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Biomedical subjects

M A Moskowitz

Publications and source records attributed to M A Moskowitz.

At least 19 recordsLinked to original sources
PubMed1992

UK-14,304, R(-)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanisms.

Intravenous administration of an alpha-adrenoceptor agonist, UK-14,304, a histamine H3 receptor agonist, R(-)-alpha-methyl-histamine (alpha-MeHA) or SMS 201-995 (a synthetic octapeptide analogue of somatostatin), blocked plasma protein (125I-albumin) extravasation within rat and/or guinea pig dura mater following unilateral electrical trigeminal ganglion stimulation or capsaicin administration. The extravasation caused by the administration of the neuropeptide mediator, substance P, was not inhibited by any of the three compounds. Blockade by UK-14,304 was completely antagonized by pretreatment with the highly selective alpha 2-antagonist, idazoxan, as was alpha-MeHA by pretreatment with the highly selective histamine H3 antagonist, thioperamide. Taken together, the results are consistent with blockade by prejunctional alpha 2, histamine H3 and probably somatostatin receptors which may be coupled to inhibition of neuropeptide release. Because 5-HT1-like agonists, which are useful for treating migraine and related headaches, share similar inhibitory properties in this in vivo model, the significance of prejunctional alpha 2, histamine H3 and somatostatin receptors to treatment of vascular headaches is suggested.

Adrenergic alpha-Agonists↗
PubMed1992

Evidence for the presence of 5-HT1B receptor messenger RNA in neurons of the rat trigeminal ganglia.

In situ hybridization histochemistry and receptor autoradiography were used to determine the presence of 5-HT1B receptor messenger RNA (mRNA) and 5-HT1B receptor proteins, respectively, in rat trigeminal ganglia. Receptor autoradiography on rat trigeminal ganglia, using appropriate 5-HT1B radioligands, did not demonstrate any specific labelling. In contrast, in situ hybridization showed that many ganglion cells contain 5-HT1B receptor mRNA, suggesting the presence of presynaptic 5-HT1B receptors on trigeminovascular neurons.

Animals↗
PubMed1992

5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation.

Antidromic stimulation of small caliber trigeminal axons causes neurogenic inflammation in the dura mater and tongue as evidenced by marked increases in mast cell activation, protein extravasation, as well as in the numbers of endothelial cytoplasmic vesicles, endothelial microvilli and platelet aggregates within ipsilateral post-capillary venules. In this report, we examined the effects of pretreatment with serotonin1 receptor agonists, dihydroergotamine (50 micrograms/kg, i.v.) and sumatriptan (100 micrograms/kg, i.v.) on the light and electron microscopic changes which develop after trigeminal ganglion stimulation. Both dihydroergotamine and sumatriptan are useful in the acute treatment of vascular headaches and bind with high affinity to 5-HT1D receptors. Both drugs decreased significantly the number of dural vessels showing endothelial or platelet changes and the numbers of activated mast cells, but did not affect the neurogenic response in the tongue. The drugs also blocked the accumulation of horseradish peroxidase reaction product within the endothelium and perivascular space on the stimulated side. The receptor is not present on trigeminovascular fibers innervating extracranial cephalic tissues. Drug mechanism probably involves inhibition of a proximal step in the pathophysiological cascade (e.g., via activation of a prejunctional receptor) because (a) receptors for sumatriptan have not been identified on mast cells whereas the inflammatory response was attenuated in mast cells as well as within platelets and the endothelium and (b) previous work indicates that sumatriptan and dihydroergotamine block neurotransmitter release. Hence, constriction of vascular smooth muscle mediated by postjunctional 5-hydroxytryptamine receptors is unlikely to explain the anti-inflammatory actions of dihydroergotamine or sumatriptan reported here.

Animals↗
PubMed1992

Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine.

