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Diabetes mellitus leads to cardiovascular complications including impaired cardiac β-adrenoceptor (β-AR) function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA) improve outcomes in heart failure patients and animal models thereof. Therefore, we have investigated the effects of EMPA on in vivo cardiac function (pressure-volume loop analysis) and β-AR-mediated contractile responses (papillary strips) in streptozotocin (STZ; 40 mg/kg, i.p.)-induced diabes in male Sprague Dawley rats (control, EMPA-treated control, diabetic, EMPA-treated diabetic) in a design reflecting late-onset treatment. 13-16 weeks after STZ injection treatment with a low dose of EMPA (10 mg/kg/day, daily oral gavage) or vehicle was administered for another 8 weeks. EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, rate of contration and rate of relaxation and increased isovolumic relaxation, whereas in vitro responses were not markedly attenuated. Treatment with EMPA showed a trend for improvement of some but not all parameters. Our results indicate that low dose EMPA treatment had limited effects on cardiac impairment despite reducing blood glucose when initiated after diabetes is manifest. Future studies with a higher dose and greater sample sizes could help to clarify the possible benefits of EMPA on the diabetic heart.

Purpose: Diabetes mellitus is a metabolic disorder leading to cardiovascular complications. Both in vivo cardiac function and β-adrenoceptor (β-AR) mediated responsiveness have been demonstrated to be blunted in the diabetic heart. Sodium glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA) have shown cardioprotective effects in patients and in some animal models. In this study, we aimed to investigate the effects of low-dose EMPA (10 mg/kg/day) on in vivo cardiac function and β-AR-mediated contractile response in streptozotocin (STZ)-induced diabetic rats. Methods: 11-12 week old male Sprague Dawley rats were divided into 4 groups; control, EMPA-treated control, diabetic, EMPA-treated diabetic. Diabetes was induced by STZ injection (40 mg/kg, i.p.). After 13-16 weeks, some of the diabetic and control rats were treated with a low dose of EMPA (10 mg/kg/day, oral gavage, once a day) or vehicle for another 8 weeks. At study end, in vivo cardiac function was evaluated by pressure-volume loop analysis. β-AR mediated contractile response was determined using isoprenaline in papillary muscle preparations. Results: EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, +dp/dt and -dp/dt and increased isovolumic relaxation, whereas in vitro responses were reduced to a minor extent. Treatment with EMPA showed a trend for improvement of some but not all parameters. Conclusion: Our results indicate that low dose EMPA treatment had limited effects on cardiac impairment although it reduced blood glucose. Future studies with a higher dose and greater sample sizes could help to clarify the possible benefits of EMPA on the diabetic heart.

beta(3)-Adrenoceptors (AR) stimulate cardiac Na+/K+ pump in healthy hearts. beta(3)-ARs are upregulated by persistent sympathetic hyperactivity; however, their effect on Na+/K+ ATPase activity and ventricular function in this condition is still unknown. Here, we investigate preventive effects of additional beta(3)-AR activation (BRL) on Na+/K+ ATPase activity and in vivo hemodynamics in a model of noradrenaline-induced hypertrophy. Rats received NA or NA plus simultaneously administered BRL in vivo infusion for 14 days; their cardiac function was investigated by left ventricular pressure-volume analysis. Moreover, fibrosis and apoptosis were also assessed histologically. NA induced an hypertrophic pattern, as detected by morphological, histological, and biochemical markers. Additional BRL exposure reversed the hypertrophic pattern and restored Na+/K+ ATPase activity. NA treatment increased systolic function and depressed diastolic function (slowed relaxation). Additional BRL treatment reversed most NA-induced hemodynamic changes. NA decreased Na+/K+ pump alpha 2 subunit expression selectively, a change also reversed by additional BRL treatment. Increasing beta(3)-AR stimulation may prevent the consequences of chronic NA exposure on Na+/K+ pump and in vivo hemodynamics. beta(3)-AR agonism may thus represent a new therapeutic strategy for pharmacological modulation of hypertrophy under conditions of chronically enhanced sympathetic activity.

Hypertrophy and dysfunction of the urinary bladder are consistently observed in animal models of type 1 and less consistently in those of type 2 diabetes. We have tested the effects of mild hyperglycemia (n = 10 per group) in a randomized, blinded study and, in a blinded pilot study, of type 2 diabetes (n = 6 per group) and its treatment with dapagliflozin (1 mg/kg per day) on weight, contraction, and relaxation of the rat bladder. Based on a combination of high-fat diet and a low dose of streptozotocin, animals in the main study reached a mean peak blood glucose level of about 300 mg/dl, which declined to 205 mg/dl at study end. This was associated with a small, if any, increase in bladder weight. In a pooled analysis of all animals of the main and the pilot study, we detected a correlation of moderate strength between blood glucose and bladder weight (r(2) = 0.2013; P = 0.0003 for Pearson correlation coefficient). Neither the main nor the pilot study found evidence for an altered contractility (responses to carbachol or KCl) or relaxation (responses to isoprenaline, fenoterol, CL 316,243, or forskolin). Treatment with dapagliflozin in the absence of hyperglycemia increased diuresis in the main study by 43% relative to control and increased bladder weight by 15% in the pooled groups of both studies (post hoc analysis). We conclude that mild hyperglycemia has no major effects on bladder hypertrophy or function.

