Abstract
The new angiotensin II (Ang II) receptor subtype blocker (AT1 receptor blocker) has been clinically used as an antihypertensive agent. However the actions of AT1 receptor blocker on myocyte hypertrophy in neonatal spontaneous hypertensive rat (SHRIzm) and WKYIzm are not fully understood. The purposes of this study were to investigate the differences in Ang II-induced myocyte hypertrophy between SHR and WKY, and which action of AT1 or AT2 receptor blocker is related to it's induction.Cardiac myocytes were prepared from the heart of neonatal SHR and WKY, and cultured in serum-free medium for 10 days. From the 2nd day of culture, Ang II was added to the culture medium. AT1 (CV-11974) or AT2 (PD-123319) receptor blocker, L type calcium channel blocker (nisoldipine), calmoduline antagonist (W-7), and protein kinase C (PKC) inhibitor (staurosporine) were added to the culture medium containing Ang II (10-8M). To assess cellular growth, cells were monitored with a video camera, and the area of the myocyte was measured using the video-micrometer system (VM-30, Olympus Co., Ltd.). BrdU uptake to DNA and colorimetric assay (MTT) for mitochondria were analyzed by ELISA reader.The results were as follows: 1) The areas of myocyte under Ang II were greater in SHR (4172 μm2) than WKY (2270 μm2). 2) Both BrdU uptake and the activity of dehydrogenase (MTT assay) were increased in SHR compared to WKY. 3) Staurosporine, CV-11974 and nisoldipine significantly suppressed the Ang II-induced hypertrophy, whereas W-7 and PD-123319 failed to suppress it.In conclusion, the cellular signals of Ang II -induced hypertrophy were upregulated. Also DNA synthesis and the activity of the hypertrophied cells were augmented in SHR, compared to WKY. These signals are transduced into the cell chiefly through AT1 receptor. The effect of AT2 receptor does not neccessarily counteract cellular growth through the AT1 receptor. PKC-dependent, rather than calcium-dependent signals seem to be critical in Ang II-induced cellular growth in SHR.
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Schedule a callMore From: Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics
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