In the last two decades, nerve growth factor (NGF), initially described as a prototypical trophic factor in the development of sensory and sympathetic innervation, has emerged as a complex regulator of neural plasticity along the micturition pathways. This review aims to summarize the current experimental and clinical evidence for a role of NGF in urinary bladder. Experimental administration of NGF elicits the states of increased sensation, urgency, and bladder hyperreflexia, resembling pathologies associated with bladder overactivity and inflammatory pain, such as overactive bladder syndrome (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS). There is strong experimental evidence, including the effective therapeutic targeting, on the direct causal role of NGF in rodent models of bladder outlet obstruction, spinal cord injury, diabetic bladder dysfunction, and interstitial inflammation. In humans, there are attempts to employ urinary NGF levels as a diagnostic marker in various forms of OAB and IC/PBS. In near future, use of novel experimental tools, such as urothelium-specific NGF transgenic mice or more specific low-molecular weight NGF receptor modulators, may provide better understanding of several unresolved issues in NGF-related bladder dysfunction. Moreover, successful experimental therapeutic approaches, such as NGF sequestering proteins or modified NGF antibodies, await the translation to the clinical treatment of bladder disorders.

Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.

AimsThe role of nitric oxide (NO) in heart failure (HF) is complex and remains controversial. We tested the hypothesis that the role of NO in isolated atria and cardiomyocytes is altered in isoproterenol-induced HF. Methods and resultsRats received isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) or vehicle for 1 week. Haemodynamic parameters were obtained by left ventricular catheterization. Effects of NOS inhibition on isolated atria and on electrically paced left ventricular myocytes were determined. Additionally, expressions of nitric oxide synthases and their allosteric modulators hsp90, caveolin-1, and caveolin-3 proteins in the left ventricles were measured. ISO increased left ventricular mass by 33% and decreased indices of left ventricular systolic and diastolic function dp/dt min and dp/dt max (both P , 0.05). Isolated atria from HF rats had a lower spontaneous beating rate (P , 0.05). NOS inhibition by L-NAME increased basal frequency and attenuated the positive chronotropic effect of beta-adrenergic stimulation in the HF group (P , 0.05). Ventricular myocytes from failing hearts had impaired cell shortening. L-NAME decreased contractility of control, but not failing myocytes. Left ventricular expressions of eNOS, hsp90, iNOS, but not nNOS or caveolins, were increased. ConclusionDespite the increased capacity for NO synthesis in isoproterenol-induced HF, NO does not sustain contractility of failing myocytes. NO may contribute to the decreased basal heart rate and it may accelerate beta-adrenergic stimulation of chronotropy.--

A minor increase in urinary albumin excretion (microalbuminuria) is known to predict adverse renal and cardiovascular events in diabetic and hypertensive patients. Recent intriguing findings show that microalbuminuria is an early and sensitive marker of future cardiovascular events even in healthy subjects. The mechanisms linking microalbuminuria with end-organ damage have not been fully explained yet; however, generalized endothelial dysfunction might play an important role. Prevailing experimental and clinical data suggest that generalized endothelial dysfunction, frequently characterized by decreased nitric oxide bioavailability, actually precedes the development of microalbuminuria. This review summarizes the current knowledge about the intricate relationship between microalbuminuria and endothelial dysfunction. On the basis of the current evidence, we propose that microalbuminuria and endothelial dysfunction are an emerging target for primary prevention strategies in cardiovascular disease. In near future, dietary components improving nitric oxide bioavailability, such as cocoa-derived flavanols may play important role in these preventive strategies.