Sumatriptan and the ergot alkaloids are useful tools for deciphering drug mechanisms in migraine and related headaches. Both neuronal and vascular mechanisms have been proposed on the basis of actions of 5-HT at receptors resembling the 5-HT1D subtype. In this Viewpoint article, Michael A. Moskowitz argues that blockade of neural transmission and the neurogenic inflammatory response provides a mechanism by which sumatriptan and ergot alkaloids alleviate vascular headaches. He postulates, with similar arguments, that sumatriptan and ergot alkaloids may block headaches that develop from meningovascular inflammatory disorders such as from viral and bacterial meningitis and from the sequelae of head injury.

Ergot Alkaloids↗
PubMed1992

Expression of c-fos-like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space.

The expression of c-fos protein was examined by immunohistochemistry in serial sections of brainstem following the instillation of either autologous arterial blood (0.3 ml) or mock cerebrospinal fluid (0.3 ml) through a catheter placed in the cisterna magna, or following catheter placement alone in pentobarbital-anesthetized Sprague-Dawley rats. After injection, blood was distributed within the subarachnoid space surrounding the brainstem and in the region of the circle of Willis. c-fos protein-like immunoreactivity was present at 1 h, peaked at 2 h and decreased by 8 h. At 2 h, immunoreactivity was strongly expressed within trigeminal nucleus caudalis (lamina I, IIo), as well as within nucleus of the solitary tract, area postrema, ependyma, pia mater and arachnoid in every animal. Moderate labeling was found in parabrachial nucleus, medullary lateral reticular nucleus and central gray. Sparse labeling was present in trigeminal nucleus caudalis (lamina III-V) and trigeminal nucleus interpolaris; few or no labeled cells were detected in other parts of the trigeminal nuclear complex, thalamus, cerebral cortex, cerebellar cortex or trigeminal ganglion. The number of positive cells was not related to the volume of injectate but was related to the amount of injected blood. The density of cell labeling evoked by injecting mock cerebrospinal fluid or after catheter placement was markedly lower than after blood in all brainstem areas. The number of labeled cells was greatly reduced within trigeminal nuclear complex, parabrachial nucleus and medullary lateral reticular nucleus, but not within the nucleus of the solitary tract, area postrema or ependyma when blood was injected into adult animals in which unmyelinated C-fibers were destroyed by neonatal capsaicin treatment. Similar results were obtained after blood was instilled into the cisterna magna of rats in which meningeal afferents were chronically sectioned at the ethmoidal foramen bilaterally. We conclude that blood in the subarachnoid space is an effective stimulus for activating c-fos expression within subpopulations of brainstem neurons. Activation within trigeminal nucleus caudalis is mediated in large part by excitation of small-caliber meningeal afferents (trigeminovascular fibers), whereas c-fos expression within nucleus of the solitary tract and area postrema may reflect direct stimulation of blood or blood products, or possibly the response to autonomic activation from noxious stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat dura mater and tongue following antidromic trigeminal stimulation.

We investigated the effects of unilateral electrical trigeminal ganglion stimulation (0.1 or 1.0 mA, 5 Hz, 5 ms, 5 min) on the morphology of blood vessels within the rat dura mater and tongue using light and transmission electron microscopy. Stimulation at both intensities caused changes which were confined to the ipsilateral post-capillary venules except in the tongue where arterioles were affected as well. Changes were more marked after 1.0 mA. Dramatic increases in the numbers of endothelial pinocytotic vesicles were found along the luminal and abluminal surfaces ipsilateral to the stimulation. Tight junctions remained largely intact, except that injected ferritin particles were occasionally trapped inside these junctions. Cytoplasmic microvilli and endothelial blebs were sometimes present as well. Approximately 80% of the examined dural post-capillary venules showed one or more of these endothelial changes. Horseradish peroxidase injected intravenously 5 min prior to stimulation was detected in the extracellular space surrounding dural blood vessels and within pinocytotic vesicles. Ferritin injected similarly, was also localized in post-capillary venule walls, interstitial spaces, intraendothelial vesicles and in vacuoles. Platelet accumulation and aggregation were present in approximately 10% of post-capillary venules in dura and tongue. These changes were associated with mast cell secretion, but neither vascular nor mast cell activation was observed in adult rats in whom C-fibers were destroyed during the neonatal period with capsaicin. The present observations provide morphological evidence which supports findings from previously reported albumin tracer studies suggesting enhanced transport and endothelial activation following electrical stimulation of small caliber afferent fibers.

