Specific regulation of peptide-induced renal prostaglandin synthesis.
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Biomedical subjects
Publications and source records attributed to A R Morrison.
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Our studies suggest that paradoxical sleep is a state in which the brainstem is in a functional mode normally associated with presentations of novel stimuli. Furthermore, the combination of atonia and an internal state of activation indicates sustained activity of a brainstem mechanism designed to dampen responses to sudden, novel stimuli in wakefulness lest the animal over react and run blindly into danger prior to stimulus analysis. This conclusion stems from two sets of data. Studies of large-amplitude waves, which characteristically occur spontaneously just prior to and during paradoxical sleep, have demonstrated that the waves are signs of alerting. These waves, termed ponto-geniculooccipital (PGO) spikes, can be induced during both slow wave and paradoxical sleep by external stimuli at a threshold below actual arousal. Whenever cats are confronted with novel stimuli during wakefulness, eye movement potentials, which are recorded from the same sites as PGO spikes but differ from them in several characteristics, assume all the characteristics of PGO spikes. These observations indicate that the central nervous system during paradoxical sleep is in a "peculiar" state of activation which is not behaviorally expressed. Other experiments have focused on the muscle atonia of paradoxical sleep. Small, bilateral dorsolateral pontine tegmental lesions create the dramatic phenomenon of paradoxical sleep without atonia which is characterized as follows: After slow wave sleep, when paradoxical sleep with muscle atonia would normally appear, cats raise their heads, make body righting movements, exhibit alternating movements of the limbs, and even attempt to stand. Throughout an episode, which shows all other aspects of paradoxical sleep, including unresponsiveness to visual stimuli, cats act as if they are being startled, searching and sometimes attacking an object. In wakefulness they show minor cerebellar signs. Presumably the lesions disrupt both the pontine excitation of the medullary inhibitory area and the inhibition of a brainstem system for mobilizing activity normally in force during paradoxical sleep. Studies of the same cats during wakefulness have shown that there in an increase in exploratory locomotor activity of 23 to 127 percent as measured in an open-field test. The existence of parallel effects on motor control in wakefulness and paradoxical sleep produced by pontine lesions suggests that the atonia of paradoxical sleep is a reflection of excessive activity of a brainstem response dampening mechanism which operates more subtly during wakefulness to produce appropriately modulated responses to various unexpected stimuli.
Perfusion of a rabbit kidney 72 h after ureter obstruction resulted in a progressive increase in bioassayable prostaglandin-like substances released in response to a fixed dose of bradykinin with time. Contralateral or normal kidneys showed no progressive increase with time of prostaglandin-like substances released in response to the same dose of agonist during perfusion. Actinomycin D, an inhibitor of RNA synthesis and cycholeximide, reversibly blocked the time-dependent progressive increase in renal prostaglandin-like substances released from the obstructed kidney. Acetylsalicylic acid, which covalently acetylates the cyclooxygenase, inhibited initial bradykinin-stimulated prostaglandin biosynthesis by 95% in the ureter-obstructed kidney, but within 60 to 90 min of perfusion there was progressive bioassayable prostaglandin E2 release in response to bradykinin which paralleled the non-aspirin-treated control. In the aspirin-treated contralateral (unobstructed control) and normal kidneys bradykinin-stimulated release of prostaglandin-like substances was inhibited by 85% and did not recover during the perfusion experiments consistent with the evidence that the control kidneys are not synthesizing new enzyme. These experiments suggest that the progressive enhanced prostaglandin release to fixed bradykinin doses in the ureter-obstructed kidney is dependent on de novo cyclooxygenase synthesis.
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The metabolic effects of imidazole were tested in rat renal cortex. Imidazole enhanced the activity of renal cortical phosphodiesterase in vitro. Imidazole inhibited glucose production in a dose-dependent fashion from a variety of substrates in the gluconeogenic pathway proximal to the triose phsophates. The stimulation in renal gluconeogenesis resulting from isoproterenol and parathyroid hormone was inhibited by imidazole. These changes correlated with an inhibition of the augmented levels of renal cortical cyclic AMP levels produced by these hormones. These studies indicate that imidazole is an effective activator of phosphodiesterase in intact renal cells and lend further support to the suggestion that the stimulation of renal gluconeogenesis produced by isoproterenol and parathyroid hormone is mediated by a release of cyclic AMP.
Prostaglandin E was found to increase the formation of cyclic acdenosine 3',5'-monophosphate (cyclic AMP) by renal cortical slices. This increased release of cyclic AMP was not influenced by the absence of Ca2+ in the incubating media. The enhanced production of cyclic AMP was probably mediated by stimulation of membrane-bound adenylate cyclase activity. An increase in adenyl cyclase activity was observed with increasing concentrations of prostaglandin E. Furthermore, prostaglandin E augmented glucose production from alpha-ketoglutarate. This effect on gluconeogenesis was abolished by the removal of Ca2+ from the incubating medium. These effects are similar to those described for parathyroid hormone and suggest that the renal cortex is a prostaglandin-dependent system. Prostaglandin E decreased cyclic AMP production and glucose production (from alpha-ketoglutarate) in response to submaximal doses of parathyroid hormone, suggesting that prostaglandin may be important in modulating the intracelluar action of parathyroid hormone in the kidney cortex.
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Large-amplitude waves recorded in the pontine tegmentum, lateral geniculate body and visual cortex herald the onset and continue throughout paradoxical sleep. The role of these ponto-geniculo-occipital (PGO) waves, or spikes, has puzzled researchers since their discovery. This paper reports experiments in cats which have demonstrated that PGO spikes are essentially an epiphenomenon, an electrical sign of the activation of a "startle network" by the neural turmoil of paradoxical sleep. Internal stimulation provided by the bursts of neural activity which characterize paradoxical sleep produces PGO spikes in the lateral geniculate body which are identical in appearance to those elicited during synchronized and paradoxical sleep by 1.55 Hz tone bursts or taps on the cage in normal cats. Cerebellar lesions result in behavioral responses to the intrinsic startles during synchronized sleep in the form of extensor or flexor jerks of the forelimbs. The jerks occur in conjunction with each PGO spike. Identical movements can be induced in the same cats in wakefulness by such startling stimuli as dropping the cat or hissing with an aerosol can. Lesions involving the auditory-visual area permit cats to be stimulated by sound in synchronized sleep without arousal, but anterior lobe lesions produce an easily aroused animal. We postulate that the phenomena observed following cerebellar lesions are the result of alteration in the control of serotonergic neurons of the pontine raphe nuclei.
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Bilateral lesions placed in the pontiene tegmentum resulted in episodes of paradoxical sleep in which the characteristic atonia of that sleep stage was absent in six cats. Following each period of synchronized sleep, in which the degree of muscle tone of the dorsal cervical muscles gradually diminished, cats with such lesions would slowly raise their heads, move their limbs at all joints, make several attempts to rise and eventually leap violently. During such episodes they were unresponsive to strong lights, touching and mild pinching. Only sound would arouse them. This behavior appeared as early as the 2nd postoperative day, the 1st day of recording. Such episodes supplanted normal paradoxical sleep with atonia and lasted unchanged for as long as 6 months in one cat until it was killed while still in good health. Complete recovery of atonia was observed in one cat after 3 weeks. Either no recovery or else eventual recovery to excessively active periods of paradoxical sleep while remaining recumbent characterized the sleep of the other four. The conclusion drawn from these experiments and from a review of the literature is that the hypotheses stating that the locus coeruleus or other isolated nuclei of the pons are specifically concerned with the initiation of paradoxical sleep are not clearly supported by available evidence.
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