Role of Vasoactive Hormone-Induced Signal Transduction in Cardiac Hypertrophy and Heart Failure.

Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably preceded by adaptive or maladaptive cardiac hypertrophy, several biochemical mechanisms have been proposed to explain the development of cardiac hypertrophy and progression to heart failure. One of these includes the activation of different neuroendocrine systems for elevating the circulating levels of different vasoactive hormones such as catecholamines, angiotensin II, vasopressin, serotonin and endothelins. All these hormones are released in the circulation and stimulate different signal transduction systems by acting on their respective receptors on the cell membrane to promote protein synthesis in cardiomyocytes and induce cardiac hypertrophy. The elevated levels of these vasoactive hormones induce hemodynamic overload, increase ventricular wall tension, increase protein synthesis and the occurrence of cardiac remodeling. In addition, there occurs an increase in proinflammatory cytokines and collagen synthesis for the induction of myocardial fibrosis and the transition of adaptive to maladaptive hypertrophy. The prolonged exposure of the hypertrophied heart to these vasoactive hormones has been reported to result in the oxidation of catecholamines and serotonin via monoamine oxidase as well as the activation of NADPH oxidase via angiotensin II and endothelins to promote oxidative stress. The development of oxidative stress produces subcellular defects, Ca2+-handling abnormalities, mitochondrial Ca2+-overload and cardiac dysfunction by activating different proteases and depressing cardiac gene expression, in addition to destabilizing the extracellular matrix upon activating some metalloproteinases. These observations support the view that elevated levels of various vasoactive hormones, by producing hemodynamic overload and activating their respective receptor-mediated signal transduction mechanisms, induce cardiac hypertrophy. Furthermore, the occurrence of oxidative stress due to the prolonged exposure of the hypertrophied heart to these hormones plays a critical role in the progression of heart failure.

p-Cymene attenuates cancer pain via inhibitory pathways and modulation of calcium currents.

BACKGROUND: Oncological pain is one of the most prevalent and difficult-to-treat symptoms in patients with cancer. p-Cymene (PC) is a monoterpene found in more than 100 different plant species, endowed with various pharmacological properties-particularly antinociceptive. HYPOTHESIS/PURPOSE: PC has antinociceptive effect in a model of oncologic pain due to the activation of the descending inhibitory pathway of pain. STUDY DESIGN: A pre-clinical, longitudinal, blind and randomized study. METHODS: Male Swiss mice were induced with S180 cells in the right hind paw, then treated daily with PC (12.5, 25 and 50 mg/kg, s.c.) and screened for mechanical hyperalgesia, spontaneous nociception, nociception induced by non-noxious palpation, tumor growth, changes in the neuromuscular function and existence of bone degradation in the tumor area. The effect of PC on Ca2+ currents (electrophysiological records), histological and neurochemical changes (immunofluorescence for Fos) were also evaluated. RESULTS: PC reduced (p < 0.05) the mechanical hyperalgesia, the spontaneous (p < 0.001) and non-noxious palpation (p < 0.001) nociceptions, not changing the tumor development, neuromuscular function or histopathological aspects of the paw affected. PC reduced Fos expression in the spinal cord (p < 0.001) and increased this expression in the PAG (p < 0.05) and in the NRM (p < 0.01). PC decreased the density of calcium channel currents (p < 0.05). CONCLUSION: These results suggest the antinociceptive effect of PC on oncologic pain, probably acting in both ascending and descending pain pathways, and modulating the calcium channel currents in order to exert its effects.

Cardioprotective Action of Ginkgo biloba Extract against Sustained ß-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway.

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic ß-adrenergic receptor stimulation (ß-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of ß1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba.