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Notes: Adenylate cyclase (AC) in pineal paniculate fractions from rabbit, rat, cow, and the vole Microtus montanus was stimulated by L-norepinephrine (NE) and L-isopro-terenol (ISO). NE stimulation of rabbit and bovine pineal AC was biphasic, with a plateau between 0.01 μM and 1.0 μM and additional stimulation by NE above 1.0 μM. Stimulation by different ISO concentrations gave a typical hyperbolic curve, and optimal stimulation by ISO exceeded that by NE.Melatonin decreased ISO and NE stimulation of AC 10–20%. Although α-ad-renergic agonists increase β-agonist-mediated adenosine-3′, 5′-cyclic monophosphate (cyclic AMP) accumulation in intact pinealocytes, similar amplification of AC stimulation was not seen with broken-cell preparations.Most (60–70%) pineal guanylate cyclase (GC) was recovered in supernatant fractions after centrifugation of homogenates at 110,000 × g; this soluble GC was unaffected by potential agonists. Low concentrations (0.01–1 nM) of NE, ISO, and phenylephrine (PE) stimulated GC in impure and purified membrane fractions, but each inhibited at concentrations above 10 μM. All concentrations of ISO and NE inhibited GC in the presence of the a-agonist PE. Melatonin alone did not affect particulate GC, but L-ISO stimulation was not seen in the presence of equivalent concentrations of melatonin.The in vitro data are consistent with both α- and β-receptor regulation of cyclic nucleotide metabolism in pinealocytes. Endogenous NE may differentially regulate cyclic AMP and guanosine-3′, 5′-cyclic monophosphate (cyclic GMP) in pineal; low NE concentrations that stimulate GC have only a slight effect on AC, but higher NE concentrations that inhibit GC maximally stimulate AC. Particulate GC and AC also were resolved by equilibrium centrifugation, to give several discrete peaks of enzyme activity. The results support the existence of several forms of AC and GC, which have different responses to adrenergic agonists.

Notes: Abstract Profiles of pancreatic secretory proteins (zymogens, lysosomal enzymes) were studied in Syrian golden hamsters after sequential stimulation of the pancreas with secretin and cholecystokinin-octapeptide (CCK). The flow rate of pancreatic juice after secretin (0.2 CU/100 g) was approximately 2.7 μl/min/100 g animal (about 55% of that in human subjects). The half-life of the secretin effect was about 60 min. The initial concentration of protein in pancreatic juice (minute-to-minute collection) in response to secretin was over 10 times larger than that in human subjects and the “wash-out” phase required〉1 hr vs 〈10 min in humans. CCK (4 ng/100 g) in minute-to-minute collections of juice produced an approximately eightfold increase in concentration of secretory products over baseline values, and the half-life of its effect was about 2 min, similar to that found in human subjects. Digestive as well as lysosomal enzyme activities in hamster pancreatic juice were 10–15 times higher than those found in human pancreatic secretions. This species difference may be relevant to the susceptibility of the hamster pancreas to carcinogens.

Notes: Abstract The possibility that pancreatic secretory abnormalities might precede the appearance of pancreatic neoplasms and thus provide clues to early detection of this malignancy has been investigated in an animal model. Syrian golden hamsters were treated with bis-(2-oxopropyl)-N-nitrosamine on two successive weeks (2 mg/100 g body weight/week). Pancreatic secretions from treated and untreated control animals were studied at approximately monthly intervals. The animals were anesthetized, their pancreatic ducts cannulated, and basal pancreatic juice collected for 30 min. Pancreatic secretion was then stimulated by sequential intravenous injection of secretin (50 ng/100 g) and C-terminal octapeptide of cholecystokinin (4 ng/100 g) 1 hr later. Four consecutive 15-min collections of fluid were made following secretin stimulation and four additional collections after CCK administration. Each collection was examined for volume, total protein, trypsin, chymotrypsin, elastase, arylsulfatase, β-d-glucuronidase, α-d-glucosidase, and leucine naphthylamidase. In addition two trypsinogen variants present in pancreatic secretions were determined. The pancreas and other organs were removed and examined histologically at the end of each experiment. Cytological atypia appeared 3 months, ductal hyperplasia 4 months, and pancreatic neoplasms 6 months after the last injection of carcinogen. Striking decreases in flow rate and output of trypsin and chymotrypsin were observed several months prior to the appearance of histologically recognizable pancreatic tumors. By contrast, output of β-d-glucuronidase and α-d-glucosidase in pancreatic juice increased markedly in the last 2 months preceding the emergence of neoplasms. The diagnostic significance of these premalignant abnormalities is illustrated most dramatically in the form of ratios of lysosomal to digestive enzymes, such as β-d-glucuronidase-trypsin or α-d-glucosidase-chymotrypsin. Highly significant increases in these ratios were observed consistently, not only in hamsters with pancreatic neoplasms, but also in animals with preneoplastic lesions (ductular hyperplasia) which preceded malignancies by about 2 months.