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Natural neuronal cell death is a well-described developmental phenomenon common to many nerve centres in a variety of animal species. Neuronal survival has been shown to depend on the presence and size of the available target tissue and it has been suggested that neuronal survival is dependent on successful competition for either a limited number of synaptic sites or a limited amount of trophic factor(s). In the lateral motor column of the lumbar spinal cord in the chick embryo, the period of axon elongation and innervation of the periphery has been shown to precede that of natural motoneurone cell death. While muscle contractile activity appears to regulate the extent of motoneurone death, to date the intracellular molecular events that initiate and regulate the developmental process of natural neuronal cell death or, more importantly, neuronal survival are unknown. Our earlier studies suggested that either contact or association between spinal cord processes and muscle cells during neuromuscular junction formation in vivo leads to an increase in cyclic GMP in whole spinal cord. We now show that treatment of chick embryos with the membrane-permeable cyclic GMP analogue, dibutyryl cyclic GMP during the period of natural motoneurone cell death prevents greater than 58% of natural motoneurone cell death in the lumbar lateral motor column.
Dibutyryl cyclic GMP was given intravenously to anesthetized dogs with doses of 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/kg, respectively. It induced decreases in blood pressure, heart rate, max LV dp/dt and total peripheral resistance with increase of stroke volume in a dose-dependent manner. Although these effects began to appear 30 sec after the administration in each dose, the duration of the effect was observed 50 sec after the administration. Effects of 1 mg/kg dibutyryl cyclic GMP on mean blood pressure and max LV dp/dt were almost equal to those of 3 micrograms/kg acetylcholine, but dibutyryl cyclic GMP was revealed to have a slower onset and longer acting effects than acetylcholine. The administration of atropine did not block the effect of dibutyryl cyclic GMP but blocked those of acetylcholine. These results indicate that dibutyryl cyclic GMP does not exert these effects through muscarinic receptors in spite of its acetylcholine-like effects.
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Ventilation of rats at high inspiratory pressures raises lung tissue content of guanosine 3',5'-cyclic monophosphate (cGMP). Hyperventilation in rabbits augments release of phospholipid into lavage fluid. Can cGMP, in the absence of hyperventilation, increase lung phospholipid release? Sprague-Dawley rats are injected with [14C]palmitate, and after 1.5 h are anesthetized and ventilated for 20 min. Three groups are ventilated at peak inspiratory pressures (PIP) of 10 cmH2O, while saline, dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), or dibutyryl cGMP (DBcGMP) is infused into the pulmonary artery. In a fourth group, saline is infused into the pulmonary artery, but ventilation is performed with PIP of 25 cmH2O. Lung tissue and lavage fluid are then analyzed for phospholipid (PL) content and for incorporation of [14C]palmitate into lavage and tissue PL fractions. Ventilation at increased pressure and infusion of DBcGMP are associated with increases in release of labeled PL into lavage fraction. The findings suggest that the increase in lavage PL release associated with hyperventilation is, at least in part, mediated by cGMP.
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The role of cyclic GMP in the insulin effect was investigated using isolated frog sartorii. A study was made of the effect of exogenous cyclic GMP, dibutyryl cyclic GMP, 8-bromo-cyclic GMP on xylose transport, glycogen synthesis and muscle respiration. Only dibutyryl cyclic GMP (1.10(-6) - 10(-4) M) alone was observed to have a stimulating effect on glycogen synthesis and respiration. The xylose transport was but slightly accelerated only following a 20 hours incubation of muscles in the cyclic GMP solution. Cyclic GMP was shown to penetrate the muscle fibres. The cyclic GMP content in muscles was equal to 22.7 +/- 2.0 pM per gram of wet weight. Insulin exerted no effect on cyclic GMP concentration in muscles. The data obtained do not allow to conclude that cyclic GMP may serve as a mediator in realization of the insulin effect on membrane and intracellular processes.
