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Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase (sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 woul... Full description

Journal Title: American journal of physiology. Heart and circulatory physiology September 1, 2018, Vol.315(3), pp.H669-H680
Main Author: Alogna, Alessio
Other Authors: Schwarzl, Michael , Manninger, Martin , Hamdani, Nazha , Zirngast, Birgit , Kloth, Benjamin , Steendijk, Paul , Verderber, Jochen , Zweiker, David , Westermann, Dirk , Blankenberg, Stefan , Maechler, Heinrich , Tschöpe, Carsten , Linke, Wolfgang A , Marsche, Gunther , Pieske, Burkert M , Post, Heiner
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1522-1539 ; DOI: 10.1152/ajpheart.00510.2017
Link: http://search.proquest.com/docview/2035244545/?pq-origsite=primo
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title: Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.
format: Article
creator:
  • Alogna, Alessio
  • Schwarzl, Michael
  • Manninger, Martin
  • Hamdani, Nazha
  • Zirngast, Birgit
  • Kloth, Benjamin
  • Steendijk, Paul
  • Verderber, Jochen
  • Zweiker, David
  • Westermann, Dirk
  • Blankenberg, Stefan
  • Maechler, Heinrich
  • Tschöpe, Carsten
  • Linke, Wolfgang A
  • Marsche, Gunther
  • Pieske, Burkert M
  • Post, Heiner
subjects:
  • Bay 41-8543
  • Deoxycorticosteroneacetate
  • Left Ventricular Capacitance
  • Pressure-Volume Analysis
  • Soluble Guanylate Cyclase Stimulator
ispartof: American journal of physiology. Heart and circulatory physiology, September 1, 2018, Vol.315(3), pp.H669-H680
description: Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase (sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 [micro]g x [kg.sup.-1] x [min.sup.-1] for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs (n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated. BAY 41-8543; deoxycorticosteroneacetate; left ventricular capacitance; pressure-volume analysis; soluble guanylate cyclase stimulator doi: 10.1152/ajpheart.00510.2017.
language: eng
source:
identifier: E-ISSN: 1522-1539 ; DOI: 10.1152/ajpheart.00510.2017
fulltext: fulltext
issn:
  • 15221539
  • 1522-1539
url: Link


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titleAcute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.
creatorAlogna, Alessio ; Schwarzl, Michael ; Manninger, Martin ; Hamdani, Nazha ; Zirngast, Birgit ; Kloth, Benjamin ; Steendijk, Paul ; Verderber, Jochen ; Zweiker, David ; Westermann, Dirk ; Blankenberg, Stefan ; Maechler, Heinrich ; Tschöpe, Carsten ; Linke, Wolfgang A ; Marsche, Gunther ; Pieske, Burkert M ; Post, Heiner
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ispartofAmerican journal of physiology. Heart and circulatory physiology, September 1, 2018, Vol.315(3), pp.H669-H680
identifierE-ISSN: 1522-1539 ; DOI: 10.1152/ajpheart.00510.2017
subjectBay 41-8543 ; Deoxycorticosteroneacetate ; Left Ventricular Capacitance ; Pressure-Volume Analysis ; Soluble Guanylate Cyclase Stimulator
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descriptionExperimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase (sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 [micro]g x [kg.sup.-1] x [min.sup.-1] for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20-30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs (n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated. BAY 41-8543; deoxycorticosteroneacetate; left ventricular capacitance; pressure-volume analysis; soluble guanylate cyclase stimulator doi: 10.1152/ajpheart.00510.2017.
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titleAcute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.
authorAlogna, Alessio ; Schwarzl, Michael ; Manninger, Martin ; Hamdani, Nazha ; Zirngast, Birgit ; Kloth, Benjamin ; Steendijk, Paul ; Verderber, Jochen ; Zweiker, David ; Westermann, Dirk ; Blankenberg, Stefan ; Maechler, Heinrich ; Tschöpe, Carsten ; Linke, Wolfgang A ; Marsche, Gunther ; Pieske, Burkert M ; Post, Heiner
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