Effects of Therapeutic Agents on Cyclic AMP Metabolism In Vitro

Weinryb, Ira; Chasin, Mark; Free, Charles A.; Harris, Don N.; Goldenberg, Harold; Michel, Inge M.; Paik, Velma S.; Phillips, Marie B.; Samaniego, S.; Hess, Sidney M.

doi:10.1002/jps.2600611003

Cited by 92 publications

(8 citation statements)

References 40 publications

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“…The prostaglandin synthetase inhibitors did not directly antagonize adrenergic responses in the presence of exogenous PGE2 (Table 2) and had no effect on adenylate cyclase activity (basal, fluoride, or guanylylimidodiphosphateactivated) in membrane preparations from rat cerebral cortex (data not shown). Furthermore, the prostaglandin synthetase inhibitors are neither potent activators nor inhibitors of phosphodiesterase (23). Thus, the effects observed in the present work appear to be the result of simple depletion and replacement of PGE2 levels in incubated rat brain slices.…”

Section: Resultscontrasting

confidence: 54%

Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series.

Partington¹,

Edwards²,

Daly³

1980

Proc. Natl. Acad. Sci. U.S.A.

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The accumulations of cyclic AMP elicited by norepinephrine in slices of rat cerebral cortex or hypothalamus were markedly reduced after incubations with prostaglandin synthetase (8,11,14-eicosatrienoate, hydrogen-donor The molecular mechanisms through which prostaglandins exert their effects in the brain remain uncertain. Prostaglandins do appear to be involved with regulation of the adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] system, either directly, through prostaglandin receptor-mediated activation of adenylate cyclase (1), or indirectly, through prostaglandin-mediated effects on norepinephrine uptake and release (2). Prostaglandin El (PGEI) has been reported to antagonize 3-adrenergic receptor-mediated inhibition of spontaneous activity of central neurons and it was suggested that this was related to inhibition of adenylate cyclase (3). In homogenates of brain tissue, the activation of adenylate cyclase by prostaglandins has been inconsistent (1) In the central nervous system, prostaglandins are not stored and released as are putative neurotransmitters, but are synthesized from arachidonic acid by the prostaglandin synthetase (8,11,14-eicosatrienoate, hydrogen donor:oxygen oxidoreductase, EC 1.14.99.1) system and continually released into the interstitial space (5). The released prostaglandins are metabolized only slowly in brain, diffusion into the circulation or cerebral spinal fluid being the primary means of elimination (6). Thus, the primary factors governing the levels of prostaglandins in the brain are those which control the activity of prostaglandin synthetase. Substances such as bacterial pyrogens and painproducing substances appear to activate prostaglandin synthetase and increase brain prostaglandin levels (7), whereas analgesic antipyretics, such as aspirin and indomethacin, inhibit prostaglandin synthetase (8, 9) and decrease brain prostaglandin levels (10)(11)(12). Correlations between the analgesic and antipyretic potency of indomethacin, aspirin, and other nonsteroid anti-inflammatory drugs and their ability to inhibit prostaglandin synthetase from brain in vitro (10, 11) and to depress brain prostaglandin levels in vivo (12) have implicated the inhibition of prostaglandin synthesis as a central mode of action for these drugs.Indomethacin, aspirin, and other related compounds inhibit prostaglandin synthetase in rat brain slices, leading to reductions in endogenous levels of prostaglandin (6) 3024The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

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Section: Resultscontrasting

confidence: 54%

Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series.

Partington¹,

Edwards²,

Daly³

1980

Proc. Natl. Acad. Sci. U.S.A.

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“…Adrenal corticosteroids, at high concentrations have been found to inhibit phosphodiesterase. 20 In the present experiments (15 and 60 min ischemia with or without 15 min recirculation) cyclic AMP phosphodiesterase was again measured in homogenates of cerebral tissue from the sham control, ischemic or ischemic plus methylprednisolone-treated animals. When assayed under conditions of high (4 mM) or low (1 uM) cyclic AMP concentrations, the activity of phosphodiesterase did not vary among the four experimental conditions (data not shown).…”

Section: / Lack Of Drug Effects In Control Animalsmentioning

confidence: 86%

Protective action by methylprednisolone, allopurinol and indomethacin against stroke-induced damage to adenylate cyclase in gerbil cerebral cortex.