When bovine adrenal zona glomerulosa cells were incubated with alpha-human atrial natriuretic polypeptide (alpha-hANP), the basal aldosterone production in the cells was hardly affected, although the angiotensin II- or K+-stimulated production was completely inhibited. alpha-hANP was found to cause the generation of cyclic GMP in the cells. When the cells were incubated with sodium nitroprusside, the drug inhibited the angiotensin II- or K+-stimulated aldosterone production, and also generated cyclic GMP in the cells. In contrast, dibutyryl cyclic GMP was found to be a stimulator of the aldosterone response rather than an inhibitor. The results obtained in this study cast doubt on the role of cyclic GMP as an intracellular second messenger for the action of ANP on aldosterone secretion.
When the homogenate of rabbit superior cervical ganglia (SCG) was incubated in the presence of [gamma-32P]ATP and Mg2+, two specific proteins were strongly labeled. Their apparent molecular weights were 90,000 and 54,000, respectively. The phosphorylation of the latter was significantly stimulated by 10-50 nM cyclic GMP but to a lesser extent by cyclic AMP, whereas that of the former was not stimulated significantly by either of the cyclic nucleotides. The purified protein kinase inhibitor from rabbit skeletal muscle did not inhibit the phosphorylation. These results indicated that the observed phosphorylation of 54K protein was dependent on cyclic GMP but not on cyclic AMP. When intact SCG was incubated in the presence of 32Pi, phosphorylation of 90K protein was stimulated by cyclic GMP, dibutyryl cyclic GMP, and 8-bromo-cyclic GMP (10 microM), whereas phosphorylation of 54K protein was not significantly stimulated by any of these substances. The present demonstration of endogenous cyclic GMP-dependent protein kinase activity and its endogenous substrate proteins raises a possibility that the physiological actions of cyclic GMP in SCG are mediated by the phosphorylation of these proteins.
Cyclic AMP and its dibutyryl derivative inhibit neuronal firing of the labellar sugar sensitive receptor of the blowfly when applied in conjunction with the stimulant sucrose. Furthermore, simultaneous application of aminophylline (phosphodieterase inhibitor) and sucrose or in combination with cyclic AMP caused a similar depression of the sugar receptors response. In contrast, dibutyryl cyclic GMP elicited an increase in sugar receptor firing when applied with sucrose to sugar receptor. Either 5'-AMP or 5'-GMP in combination with sucrose had no discernable effect on the sugar receptors response. Different ratio combinations of cyclic AMP and dibutyryl cyyclic GMP showed the striking inhibitory effect of cyclic AMP upon the dibutyryl cyclic GMP elicited increases in receptor firing frequency. Therefore, it is suggested that these two nucleotides may be mediating different but complimentary aspects of sugar receptor function in a push-pull manner.
The effects of dibutyrl cyclic GMP (db-cGMP) and dibutyryl cyclic AMP (db-cAMP) on potassium-stimulated 45Ca uptake by the P2 fraction of Gray and Whittaker were investigated with the following results. (1) db-cGMP inhibited the initial rate of potassium-stimulated 45Ca-uptake in a dose-dependent manner in 0.1 mM Ca0 medium, but had no effect on the uptake in low K+ medium. In 0.1 mM Ca0 medium, the concentration of db-cGMP causing 50% inhibition was about 3 mM. db-cAMP (5 mM) had no effect on the uptake. (2) db-cGMP-inhibited potassium-stimulated 45Ca uptake in 1 mM Ca0 medium, though less than in 0.1 mM Ca0 medium. (3) db-cGMP inhibited potassium-stimulated 45Ca uptake by synaptosomes (pinched-off nerve terminals) more than the uptakes by other subfractions of P2 fraction. It is suggested from the results that cGMP inhibits the Ca influx resulting from depolarization of the nerve endings in situ.
The effects of dibutyryl cyclic AMP (db-cAMP) and dibutyryl cyclic GMP (db-cGMP) were tested on Ca2+-ATPase, Mg2+-ATPase, and (Ca2+ + Mg2+)-ATPase activities in lysed synaptosomes prepared from whole rat brains (minus cerebellum). At concentrations from 0.1 to 2.0 mM, db-cGMP produced a selective, concentration-dependent increase in Ca2+-ATPase activity. Both db-cGMP and db-cAMP slightly reduced Mg2+-ATPase activity, whereas neither compound had concentration-dependent effects on (Ca2+ + Mg2+)-ATPase activity. These findings suggest that the Mg2+-independent, Ca2+-ATPase activity in rat brain is regulated by a cyclic GMP-dependent process. Further, the data provide evidence that the Ca2+-ATPase activity in lysed synaptosomal membranes represents an enzyme that is distinguishable from both the Mg2+ -and (Ca2+ + Mg2+)-ATPase.
