Biomedical subjects
Publications and source records attributed to M A Moskowitz.
Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.
Bovine cerebral microvessels (arterioles and capillaries) synthesize prostacyclin (PGI2, measured as 6-keto PGF1 alpha), PGF2 alpha, PGE2 and thromboxane A2 (measured as TXB2) when incubated in glucose-bicarbonate buffer for 30 minutes. Rapid freezing and thawing decreased the subsequent synthesis of 6-keto PGF1 alpha by cerebral microvessels and raised the basal levels of this metabolite within the incubation medium. At low concentrations, the addition of arachidonic acid (0.16 microM) did not stimulate prostacyclin or prostaglandin production; at higher concentrations (16 microM), the synthesis of PGI2 and PGF2 alpha was inhibited. Activation of lipase by the peptide melittin stimulated the synthesis of all arachidonic acid metabolites to the same extent. Thus cerebral microvessels deacylate cellular lipids and metabolize endogenous arachidonic acid to form prostaglandins, prostacyclin and related compounds as previously demonstrated in larger blood vessels. The synthesis and release of these molecules may be important for modulating the tone and reactivity of small blood vessels within the brain.
The headache phase of migraine may develop as the result of an abnormal interaction (and perhaps an abnormal release) of vasoactive neurotransmitters from terminals of the trigeminal nerve with large intracranial and extracranial blood-vessels. These blood-vessels, which dilate during the headache phase of migraine, are thought to receive axonal projections from all three divisions of the trigeminal nerve. Substance P, a potent vasodilating peptide, seems to be released from trigeminal nerve endings in response to nervous stimulation and is involved in the transmission of painful stimuli within the periphery. The vasoactive molecule serotonin, implicated in the pathogenesis of migraine, coexists with substance P in some terminals of the central nervous system and is present within the trigeminal ganglia. Within this nerve serotonin may modulate the function of primary sensory neurons. The abnormal release of substance P or as yet unidentified peptides or other transmitters from the fifth cranial nerve may explain both the hemicranial pain and the vasodilation which are characteristic of the headache of migraine.
Electrolytic lesions of the nucleus raphe dorsalis and medianus reduce the concentration of serotonin (5-hydroxytryptamine) within rat brain intraparenchymal blood vessels. The concentration of serotonin within these vessels increases or decreases after the administration of drugs that modify the biosynthesis and degradation of serotonin or destroy nerve terminals by an uptake-dependent mechanism. These studies provide evidence for the existence of a serotonin-containing pathway seemingly analogous to the neuronal projection that terminates on small parenchymal blood vessels from noradrenergic neurons of the locus coeruleus.
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Madin-Darby canine kidney cells (MDCK) synthesize prostaglandin (PG) F(2alpha), PGI(2) (measured as 6-keto-PGE(1alpha)), PGE(2), PGD(2), and thromboxane A(2) (measured as thromboxane B(2)). When incubated in the presence of norepinephrine (6 muM), the syntheses of these arachidonic acid metabolites are stimulated 3-fold. Norepinephrine's effect can be antagonized by the addition of alpha-adrenergic receptor blocking agents (phenoxybenzamine>phentolamine>yohimbine>dibenamine>tolazoline) but not by the beta-adrenergic blocking drug propranolol. Norepinephrine's stimulation is also inhibited by low concentrations of dihydroergotamine, bromocryptine, ergocryptine, and ergotamine. The stimulation of PG synthesis by norepinephrine is reversible, continues during the 24 hr of incubation, and requires the presence of norepinephrine at the receptor site but it is not blocked by the addition of colchicine, cytochalasin B, or cycloheximide. Neither phenoxybenzamine nor ergotamine at concentrations that block norepinephrine's stimulation of PG biosynthesis suppresses the increase in PG synthesis induced by exogenous arachidonic acid, suggesting that the alpha-adrenergic regulation is not occurring primarily at the cyclooxygenase step in the metabolism of arachidonic acid. In mouse lymphoma cells (WEHI-5), low concentrations of isoproterenol or norepinephrine stimulate the synthesis of thromboxane, an effect that can be blocked by the addition of propranolol but not by relatively high concentrations of phenoxybenzamine or ergotamine. Taken together, these results suggest that alpha-adrenergic receptor stimulation promotes the deacylation of phospholipids by MDCK cells whereas beta-adrenergic mechanisms lead to activation of similar pathways in WEHI-5 cells.