Animals↗
PubMed1992

Chronic parasympathetic sectioning decreases regional cerebral blood flow during hemorrhagic hypotension and increases infarct size after middle cerebral artery occlusion in spontaneously hypertensive rats.

Regional cerebral blood flow (rCBF) during controlled hemorrhagic hypotension (140-20 mm Hg) was assessed 10-14 days after chronic unilateral sectioning of parasympathetic and/or sensory fibers innervating pial vessels in spontaneously hypertensive rats (SHR). rCBF was measured in the cortical barrel fields bilaterally by laser Doppler blood flowmetry. Immunohistochemistry of middle cerebral artery (MCA) whole mount preparations was used to verify the surgical lesion. During hemorrhagic hypotension, rCBF was equivalent on the two sides in shams, after selective sensory denervation, or in parasympathetically sectioned animals exhibiting small decreases (less than or equal to 30%) in immunoreactive vasoactive intestinal peptide (VIP)-containing fibers. After chronic parasympathetic denervation, decreases in perfusion pressure were accompanied by greater reductions in rCBF on the lesioned side; changes in vascular resistance were also attenuated on that side. The rCBF response to hypercapnia (PaCO2 50 mm Hg), however, was symmetrical and robust. To examine the effects of impaired neurogenic vasodilation on the pathophysiology of cerebral ischemia, infarct size was measured 24 h following tandem MCA occlusion in denervated animals. Infarction volume was larger after selective parasympathetic sectioning (sham, 156 +/- 27 vs. 196 +/- 32 mm3, respectively) but only in those denervated animals demonstrating greater than or equal to 40% decrease in immunoreactive VIP-containing fibers within the ipsilateral MCA. Lower than expected blood flow/perfusion pressure in the cortex distal to an occluded blood vessel may relate the observed blood flow responses to the occurrence of larger cortical infarcts in parasympathetically denervated animals. If true, the findings suggest a novel role for neurogenic vasodilation in the pathophysiology of cerebral ischemia and in rCBF regulation within the periinfarction zone.

Animals↗
PubMed1992

Predicting in-hospital mortality. A comparison of severity measurement approaches.

Hospital mortality statistics derived from administrative data may not adjust adequately for patient risk on admission. Using clinical data collected from the medical record, this study compared the ability of six models to predict in-hospital death, including one model based on administrative data (age, sex, and principal and secondary diagnoses), one on admission MedisGroups score, and one on an approximation of the Acute Physiology Score (APS) from the revised Acute Physiology and Chronic Health Evaluation (APACHE II), as well as three empirically derived models. The database from 24 hospitals included 16,855 cases involving five medical conditions, with an overall in-hospital mortality rate of 15.6%. The administrative data model fit least well (R-squared values ranged from 1.9-5.5% across the five conditions). Admission MedisGroups score and the proxy APS score did better, with R-squared values ranging from 4.9% to 25.9%. Two empirical models based on small subsets of explanatory variables performed best (R-squared values ranged from 18.5-29.9%). The preceding models had the same relative performances after cross-validation using split samples. However, the high R-squared values produced by the full empirical models (using 40 or more explanatory variables) were not preserved when they were cross-validated. Most of the predictive clinical findings were general physiologic measures that were similar across conditions; only a fifth of predictors were condition-specific. Therefore, an efficient approach to risk-adjusting in-hospital mortality figures may involve adding a small subset of condition-specific clinical variables to a core group of acute physiologic variables. The best predictive models employ condition-specific weighting of even the generic clinical findings.

Databases, Factual↗
PubMed1992

Self-report versus medical record functional status.