Taylor¹,

Palmer²,

Callahan³

1984

Stroke

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SUMMARY Adenylate cyclase activity was investigated in either homogenate or particulate fractions from the frontal cerebral cortex of the gerbil following five experimental conditions of bilateral ischemia. After periods of 15 min ischemia, 15 min ischemia plus 15 min of recirculation or 60 min ischemia the enzyme generally displayed enhanced responses to GTP, norepinephrine (NE), dopamine (DA), NE + GTP and DA + GTP. Pretreatment of the gerbils with methylprednisolone, allopurinol or indomethacin did not significantly influence the outcome of these findings. When the animals were subjected to 60 min ischemia plus 15 min of reflow, enzyme responses to the stimulatory agents including forskolin and NaF were all reduced. Pretreatment with methylprednisolone, allopurinol or indomethacin prevented the damage to adenylate cyclase in the 60 min ischemia plus 15 min reflow animals. When animals were made ischemic for 15 min followed by one week of recovery, enzyme sensitivity to GTP, calmodulin-Ca + + , NE, combinations thereof and forskolin were reduced in only the particulate fractions. Enzyme damage was reversed following methylprednisolone. Enzyme damage may result from generation of free radicals during reflow and drugs that either inhibit synthesis pathways generating free radicals, stabilize cell membranes or act as free radical scavengers may be therapeutically beneficial under specific conditions of stroke. Stroke Vol 15, No 2, 1984 CYCLIC NUCLEOTIDES, namely adenosine 3', 5'-monophosphate (cyclic AMP) and guanosine 3', 5'-monophosphate (cyclic GMP) appear to be involved as a consequence of traumatic insults to the brain. Thus seizures, cerebral contusion, cerebral concussions, stab wounds, anoxia and ischemia are all associated with rapid alterations in brain cyclic nucleotide levels. '" 6 With regard to ischemia, bilateral clamping of the common carotid arteries in gerbils evoked a marked rise in cerebral levels of cyclic AMP concomitant with a drop in cyclic GMP concentrations. Under conditions of reflow of blood to the brain cerebral levels of both cyclic AMP and cyclic GMP were increased. 4 The question herein was what perturbations did bilateral ischemia cause to the enzymes responsible for formation of the two cyclic nucleotides? Schwartz et al,7 demonstrated that adenylate cyclase (EC 4.6.1.1) activity did not change in gerbil cerebral cortex up to an hour after clamping one carotid artery. However, if recirculation of blood was allowed the activity of the enzyme declined up to 5 hr post-ischemia. In follow-up investigations we reported that periods of bilateral ischemia (15 min with or without 15 min reflow and 60 min -no reflow) resulted in an enhanced sensitivity of cerebral adenylate cyclase to catecholamines and GTP. However, after 60 min of bilateral ischemia followed by 15 min of recirculation neurohumoral activation of adenylate cyclase was now From the Frist-Massey Neurological Institute,

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“…The barbiturates or meprobamate do not appear to act via cyclic AMP (WEINRYB and CHASIN, 1972;BEER et aI., 1972), whereas the benzodiazepines may (see also SCHULTZ, 1974a, b;SCHULTZ and HAMPRECHT, 1973). Evidence is accumulating that AMP (FABER and GREENBERG, 1975, and personal communication) and GMP (SURIA and COSTA, 1975a, b) are critically involved in slow potentials and subthreshold conductance changes in nervous system excitability and repetitive discharges that occur over rather longer time periods; their involvement in the short-lived processes, such as spike generation and propagation, may not be appreciable.…”

Section: H) Cyclic Ampmentioning

confidence: 92%

“…In somewhat related studies, it has been suggested that benzodiazepines act on the cAMP systems; at least they have weak phosphodiesterase inhibiting activity (SCHULTZ and HAMPRECHT, 1973;WEINRYB and CHASIN, 1972) and cAMP formation stimulated by prostaglandin, histamine, or NE is depressed (SCHULTZ and HAMPRECHT, 1973;SCHULTZ, 1974a, b). CROWLEY et aI.…”

Section: Mechanisms Of Actionmentioning

confidence: 97%

The Pharmacology of Sedative/Hypnotics, Alcohol, and Anesthetics: Sites and Mechanisms of Action

Smith¹

1977

Drug Addiction I

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Effects of Therapeutic Agents on Cyclic AMP Metabolism In Vitro

Cited by 92 publications

References 40 publications

Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series.

Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series.

Protective action by methylprednisolone, allopurinol and indomethacin against stroke-induced damage to adenylate cyclase in gerbil cerebral cortex.

The Pharmacology of Sedative/Hypnotics, Alcohol, and Anesthetics: Sites and Mechanisms of Action

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