A deficiency of hepatic dihydropteridine reductase (DHPR) activity was found in a neurologically impaired infant with mild hyperphenylalaninemia and normal levels of hepatic phenylalanine hydroxylase. DHPR is required for the regeneration of tetrahydrobiopterin, an essential cofactor in aromatic amino acid hydroxylation, a necessary step in the biosynthesis of the neurotransmitters, dopamine and serotonin. Evidence for decreased synthesis of these transmitters in this patient was provided by the finding of reduced levels of homovanillic acid and 5-hydroxyindole acetic acid, metabolites of dopamine and serotonin, respectively, in the cerebrospinal fluid and urine. Treatment with dopamine and serotonin precursors, L-3,4 dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, was associated with improvement in temperament and motor tone and less frequent seizures. However, there was no improvement in gross motor function or language development.
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To determine whether spinal cord lesions disrupt the diurnal activity of the human pineal, urinary melatonin levels were measured over 24 hours (4 or 8-hourly intervals) in male patients with clinical evidence of cervical spinal cord transection. During the waking state, levels of melatonin in these subjects ranged from 3.2--13.5 ng/4 hours; during sleep and darkness, values ranged from 1.8--10.5 ng/4 hours. Levels of serum cortisol, aldosterone, and growth hormone showed rhythmic variations in these subjects. The absence of significant nocturnal melatonin increases distinguishes quadriplegic subjects from normal males and from one subject with a lesion of the lumbar spinal cord. These differences may be caused by "decentralization" of the pineal organ due to a lesion within the cervical spinal cord interrupting descending sympathetic fibers. If so, the human pineal, like that of other mammals, is regulated, at least in part, by activity within the central nervous system via sympathetic nervous connections.
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At 1 h after intraperitoneal administration of D-amphetamine sulphate (15 mg/kg), rat brain polyribosomes show disaggregation accompanied by reduced capacity for in vitro peptide chain elongation. The direct action of amphetamine on cell-fine protein-synthesizing systems was therefore explored. When brain or liver polyribosomes from untreated rats were incubated with pH 5 enzyme, peptide chain elongation was not inhibited by the addition 4 mM amphetamine to the medium. On the other hand, an initiation-dependent system consisting of rat liver of brain mRNA and wheat germ S-30 fraction showed inhibition of [3H]leucine incorporation by 50% when 4 mM amphetamine were added. The metabolites of amphetamine, p-hydroxyamphetamine and p-hydroxynorephedrine, had no inhibitory action in either system, but the potent neurotoxin p-chloroamphetamine was a more powerful inhibitor of initiation than amphetamine. By using [3H]amphetamine, it was shown that amphetamine binds to the 80-S ribosomes of the wheat germ system. This binding depended on the presence in the system of natural liver or brain mRNA or several synthetic mRNAs, but was not promoted by polyuridylic acid as the messenger. Significantly, polyuridylic acid-dependent polyphenylalanine synthesis by the wheat germ system was not inhibited by amphetamine or p-chloroamphetamine. Therefore, it was concluded that amphetamine inhibits protein synthesis by interfering with initiation through a step related to formation of the mRNA ribosome complex.
Periodic apnea and exercise hypoventilation were observed in a 14-year-old boy. Hyperphagia, obesity, serum hyperosmolality without diabetes insipidus or appropriate thirst, and retardation of growth and sexual development indicated a hypothalamic disorder. Neurologic evaluation was normal except for electroencephalographic changes induced by apnea. Pulmonary function tests, resting arterial blood gases in the wakeful state, and ventilatory response to inhaled CO2 were also normal. Acute hypoxemia and respiratory acidosis occurred with apnea during sleep and with insufficient ventilation during exercise. The central origin of sleep apneas was shown by esophageal pressure monitoring. The hypothalamic dysfunction and exercise hypoventilation distinguish this patient from others with obesity and periodic apnea.
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