After binding a sensitizing tumor antigen, human leukocytes undergo a series of changes that lead to a loss of their glass-adherent properties; a phenomenon called leukocyte adherence inhibition (LAI). After surgery or when patients have a large tumor burden, their test results become negative. This study shows that in vitro incubation of the leukocytes for 5 min with PGE2 converted to positive the negative test, in an immunologically specific manner. The effect was critically dose-dependent, too little or too much did not alter the result. The same effect was achieved with PGE2, PGI2, aminophylline or other drugs that raise intracellular nucleotides, including dibutyryl cyclic AMP and dibutyryl cyclic GMP. Dibutyryl cyclic AMP stimulated a stronger response and 100 times less was needed than of dibutyryl cyclic GMP. Prostaglandins did not mediate LAI since Indomethacin failed to inhibit a positive test. Nonetheless, arachidonate metabolites were critical for the LAI phenomenon since BPB and mepacrine, inhibitors of phospholipase A2, negated the LAI response. Moreover, ETYA, phenidone and NDGA, inhibitors of the lipoxygenase metabolic pathway, all negated the positive LAI response. The positive response was especially sensitive to nullification by ETYA. Although the last-named drugs inhibit other arachidonate metabolic pathways too, conclusive evidence that the metabolites of the lipoxygenase pathway, and leukotrienes in particular, mediate the LAI response was the fact that FPL 55712, a competitive antagonist of SRS, nullified a positive response at levels as low as 10(-13) M. The results imply that prostaglandins were able to modulate the expression of LAI by affecting intracellular nucleotides, but leukotrienes, it seems, were the metabolites that mediated leukocyte nonadherence after monocytes recognized and bound tumor antigen.
The effects of caerulein and dibutyryl cyclic GMP on isolated rat islets were studied using the perifusion system. One, 20, 50 and 100 nM caerulein stimulated insulin secretion in the perifused rat islets, in a dose dependent manner. Insulin secretion reached a maximal level in the presence of 50 nM caerulein. Caerulein-induced insulin secretion showed a predominant first and minimal second phase. After cessation of stimulation with 50 nM caerulein, the insulin secretion level did not return to the basal value, but enhanced hormone secretion was sustained to a significant extent (p less than 0.01). The simultaneous administration of 10(-3) M dibutyryl cyclic GMP, a specific membrane antagonist against cholecystokinin (CCK), inhibited the first and second phases of caerulein-induced insulin secretion. Moreover, with this nucleotide, "persistent" insulin secretion induced by 50 nM caerulein was inhibited. These data indicate that caerulein directly stimulates pancreatic B cells and that this peptide causes "persistent" insulin secretion. Dibutyryl cyclic GMP counteracts the effects of caerulein. Thus, both pancreatic B cells and pancreatic acinar cells possibly possess a CCK receptor.
The hypothesis that elevation of intracellular guanosine 3':5' cyclic monophosphate (cyclic GMP) concentrations may increase electrical stability of the myocardium was examined by determination of ventricular fibrillation thresholds (VFT) on isolated perfused hearts of the rat. Hearts were paced to circumvent any complicating effects of bradycardia. Using this system, carbachol produced a concentration-related reduction in VFT. The reduction in VFT produced by carbachol was not significantly modified by a high concentration of atenolol (10(-5)M), indicating that the increased vulnerability to ventricular fibrillation was not an indirect consequence of catecholamine release from intramyocardial stores. Atropine (10(-6)M) blocked the carbachol-induced reduction in VFT. At the concentrations of carbachol used to reduce VFT, myocardial cyclic GMP concentrations were also elevated. The dibutyryl analogue of cyclic GMP (10(-4)M) mimicked the effect of carbachol in reducing VFT. Carbachol potentiated the adrenaline (3 X 10(-7)M)-induced reduction in VFT.