The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus

Abstract

BackgroundDiabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)—soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy.MethodsType-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10 mg/kg/day) or with placebo orally for 8 weeks. Left ventricular (LV) pressure–volume (P–V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively.ResultsDM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5 ± 3.3 vs. 83.0 ± 5.5 mmHg, P < 0.05) and diastolic function (time constant of LV pressure decay (Tau): 17.3 ± 0.8 vs. 10.3 ± 0.3 ms, P < 0.05). Cinaciguat treatment effectively prevented DM related molecular, histological alterations and significantly improved systolic (PRSW: 66.8 ± 3.6 mmHg) and diastolic (Tau: 14.9 ± 0.6 ms) function.ConclusionsCinaciguat prevented structural, molecular alterations and improved cardiac performance of the diabetic heart. Pharmacological activation of sGC might represent a new therapy approach for diabetic cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0309-x) contains supplementary material, which is available to authorized users.

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

“…One can speculate that this might be a consequence of the observed compensatory upregulation of ANF and subsequent activation of particulate GC in other organs. Thus preserved plasma cGMP is seen as a sign of overspill of cGMP from different tissues 5. Vardenafil effectively restored the activity of the cGMP–PKG axis, as shown by increased plasma/cardiac cGMP concentrations and p‐VASP/VASP ratio.…”

“…The restoration of NO‐cGMP‐PKG axis has been proven to be cytoprotective in different cardiovascular diseases6, 17, 18 including diabetic cardiomyopathy 5, 6, 12. Phosphodiesterase‐5A inhibitors block one of the main regulator of cGMP degradation thereby preserving and/or increasing intracellular cGMP concentration 4.…”

“…Invasive haemodynamic investigation was performed as described earlier5 with a 2 F microtip pressure‐conductance microcatheter (SPR‐838; Millar Instruments, Houston, TX, USA) system under isoflurane anaesthesia (1–2%). Heart rate (HR), mean arterial blood pressure (MAP), EF, cardiac output (CO), stroke work (SW), maximal slope of systolic pressure increment (dP/dt max ) and diastolic pressure decrement (dP/dt min ), time constant of LV pressure decay (Tau W ) were calculated.…”

“…Cardiomyocyte diameter was measured as described previously 5. Fibrotic remodelling was evaluated on MT and PicroSirius stained sections.…”

“…Essential regulators of this system are the phosphodiesterases (PDEs) as they are able to degrade cGMP to 5′‐GMP 4. Phosphodiesterase‐5A (PDE5A) is specific for cGMP molecules4 and has been described to be upregulated in different types of HF and in diabetic cardiomyopathy in particular 5, 6. Theoretically, the above‐mentioned upregulation of PDEs coupled with the enhanced nitro‐oxidative stress3 could notably contribute to the impaired cGMP–PKG signalling in the myocardium of HFpEF patients 7, 8…”