The importance of assessing functional status in the hospitalized patient is gaining recognition. However, the availability and accuracy of medical record functional status data are uncertain. We collected data on 2,504 patients greater than 65 years of age discharged alive. A personal interview conducted 2 days before discharge recorded the patient's self-reported ability to perform 5 activities of daily living scales. Medical record abstraction was used independently to determine ability to perform the same activities of daily living scales. Patients who required any human assistance to perform a function were considered dependent. Patients were also contacted after discharge to determine the site of posthospital care (28% discharged to a nursing home). The amount of missing medical record functional status data varied by function from 20% for bathing to 50% for dressing. Ten percent of patients had no medical record functional status documentation concerning any of the five functions. The prevalence of self-reported dependence at discharge varied by function from 24% for feeding to 93% for bathing. The total number of dependencies differed between the two methods (medical records, 2.3 +/- 1.9; self-report data, 3.2 +/- 1.5). There was exact agreement between the two methods on the total number of dependencies in 28% of cases and differences of greater than or equal to 3 in 20%. In a stepwise logistic model predicting discharge to a nursing home and adjusting for other relevant variables, the number of dependencies as determined by self-report and medical record data each remained significant (Odds Ratios = 1.6). Self-report and medical record functional status data differ substantially, and the medical record data remain independently associated with nursing home placement. Several possible explanations for this finding are explored.

Activities of Daily Living↗
PubMed1992

Postoperative adverse events of common surgical procedures in the Medicare population.

Mortality rates are the most widely used measure in assessing patient outcome from hospitalization. However, they may be an insensitive measure of quality for surgical patients because death is a relatively rare outcome. A random sample of patient data (n = 8126) selected from the Medicare files of seven states was used to identify, through chart abstraction, clinical postoperative complications of surgery that could serve as measures of quality. Four surgical procedures were studied: 1) coronary artery bypass grafting; 2) coronary angioplasty; 3) cholecystectomy; and 4) prostatectomy. Severity at admission was controlled for using severity-of-illness models developed with chart-abstracted data to predict adverse events after these four procedures. 30-day mortality rates ranged from 1.0% to 6.6%, while the prevalence of postoperative adverse events identified from chart review was greater (6.9% to 33.3%). There were significant differences between patients with and without adverse events. For example, coronary artery bypass graft patients with adverse events had prolonged postsurgical lengths of stay (18.5 +/- 13.2 vs. 13.2 +/- 6.2, P less than 0.001) and higher mortality rates (15.2% vs. 2.6%, P less than 0.001). The R-square values using clinical indicators at admission to predict the occurrence of any adverse event ranged from 0.05 to 0.13. Clinically meaningful adverse events of surgery can be successfully identified through chart abstraction and appear to be valid measures of postoperative complications among surgical patients. Severity adjustment at admission only modestly predicts the occurrence of these adverse events.

Aged↗
PubMed1992

L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia.

L-Arginine (> or = 30 mg kg-1, i.v.), but not D-arginine (300 mg kg-1) administered 5 min after unilateral common carotid/middle cerebral artery occlusion increased regional cerebral blood flow (rCBF) within the dorsolateral ischaemic cortex in spontaneously hypertensive rats. L-Arginine (300 mg kg-1) increased rCBF from 22 +/- 2.7 to 33 +/- 4% of baseline as measured by laser-Doppler flowmetry. This increase may explain the ability of L-arginine to reduce infarct size following focal cerebral ischaemia, as reported previously. The mechanism appears to be mediated by nitric oxide since topical L-NAME (1 microM), a nitric oxide synthase inhibitor, decreased pial arteriole calibre from 115 +/- 2.2 to 106 +/- 0.9% of baseline following L-arginine infusion (300 mg kg-1).

Amino Acid Oxidoreductases↗
PubMed1992

CP-93,129, sumatriptan, dihydroergotamine block c-fos expression within rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges.

