carbon monoxide; CORM-2; Hypoxia; K _ATP channel

Figure

• 

  Fig. 1 Effects of CORM-2 on ANP secretion and atrial contractility. (A) Effects of CORM-2 (10, 50, 100 µM) on ANP secretion (a), SAP (b), DAP (c) and APP (d) as a function of time in high-stretched atria. (B) Relative percent changes in atrial parameters by CORM-2. Values are expressed by the relative percent change from the mean of the first five control values (fraction no. 1–5) and the last five peak values (fraction no. 21–25). Values are expressed as the means ± SEM. Arrow indicates the time to start to perfuse CORM-2 with high atrial stretch. CORM, carbon monoxide releasing molecule; ANP, atrial natriuretic peptide; SAP, systolic atrial pressure; DAP, diastolic atrial pressure; APP, atrial pulse pressure. *** vs. vehicle group, p < 0.005; # vs. corresponding group, p < 0.05, ##p < 0.01.

• 

  Fig. 2 Comparison of changes in ANP secretion (A) and atrial contractility (B) in response to (a) CORM-2, (b) CORM-3, (c) hemin, and (d) ZnPP. Values are expressed by the relative percent change from the mean of the first five control values (fraction no. 1–5) and the last five peak values (fraction no. 21–25). CORM, carbon monoxide releasing molecule; ANP, atrial natriuretic peptide; ZnPP, zinc porphyrin; APP, atrial pulse pressure. Legends are the same as in Fig. 1. Values are expressed as the means ± SEM. *** vs. vehicle group, p < 0.005

• 

  Fig. 3 Effects of wide range of doses of CORM-2 (A) and hemin (B) on ANP secretion and atrial contractility. Values are expressed by the relative percent change from the mean of the first five control values (fraction no. 1–5) and the last five peak values (fraction no. 21–25). CORM, carbon monoxide releasing molecule; ANP, atrial natriuretic peptide; APP, atrial pulse pressure. Legends are the same as in Fig. 1. Values are expressed as the means ± SEM.

• 

  Fig. 4 Modulation of CORM-2-induced suppression of ANP secretion (A), APP (B), ECF translocation (C) and ANP concentration (D) by several modulators. Twenty minutes before sample collection, atria were pretreated with KATP channel activator (pinacidil, 50 µM), mitochondrial KATP channel blocker (5-hydroxydecanoic acid; 5-HD, 100 µM), L-type Ca2+ channel blocker (diltiazem; Dilt, 50 µM), high-conductance Ca2+-activated K+ channel blocker (paxillin, 25 µM), nitric oxide synthase inhibitor (L-NAME; 100 µM), PI3K inhibitor (wortmannin; Wort, 10 µM) (LY-294002; LY, 10 µM), and soluble guanylate cyclase inhibitor (ODQ, 100 µM) or vehicle was perfused into atria after 10-min control period. Relative percent changes in atrial parameters by CORM-2 and vehicle in the presence of modulators are shown. CORM, carbon monoxide releasing molecule; ANP, atrial natriuretic peptide; APP, atrial pulse pressure; ECF, extracellular fluid. Values are expressed as the means ± SEM. * vs. vehicle group, p < 0.05, **p < 0.01, *** p < 0.005.

• 

  Fig. 5 Comparison of responsiveness of ANP secretion (A) and atrial contractility (B) by CORM-2 (10 nM, 50 µM) in normoxic and hypoxic conditions. CORM, carbon monoxide releasing molecule; ANP, atrial natriuretic peptide; APP, atrial pulse pressure. Values are expressed as the means ± SEM. * vs. vehicle group, p < 0.05, **p < 0.01.

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