The purpose of the proposed research is to investigate the role of the A1 adrenergic receptor in liver regeneration and carcinogenesis. A1 adrenergic receptor belongs to the group of calcium mobilizing receptors which exert cell regulatory influences by stimulation of PIP2 turnover, followed by release of diacylglycerols and IP3. We had originally shown that norepinephrine (NE) stimulates mitogenesis induced by EGF in serum free hepatocyte cultures through the A1 adrenergic receptor. In more recent studies we have found the following: A. Norepinephrine partially inhibits the mito-inhibitory effect of TGF beta on normal hepatocytes and especially on hepatocytes obtained from regenerating liver between 10 to 20 hours after 2/3 partial hepatectomy. B. The increased sensitivity to A1 adrenergic receptor during liver regeneration is associated with uncoupling of the A1. It is preceded by a sharp prop of the ras protein in the hepatocyte plasma membrane and evaluation of cytoplasmic levels of diacylglycerols. C. Blockade of the A1 adrenergic receptor by the specific antagonist prazosin causes a substantial decrease in the peak of DNA synthesis seen at 24 hours after partial hepatectomy. D. Blockage of the A1 adrenergic receptor by prazosin stimulates development of early neoplastic foci and enhances the numbers and growth of GGT+ early neoplastic foci of hepatocytes in the phenobarbital promotion protocol. E. In relation to hepatic tumor promotion, A1 blockage inhibits DNA synthesis seen during the augmentative hyperplasia associated with phenobarbital and a-Hexachlorocyclohexane but it does not affect the DNA synthesis stimulated by peroxisome proliferators. The above findings (described in detail in this proposal) warrant further investigation of the mode of action of the A1 adrenergic receptor in liver regeneration and carcinogenesis. Studies will be conducted on the mechanisms of liver regeneration during A1 blockage. The mode of action of A1 adrenergic receptor will be explored in hepatocyte cultures as well as in whole animal studies. The properties of A1 in normal hepatocytes will be compared to those in early neoplastic cells. The effect of A1 in normal hepatocytes will be compared to those in early neoplastic cells. The effect of A1 blockage on the growth of early neoplastic hepatocytes as well as facultative stem cells will also be studied. The impact of A1 stimulation or blockade as a component of hepatic tumor promotion will also be investigated. It was shown in recent studies that the c-onc counterpart of the oncogene mas is the receptor for angiotensin II. In view of the fact that angiotensin II, similar to norepinephrine, also operates through a calcium mobilizing receptor and act as a mitogenic amplifier for several cell types, the above findings warrant the investigation of the possibility that the A1 adrenergic receptor may potentially function as a cellular proto-oncogene for liver neoplasia.
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