Background The sodium–glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. Methods Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure–volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. Results Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia–reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. Conclusions Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.

function is considered to be precisely measurable only by invasive hemodynamics. We aimed to correlate strain values measured by speckle-tracking echocardiography (STE) with sensitive contractility parameters of pressure-volume (P-V) analysis in a rat model of exercise-induced left ventricular (LV) hypertrophy. LV hypertrophy was induced in rats by swim training and was compared with untrained controls. Echocardiography was performed using a 13-MHz linear transducer to obtain LV long-and short-axis recordings for STE analysis (GE EchoPAC). Global longitudinal (GLS) and circumferential strain (GCS) and longitudinal (LSr) and circumferential systolic strain rate (CSr) were measured. LV P-V analysis was performed using a pressure-conductance microcatheter, and load-independent contractility indices [slope of the end-systolic P-V relationship (ESPVR), preload recruitable stroke work (PRSW), and maximal dP/dt-enddiastolic volume relationship (dP/dtmax-EDV)] were calculated. Trained rats had increased LV mass index (trained vs. control; 2.76 Ϯ 0.07 vs. 2.14 Ϯ 0.05 g/kg, P Ͻ 0.001). P-V loop-derived contractility parameters were significantly improved in the trained group (ESPVR: 3.58 Ϯ 0.22 vs. 2.51 Ϯ 0.11 mmHg/ l; PRSW: 131 Ϯ 4 vs. 104 Ϯ 2 mmHg, P Ͻ 0.01). Strain and strain rate parameters were also supernormal in trained rats (GLS: Ϫ18.8 Ϯ 0.3 vs. Ϫ15.8 Ϯ 0.4%; LSr: Ϫ5.0 Ϯ 0.2 vs. Ϫ4.1 Ϯ 0.1 Hz; GCS: Ϫ18.9 Ϯ 0.8 vs. Ϫ14.9 Ϯ 0.6%; CSr: Ϫ4.9 Ϯ 0.2 vs. Ϫ3.8 Ϯ 0.2 Hz, P Ͻ 0.01). ESPVR correlated with GLS (r ϭ Ϫ0.71) and LSr (r ϭ Ϫ0.53) and robustly with GCS (r ϭ Ϫ0.83) and CSr (r ϭ Ϫ0.75, all P Ͻ 0.05). PRSW was strongly related to GLS (r ϭ Ϫ0.64) and LSr (r ϭ Ϫ0.71, both P Ͻ 0.01). STE can be a feasible and useful method for animal experiments. In our rat model, strain and strain rate parameters closely reflected the improvement in intrinsic contractile function induced by exercise training. speckle-tracking echocardiography; pressure-volume analysis; athlete's heart; contractility; strain LONG-TERM EXERCISE TRAINING induces physiological left ventricular (LV) hypertrophy, a molecular and cellular growth process of the heart in response to altered loading conditions (6). In contrast to pathological hypertrophy, this adaptation leads to maintained or even enhanced cardiac function (2, 14). Hemodynamic changes of exercise-induced hypertrophy were characterized by our research group in a rat model, focusing also on the improved LV inotropic state (23). Contractility is the intrinsic ability of the myocardium to generate force and to shorten independently of changes in preload or afterload with fixed heart rates. In the past few decades, efforts have been made to transfer the physiological concept of contractility to the intact beating heart (4).Pressure-volume (P-V) analysis recently became the gold standard to investigate in vivo hemodynamics in animal models. During preload reduction maneuvers such as gradual occlusion of vena cava inferior, load-independent indices of myocardial contractility could be obtained (20). Th...

AimsHeart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.Methods and resultsZucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.ConclusionsWe report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.