1. The effects of intravenously administered 5-HT1B receptor agonists were examined on c-fos like immunoreactivity, an indicator of neuronal activation, within the brain stem. C-fos was induced by injecting an algesic, vasoconstrictor substance (0.3 ml of autologous blood) or a pro-inflammatory molecule, carrageenin (1 mg in 0.1 ml saline) into the cisterna magna of pentobarbitone-anaesthetized Sprague-Dawley rats and was visualized in serial sections (50 micrometers) by use of a polyclonal antiserum. 2. As previously reported, the injection of blood caused significant labelling within laminae I, IIo of the trigeminal nucleus caudalis, a major nociceptive brain stem nucleus, as well as within nucleus of the solitary tract and area postrema. A similar pattern of expression with fewer cells per section was detected after carrageenin instillation. The number of expressing cells was reduced by 54% in trigeminal nucleus caudalis but not within the nucleus of the solitary tract or area postrema when blood was injected in adult rats neonatal capsaicin treatment. 3. Pretreatment with 5-HT1 agonists with some selectivity for the 5-HT1B receptor, CP-93,129 (460 nmol kg-1 x 2, i.v.), sumatriptan (720 nmol kg-1 x 2, i.v.) or dihydroergotamine (86 nmol kg-1 x 2, i.v.) reduced positive cells by 39%, 31%, and 33% respectively in trigeminal nucleus caudalis but not in nucleus of the solitary tract or area postrema after blood instillation. Pretreatment with the analgesic morphine (15 mumol kg-1, s.c.) also decreased the number of positive cells by 63% in trigeminal nucleus caudalis. 4. CP-93,129 (460 nmol kg-1 x 2, i.v.) reduced the number of c-fos labelled cells by 47% within lamina I, IIo after carrageenin instillation. 5. Drug-induced blockade appeared to be tissue-dependent. Pretreatment with sumatriptan (720 nmol kg-1 x 2, i.v.) did not block c-fos expression in trigeminal nucleus caudalis following formalin application to the nasal mucosa.6. Drug-induced blockade may be mediated by an action on primary afferent (trigeminovascular) fibres in as much as CP-93,129 (460 nmol kg-' x 2, i.v.) did not reduce the number of expressing cells within the trigeminal nucleus caudalis following blood instillation in rats treated as neonates with capsaicin.7. We infer from these results that the analgesic actions of agonists at 5-HTB receptors (the receptor subtype analogous to 5-HTID in man) need not depend upon the presence of vasodilatation and, that 5-HTID receptor-mediated blockade of neurotransmission contributes significantly to the analgesic effects of these drugs in headache.8. Based on the demonstrated effects of 5-HTB/D agonists against the actions of two chemicallyunrelated meningeal stimulants, we suggest that treatment with 5-HTID agonists may be useful for the alleviation of pain in other headache conditions associated with meningeal irritation. Bacterial, viral(including AIDS meningovascular inflammation) and other forms of chemical meningitis merit further investigation.

Animals↗
PubMed1992

Pial vessel caliber and cerebral blood flow become dissociated during ischemia-reperfusion in cats.

The relationship between pial arteriolar caliber and cerebral blood flow (CBF) was examined in 11 cats subjected to reperfusion for up to 120 min after 10 min of global cerebral ischemia induced by four-vessel occlusion and systemic hypotension. Thirty minutes after reperfusion CBF, as assessed by radiolabeled microsphere injection, had increased to 588% of control in middle cerebral artery (MSEC) cortical gray matter territory. The caliber of MSEC pial arterioles measured using the closed cranial window technique (greater than 33 to less than 213 microns) increased to 172% of baseline. By 60 min of reperfusion, CBF was 76% of basal levels, but pial arterioles remained 133% of baseline. After 120 min, CBF approximated baseline values, but pial dilatation persisted (115% of control). Intracranial pressure measurements did not differ significantly from resting values. At 45 min and beyond, total cerebrovascular resistance did not differ from resting values. The coexistence of vasodilatation within pial arterioles and normal blood flow in cortical gray matter indicates that pial vessels (greater than 33 microns) cannot be responsible for normal blood flow restoration following postocclusive hyperemia. Resistance during the posthyperemic phase must be increased selectively within parenchymal vessels to account for normal total cerebrovascular resistance, pial vessel dilatation, and normal-low parenchymal blood flow. Whether obstruction rather than vasoconstriction explains the resistance changes within intraparenchymal vessels remains for further study.

