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Effects of acetylcholinesterase blockade, central and peripheral, in the cardiocirculatory function and inflammation observed in spontaneously hypertensive rats

Abstract

It is well documented an autonomic imbalance in the experimental models of hypertension and also in hypertensive patients, characterized by an increase in sympathetic activity and decrease in vagal activity. More recently, it has been observed that inflammatory aspects have been documented in arterial hypertension leading to the derangement of target organs such as the heart and blood vessels. Even though the sympathetic overactivity has received most of the attention from the investigators, the decrease in parasympathetic activity has not received the same consideration in several physiopathological conditions. However, an increase in parasympathetic activity may have benefic effects during the development of arterial hypertension. As observed in patients with essential hypertension, the spontaneously hypertensive rats (SHR) also show an increased sympathetic drive combined with a decreased parasympathetic function. On the other hand, the parasympathetic neurotransmission can be augmented by the acetylcholinesterase inhibition. The benefic effect of the chronic blockade of the acetylcholinesterase with donepezil (compound that crosses the blood brain barrier) or pyridostigmine (compound that does not cross the blood brain barrier) has never hitherto been investigated in patients or experimental model of arterial hypertension, as is the case of the SHR. Therefore, it is proposed in the current study to investigate if an increase in the availability of acetylcholine by means of the blockade of acetylcholinesterase with donepezil or pyridostigmine will improve the sympatho vagal balance during the development of hypertension in SHR and prevent the cardiocirculatory dysfunction. In addition, it is expect that any increase in parasympathetic function will attenuate the inflammatory outcomes already described during the onset of hypertension and prevent the derangement of target organs such as the heart and blood vessels.Therefore, normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) will be divided into four groups as follows: I) Wistar Kyoto; II) SHR; III) SHR + pyridostigmine; IV) SHR + donepezil. The subjects will receive donepezil (1.4 mg/kg/day) or pyridostigmine (1.5 mg/kg/day) administered by Alzet minipump during 15 weeks. After the 15 weeks the animals will receive cannula into the femoral artery and vein and will be submitted to the following protocols: 1) recording of arterial pressure and heart rate; 2) determination of the sympathovagal balance with atropine and propranolol; 3) evaluation of the cardiac function by means of the Millar catheter; 4) evaluation of the cardiac remodeling looking at hypertrophy of the cardiomyocytes and interstitial fibrosis; 5) exam of the morphology of the aorta; 6) exam of the structure and function of the arteries of the mesenteric bed. Four other groups of rats, without previous cannulation, will be submitted to the following protocols: 1) measurement of the plasma inflammatory cytokines (IL-1±, IL-6, IL-10, TNF-± and IFN-³); 2) measurement of the vascular inflammation: infiltration of lymphocytes, macrophages and neutrophils; expression of molecules of cellular adhesion (VCAN-1 and ICAN-1); regulatory lymphocytes T mediators (TGF-² and Foxp 3); 3) measurement of the plasma concentration of norepinephrine; 4) measurement of the acetylcholinesterase activity, ± -7nAChR receptor and vesicular acetylcholine transporter in the heart and the aorta.After the conclusion of the above protocols it is expected that the chronic administration of pyridostigmine, or donepezil, will improve the sympathovagal balance, impair the inflammatory process and prevent the cardiocirculatory dysfunction, particularly the development of hypertension observed in SHR. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LATARO, RENATA M.; SILVA, MARCONDES A. B.; MESTRINER, FABIOLA L.; CAU, STEFANY B. A.; TOSTES, RITA C. A.; SALGADO, HELIO C. Chronic Treatment With Acetylcholinesterase Inhibitors Attenuates Vascular Dysfunction in Spontaneously Hypertensive Rats. AMERICAN JOURNAL OF HYPERTENSION, v. 32, n. 6, p. 579-587, JUN 2019. Web of Science Citations: 1.
LATARO, RENATA M.; SILVA, CARLOS A. A.; TEFE-SILVA, CRISTIANE; PRADO, CIBELE M.; SALGADO, HELIO C. Acetylcholinesterase Inhibition Attenuates the Development of Hypertension and Inflammation in Spontaneously Hypertensive Rats. AMERICAN JOURNAL OF HYPERTENSION, v. 28, n. 10, p. 1201-1208, OCT 2015. Web of Science Citations: 15.
DURAND, MARINA T.; BECARI, CHRISTIANE; DE OLIVEIRA, MAURO; DO CARMO, JUSSARA M.; AGUIAR SILVA, CARLOS ALBERTO; PRADO, CIBELE M.; FAZAN, JR., RUBENS; SALGADO, HELIO C. Pyridostigmine Restores Cardiac Autonomic Balance after Small Myocardial Infarction in Mice. PLoS One, v. 9, n. 8 AUG 18 2014. Web of Science Citations: 9.

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