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Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
PDE V is the only cGMP-selective isoenzyme and inhibitors of this PDE elevate the intracellular levels of cGMP rather than cAMP. PDE V is found predominantly in smooth muscle, platelets and the lungs. Selective inhibitors include zaprinast, dipyridamole, SK&F 96231 and MY5445. They relax smooth muscle by elevating intracellular cGMP and therefore potentiate the relaxant activity of sodium nitroprusside rather than isoprenaline. Zaprinast is a poor bronchodilator, but it inhibits histamine release from mast cells and may reduce endothelial cell permeability and plasma leakage. It inhibits exercise-induced asthma but not histamine-induced bronchospasm, suggesting an effect on neuronal pathways involved in bronchoconstriction (Murray & England 1992, Raeburn et al. 1993).
Endocardial Endothelial Modulation of Myocardial Contraction
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Stanislas U. Sys, Puneet Mohan, Luc J. Andries, Gilles De Keulenaer, Paul F. Fransen, Dirk L. Brutsaert
Recently, we reported for the first time, a novel concentration-dependent positive inotropic effect of NO-releasing nitrovasodilators (sodium nitroprusside and SIN-1) in muscles with damaged EE which contrasted with their negative inotropic effect in muscles with intact EE (Figure 1-4); these opposite responses were both mediated by cGMP (Mohan et al., 1996). Concentration response curves with addition of another nitro vasodilator, S-nitroso-acetyl-penicillamine (SNAP), and a cGMP analogue, 8-bromo-cGMP, resulted in a biphasic inotropic response. While administration of low concentrations induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. The response to high concentrations of 8-bromo cGMP was shifted to the right in muscles with damaged EE, while cholinergic stimulation shifted the curve leftward. Zaprinast, a cGMP-phosphodiesterase inhibitor, caused a monophasic concentration-dependent positive inotropic effect; damaging the EE shifted the terminal portion of the curve upward. Concomitant cholinergic or adrenergic stimulation modified the inotropic response to zaprinast to negative. The results thus suggest that the response to an increase in intracellular cGMP depends on the state of EE and on concomitant cholinergic or adrenergic stimulation. Although the precise evidence for the nature and magnitude of myocardial cGMP regulation by EE is lacking, we have hypothesised from these observations that an intact EE would induce a higher cGMP level in the underlying cardiomyocytes due to basal NO release while damaging the EE would lower the cGMP level. In blood vessels, tissue cGMP levels have been frequently reported to be significantly higher in endothelium-intact than in denuded vessels (for references see Ignarro, 1989), although this feature has not yet been confirmed in cardiac tissue. In the presence of an intact EE, nitrovasodilators or exogenous nitric oxide would thus cause a further elevation in already high baseline myocardial cGMP levels leading to a negative inotropic response while in case of damaged or dysfunctional EE, a similar increase in the myocardial cGMP by exogenous nitric oxide donors from a lower baseline myocardial cGMP level would result in a positive inotropic response. Accordingly, responses to exogenous cGMP or agents causing elevation in cGMP may depend on the basal cGMP levels which in turn may be determined by the state of the overlying EE.
Tadalafil for the treatment of benign prostatic hyperplasia
Published in Expert Opinion on Pharmacotherapy, 2019
Fabiola Zakia Mónica, Gilberto De Nucci
In the early 1980s, zaprinast was introduced as the first-in-class PDE5 inhibitor. Later, Viagra (sildenafil citrate) was launched on the market in 1998 as the first oral treatment for male erectile dysfunction (ED). Although sildenafil was first developed for treating patients with hypertension [8] and angina pectoris [9], its efficacy was not demonstrated in these conditions. The impact of sildenafil has stimulated academic, clinical and industrial research to better understand the NO-cGMP-PDE5 pathway in several organs and systems and the pathophysiology of ED. In 2003, two other PDE5 inhibitors named vardenafil, a closely related structural analog of sildenafil and tadalafil, a tetrahydro-β-carboline derivative were approved by the Food and Drug Administration (FDA) for treating patients with ED. In 2012, avanafil, a PDE5 inhibitor was also approved by FDA. Although other PDE5 inhibitors are commercially available as lodenafil carbonate [2,10], udenafil [11] and mirodenafil [12,13] they have not been approved by FDA. In 2011, the therapeutic indication of tadalafil was expanded by FDA to treating patients with lower urinary tract symptoms secondary with benign prostatic hyperplasia (LUTS-BPH) with or without ED. This review highlights major preclinical and clinical studies of tadalafil (Box 1) in the treatment of LUTS-BPH. We decided to also focus on the preclinical data to understand the rationale of repurposing tadalafil in the treatment of BPH even in patients without ED.
Role of the nitric oxide-soluble guanylyl cyclase pathway in cognitive deficits in streptozotocin-induced diabetic rats
Published in Psychiatry and Clinical Psychopharmacology, 2019
Yusufhan Yazir, Selen Polat, Tijen Utkan, Feyza Aricioglu
Today there is accumulating evidence that PDEs have noticeable effects on cognition. Especially endogenous PDE-5 has been documented to have a major role in the cognitive functions [31,44,45]. PDE-5 is expressed in certain brain areas such as the cerebellar Purkinje cells [46] hippocampus, caudate, substantia nigra, and cerebellum [47]. It is reported that PDEs can affect neuronal cell survival and also play a part in neurodegenerative diseases, such as Alzheimer’s disease when functioning incorrectly [48]. Many clinical and experimental findings point to the fact that NO-cGMP-PKG is the central mechanism of a network of signalling pathways that interconnects neuroinflammation, neurodegeneration, and cognitive disorders, leading to increased pharmaceutical interest in PDE-5 inhibitors as promising therapeutic agents for neurodiseases. Inhibition of PDE-5 and accumulation of cGMP may inhibit neuroinflammation and improve synaptic plasticity and memory [49,50]. Latest findings suggest that PDE-5 has a crucial role in the processes of cognition under normal and/or pathological situations [50,51]. It also regulates neurogenesis and apoptosis [52]. Although the underlying mechanism has yet to be fully elucidated, it has been suggested that PDE-5 inhibitors enhance memory via a central mechanism [53]. Recently authors have reported diabetes-related cognitive decline and PDE-5 inhibitors might be beneficial to diabetes-induced cognitive deficits in rats [18]. Despite the significant pharmacological effects of zaprinast, less is known about its role in cognition.
Zaprinast and avanafil increase the vascular endothelial growth factor, vitamin D3, bone morphogenic proteins 4 and 7 levels in the kidney tissue of male rats applied the glucocorticoid
Published in Archives of Physiology and Biochemistry, 2022
Zübeyir Huyut, Nuri Bakan, Halil İbrahim Akbay, Serkan Yıldırım, Mehmet Ramazan Şekeroğlu
In this study, 24 male wistar albino rats (at eight-month old and 300–380 g) were used. Ethics committee approval was obtained from the Van Yuzuncu Yıl University Experimental Animals Local Ethics Committee, and all procedures were performed in accordance with the ethical rules stated in Declaration of Helsinki in 2000. During the study, the rats were fed with standard pellet feed in dark and light room conditions for per day at 12 h. The dose and duration for the DEX and inhibitor administration were determined according to the pharmacological dose and duration used in previous studies (Yaman et al. 2011, Affshana and Ptriya 2015, Wetzl et al. 2017, Huyut et al.2018). Rats were randomly divided into four groups (n = 6), which generated as follows:Control group: An empty syringe needle was dipped subcutaneously once a day for 28 days and removed. Rats of this group were fed with standard pellet feed during the study.DEX group: 120 µg/kg of DEX was injected subcutaneously once a day for 28 days.DEX + zaprinast group: 120 µg/kg of DEX was administered subcutaneously once daily for 28 days and also 10 mg/kg of zaprinast was given orally the same time.DEX + avanafil group: 120 µg/kg of DEX was administered subcutaneously once daily for 28 days and also 10 mg/kg of avanafil was given orally the same time.