Animals↗
PubMed1992

Oxygen radicals in cerebral ischemia.

Superoxide production was measured as the superoxide dismutase (SOD)-inhibitable portion of nitro blue tetrazolium (NBT) reduction after cerebral ischemia-reperfusion in anesthetized cats equipped with cranial windows. Significant superoxide production was found in the early reperfusion period and continued for more than 1 h after ischemia. Superoxide was not detected in control animals not subjected to ischemia, during ischemia, and at 120 min of reperfusion. After ischemia, the vasoconstrictor response to arterial hypocapnia was reduced. This effect was prevented by pretreatment with SOD plus catalase or by deferoxamine. The response to topical acetylcholine was converted to vasoconstriction after ischemia. The normal vasodilator response reappeared spontaneously at 120 min of reperfusion. The vasodilator response to acetylcholine was preserved in animals pretreated with SOD plus catalase. Blood-brain barrier permeability to labeled albumin and horseradish peroxidase was increased after ischemia. These effects were minimized by pretreatment with SOD and catalase. We conclude that superoxide generation occurs during reperfusion after cerebral ischemia for a fairly long period and that superoxide and its derivatives are responsible at least in part for the vasodilation and the abnormal reactivity as well as for the increase in blood-brain barrier permeability to macromolecules seen after ischemia. Furthermore, the findings suggest that the agent responsible for the vascular abnormalities is hydroxyl radical generated via the iron-catalyzed Haber-Weiss reaction.

Acetylcholine↗
PubMed1992

L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR.

L-Arginine, but not D-arginine, serves as a precursor for the synthesis of nitric oxide (NO), a potent dilator of cerebral blood vessels. We examined the effects of administering L-arginine (300 mg/kg ip) on the volume of infarction in two models of focal cerebral ischemia in spontaneously hypertensive rats (SHR). L-Arginine was administered before (16 and 3 h) and after (5 min and 2 h) vessel occlusion, and animals were killed 24 h later. L-Arginine treatment decreased infarct size in rats subjected to distal middle cerebral arterial (MCA) plus ipsilateral common carotid arterial (CCA) occlusion by 31% [147 +/- 12 (saline) vs. 101 +/- 9 mm3 (L-arginine), P < 0.05]. D-Arginine, administered according to the same dosage and protocol, was without effect. In the group subjected to proximal MCA occlusion, L-arginine decreased infarction size in the striatum by 28% [47 +/- 5 (saline) vs. 34 +/- 3 mm3 (L-arginine), P < 0.05] and neocortex by 11% [193 +/- 7 (saline) vs. 171 +/- 8 mm3 (L-arginine), P < 0.05]. Changes in blood pressure or other measured physiological parameters did not account for the observed differences. The possible use of L-arginine for the treatment of focal cerebral ischemia merits further investigation.

Animals↗
PubMed1992

Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles.

The cerebral vasodilator response induced by topical nitroglycerin and nitroprusside was examined in cats equipped with cranial windows for the observation of the cerebral microcirculation. In cats subjected to chronic unilateral trigeminal ganglionectomy, the vasodilator responses to nitroprusside and nitroglycerin were markedly depressed on the denervated side. Application of a selective calcitonin gene-related peptide (CGRP) antagonist [CGRP(8-37)] on the innervated side reduced the response to nitrodilators to the same extent as seen on the denervated side. The vasodilator response to acetylcholine was unaffected by trigeminal ganglionectomy. CGRP(8-37) almost abolished the vasodilator response to nitroglycerin and sodium nitroprusside and to CGRP, but did not affect the response to adenosine or to adenosine diphosphate. Pretreatment with LY83583, a drug that lowers cyclic GMP levels, diminished the vasodilation to CGRP and to nitroprusside but not to adenosine. We conclude that the nitrovasodilators activate sensory fibers to release CGRP, which in turn relaxes cerebral vascular smooth muscle by activating guanylate cyclase. Hence, nitrovasodilators possess a novel mechanism of action within the cephalic circulation which may explain both the occurrence of vasodilation and headache.

Aminoquinolines↗