Adrenergic antagonists, and a possible link between the increase in cyclic adenosine 3′,5′‐monophosphate and DNA synthesis during liver regeneration

Abstract

The cyclic-AMP concentration in the liver remnant after 70% hepatectomy increases i n a biphasic manner with peak values at 3 and 12 hours, and DNA synthesis begins at 18 hours. Propranolol (dt) injected at 30 minutes after surgery stopped the first wave of cyclic-AMP accumulation, but did not affect the second accumulation or the initiation of DNA synthesis, However, d l , propranolol injected at eight hours equally delayed (by 6 to 8 hours) the second wave of cyclic-AMP accumulation and the initiation of DNA synthesis, Propranolol (cll) did not affect DNA replication per se, since it was totally ineffective after the second wave of cyclic-AMP accumulation had passed and DNA synthesis had been initiated. Propranolol ( d l ) action was not due to a blockade of p-adrenergic receptors, since its d or 1 isomers were separately without effect, as were unrelated P-adrenergic blockers (KO 1313 and M&B 17-803A).On the other hand, an activation of a-adrenergic receptors may be involved in the induction of hepatocyte proliferation, since a-adrenergic antagonists, such as phenoxybenzamine and phentolamine, both delayed and considerably reduced the second wave of cyclic-AMP accumulation and the subsequent initiation of DNA synthesis. It is concluded that the second wave of cyclic-AMP accumulation is somehow associated with the initiation of DNA synthesis.

Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha 1 adrenergic response.

“…Since cells enlarge before division, these same events may be important when cells grow by hypertrophy. Other evidence besides our study for alpha adrenergic involvement in growth regulation is the inhibition by phentolamine of liver cell regeneration after partial hepatectomy (19).…”

DL‐propranolol negatively regulates the transcription of proliferating cell nuclear antigen (PCNA)‐gene and thereby suppresses DNA synthesis in regenerating rat liver

“…There have been several reports suggesting that cAMP may play an important role as a positive regulator in hepatocyte proliferation on the basis of the following findings. A biphasic rise of hepatic cAMP levels, which precedes DNA synthesis, occurs after Pit (6). The treatment with d/-propranolol (PRL), a 13-receptor antagonist, causes a delay of the second wave of hepatic cAMP levels as well as the DNA synthesis with an equal duration (6).…”

Enhancement in .BETA.-Adrenergic Responsiveness of Adenylate Cyclase in Rat Liver after Galactosamine Administration.

“…The involvement of ,9-adrenergic stimula tion in the regulation of DNA synthesis has been shown in liver regeneration after partial hepatectomy (8). In addition, cyclic AMP (8) and cyclic AMP-dependent protein kinase (9) have been implicated in the control of liver re generation after partial hepatectomy.…”

“…In addition, cyclic AMP (8) and cyclic AMP-dependent protein kinase (9) have been implicated in the control of liver re generation after partial hepatectomy. Thus, it is conceivable that modulation of the hepatic cyclic AMP level could be an important factor for the induction of DNA synthesis in the re generating liver after the intoxication with a hepatotoxin such as CCl4.…”