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This study investigated whether ivabradine, a selective I f current inhibitor reducing heart rate (HR), is able to improve survival and prevent left ventricular (LV) remodeling in isoproterenol-induced heart damage. Wistar rats were treated for 6 weeks: controls (n = 10), ivabradine (10 mg/kg/day orally; n = 10), isoproterenol (5 mg/kg/day intraperitoneally; n = 40), and isoproterenol plus ivabradine (n = 40). Isoproterenol increased mortality, induced hypertrophy of both ventricles and LV fibrotic rebuilding, and reduced systolic blood pressure (SBP). Ivabradine significantly increased survival rate (by 120%) and prolonged average survival time (by 20%). Furthermore, ivabradine reduced LV weight and hydroxyproline content in soluble and insoluble collagen fraction, reduced HR and attenuated SBP decline. We conclude that ivabradine improved survival in isoproterenol-damaged hearts., (© 2020 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

There is a great urgency of detecting and monitoring myocardial fibrosis in clinical practice with the aim to improve and personalize therapy against cardiac remodelling. Hence, the aim of this study was to describe alterations in and show potential correlations between the structural characteristics and the molecular and biochemical markers of cardiac remodelling on a model of isoproterenol-induced heart failure. Two groups of 3-month-old male Wistar rats (n = 8 per group) were sacrificed after four weeks of treatment: control (placebo), ISO (5 mg/kg/day intraperitoneally). Chronic ISO treatment led to heart failure (HF) characterized by significant reduction of systolic blood pressure (SBP) accompanied by an increase in left ventricular weight (LVW) along with increased collagen content in the LV. The collagen content correlated negatively with SBP (R = -0.776, P < 0.001) and positively with LVW (R = 0.796, P < 0.001), with Col1a1 (0.83; P < 0.001) and Acta2 (0.73; P < 0.01). Moreover, the mRNA expression of fibrotic remodelling indicator, i.e. TGF-β1 tended to increase, while the level of fibrinolysis markers (MCP-1, TIMP-2, MMP) were unchanged. The plasma markers of collagen, procollagen I C-terminal propeptide (PICP) was 37.34 ± 7.10 pg/mL in control and was reduced by 42% (P < 0.05) in the ISO group and procollagen III N-terminal propeptide (PIIINP) was 1216.7 ± 191.0 pg/mL in control and was decreased by 66% (P < 0.05) in the ISO group. Surprisingly, there was no positive correlation between plasma markers of collagen, i.e. PICP and PIIINP and collagen content or molecular markers of collagen. However, both PICP and PIIINP correlated with BW (R = 0.712, resp. 0.803, P < 0.001), which was significantly reduced (by 25%, P < 0.05) in the ISO group. In conclusion, we assume that the collagen content of the left ventricle does not need unavoidably correlate with plasma markers of collagen, which might be affected by confounding factors in heart failure, such as loss of body weight, presumably associated with a catabolic condition.

Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with N G -nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction., Competing Interests: The authors declare no conflict of interest.

Objective: Blood pressure enhancement induced by continuous light exposure represents an attractive but rarely investigated model of experimental hypertension., Design and Methods: The aim of this study was to show whether the combination of continuous light (24 h/day) exposure and chronic N-nitro-L-arginine-methyl ester (L-NAME) treatment induces remodelling of the left ventricle and whether captopril or melatonin can modify these potential alterations. Six groups of 3-month-old Wistar rats (nine per group) were treated for 6 weeks: control (untreated), L-NAME (40 mg/kg per day), exposed to continuous light, L-NAME treated and exposed to continuous light (L24), L24 rats treated with either captopril 100 mg/kg per day, or melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP), relative weights of the left ventricle, endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) expression in tissues, malondialdehyde and advanced oxidation protein product concentrations in the plasma and hydroxyproline levels in collagenous protein fractions were measured., Results: The continuous light and L-NAME treatment led to hypertension, left ventricular hypertrophy (LVH) and fibrosis. An increase in SBP was completely prevented by captopril and partly by melatonin in the L24 group. Both drugs reduced oxidative damage and attenuated enhanced expression of ACE in the myocardium. Neither of the drugs prevented the attenuation of eNOS expression in the combined hypertensive model. Only captopril reduced LVH development in L24, whereas captopril and melatonin reduced left ventricular hydroxyproline concentrations in soluble and insoluble collagen, respectively. The total hydroxyproline concentration was reduced only by melatonin., Conclusion: In hypertension induced by a combination of continuous light and L-NAME treatment, melatonin and captopril protect the heart against pathological left ventricular remodelling differently.