Organ bath experiments are a key technology to assess contractility of smooth muscle. Despite efforts to standardize tissue specimen sizes, they vary to a certain degree. As it appears obvious that a larger piece of tissue should develop greater force, most investigators normalize contraction data for specimen size. However, they lack agreement which parameter should be used as denominator for normalization. A pre-planned analysis of data from a recent study was used to compare denominators used for normalization, i.e., weight, length, and cross-sectional area. To increase robustness, we compared force with denominator in correlation analysis and also coefficient of variation with different denominators. This was done concomitantly with urinary bladder strips and aortic rings and with multiple contractile stimuli. Our urinary bladder data show that normalization for strip weight yielded the tightest but still only moderate correlation (e.g., r(2) = 0.3582 for peak carbachol responses based on 188 strips). In aorta, correlations were even weaker (e.g., r(2) = 0.0511 for plateau phenylephrine responses normalized for weight based on 200 rings). Normalization for strip size is less effective in reducing data variability than previously assumed; the normalization denominator of choice must be identified separately for each preparation.

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Mechanical activity of the heart is adversely affected in metabolic syndrome (MetS) characterized by increased body mass and marked insulin resistance. Herein, we examined the effects of high carbohydrate intake on cardiac function abnormalities by evaluating in situ heart work, heart rate, and electrocardiograms (ECGs) in rats. MetS was induced in male Wistar rats by adding 32% sucrose to drinking water for 22–24 weeks and was confirmed by insulin resistance, increased body weight, increased blood glucose and serum insulin, and increased systolic and diastolic blood pressures in addition to significant loss of left ventricular integrity and increased connective tissue around myofibrils. Analysis of in situ ECG recordings showed a markedly shortened QT interval and decreased QRS amplitude with increased heart rate. We also observed increased oxidative stress and decreased antioxidant defense characterized by decreases in serum total thiol level and attenuated paraoxonase and arylesterase activities. Our data indicate that increased heart rate and a shortened QT interval concomitant with higher left ventricular developed pressure in response to β-adrenoreceptor stimulation as a result of less cyclic AMP release could be regarded as a natural compensation mechanism in overweight rats with MetS. In addition to the persistent insulin resistance and obesity associated with MetS, one should consider the decreased heart work, increased heart rate, and shortened QT interval associated with high carbohydrate intake, which may have more deleterious effects on the mammalian heart.

Aims Diabetes mellitus is a chronic metabolic disease, which results in serious cardiac complications. It has been shown that hemodynamic parameters are impaired in diabetic rat heart. Leptin is a hormon secreted from adipose tissue and have important effects on glucose metabolism. The effect of leptin treatment on cardiac hemodynamic parameters in streptozotocine (STZ) induced diabetic rat heart has not been studied yet. Thus, we aimed to investigate whether leptin treatment could ameliorate impaired basal cardiac hemodynamic parameters in STZ diabetic rat. Methods Male Sprague-Dawley rats were used for this study. The rats were divided into 3 groups; control (C), diabetic (D), leptin treated diabetic group (Lep). Diabetes was induced by single dose streptozotocin injection (40 mg/kg, i.v.). At the end of 10-week-diabetes period some of the diabetic rats were treated with leptin (150 μg/kg/day, via osmotic minipump) for 14 days. In vivo cardiac hemodynamic parameters were determined through pressure-volume (PV loop) relations. First pressure in carotid artery [systolic arterial pressure (SP), diastolic arterial pressure (DP), mean arterial pressure (MAP)] were measured, then PV loops were recorded under isofluoran anesthesia (%2). Cardiac hemodynamic parameters include heart rate (HR), end systolic pressure (ESP), end diastolic pressure (EDP), the rate of contraction and relaxation (dp/dtmax and dp/dtmin), end systolic volume (ESV), end diastolic volume (EDV), stroke volume (SV), cardiac output (CO), ejection fraction (EF), isovolumic relaxation constant (Tau, Weiss and glantz method), end systolic elastance (Ees), cardiac stiffness, preload recruitable stroke work (PRSW) and dp/dt-EDV relation. To assess preload recruitable cardiac parameters inferior vena cava occlusion was made. Results PV loop analysis showed that almost all cardiac hemodynamic parameters were altered in diabetic state as expected. Heart rate of rats were decreased in D group, leptin treatment did not improve it significantly. ESP values were decreased in D group. Leptin treatment increased it markedly, however it did not reach control levels. EDP values did not differ between the groups. Both dp/dtmax and dp/dtmin values were significantly attenuated in D group, leptin treatment ameliorated it markedly. EDV values were enhanced in D group, and decreased after leptin treatment. There were no significant changes in SV between the groups. CO was found to be attenuated in D group. EF values were not changed. Tau values were increased markedly in D group, and improved with leptin treatment, however it was still high compared to C group. Ees was decreased in D group. No significant change was seen after leptin treatment. The stiffness of the left ventricle was increased in D group and decresed after leptin treatment. PRSW was attenuated in D group and leptin treatment improved it markedly. dp/dt-EDV relation was also decreased in D group and ameliorated partly in Lep group. SP, DP and MAP were decreased in D group and ameliorated in Lep group. Conclusion In vivo cardiac experiments showed that heart function was impaired in diabetic rats. Leptin exerted beneficial effects on these parameters, however the values did not reach control levels. This may be related to chosen dose of leptin, which has been demonstrated effective in a previous study. To confirm the dose dependency of the effect, cardiac parameters should be evaluated in rats treated with a higher dose of leptin.