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Alogna, A; Schwarzl, M; Manninger, M; Hamdani, N; Zirngast, B; Kloth, B; Steendijk, P; Verderber, J; Zweiker, D; Westermann, D; Blankenberg, S; Maechler, H; Tschöpe, C; Linke, WA; Marsche, G; Pieske, BM; Post, H.
Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo.
Am J Physiol Heart Circ Physiol. 2018; 315(3):H669-H680 Doi: 10.1152/ajpheart.00510.2017 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Albori Jochen
Mächler Heinrich
Manninger-Wünscher Martin
Marsche Gunther
Zirngast Birgit
Zweiker David

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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 μg·kg-1·min-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.
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Blood Pressure - administration & dosage
Cardiomegaly - etiology, metabolism, physiopathology
Connectin - metabolism
Cyclic GMP - metabolism
Cyclic GMP-Dependent Protein Kinases - metabolism
Desoxycorticosterone Acetate - toxicity
Female - administration & dosage
Heart Ventricles - drug effects, metabolism
Morpholines - pharmacology
Nitroglycerin - pharmacology
Pyrimidines - pharmacology
Soluble Guanylyl Cyclase - metabolism
Swine - administration & dosage
Vascular Capacitance - administration & dosage
Vasodilator Agents - pharmacology
Ventricular Function, Left - administration & dosage

Find related publications in this database (Keywords)
BAY 41-8543
left ventricular capacitance
pressure-volume analysis
soluble guanylate cyclase stimulator
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