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M A Moskowitz

Publications and source records attributed to M A Moskowitz.

At least 199 records · Page 11Linked to original sources
PubMed1994

Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development.

Pharmacological data suggest that the actions of antimigraine drugs such as sumatriptan may be mediated by 5-HT1D-like serotonin receptors on trigeminovascular nerve endings. We sought molecular evidence for the expression of an mRNA species encoding the 5-HT1D receptor subtype in guinea pig and human trigeminal ganglia, using the polymerase chain reaction with oligonucleotides uniquely homologous to the coding sequences of the 5-HT1B/D family (human 5-HT1D alpha and 5-HT1D beta; rat 5-HT1B). A single band of predicted size was observed in samples from guinea pig trigeminal ganglia; sequence analysis revealed the presence of a single message, which was 85% and 71% identical to the human 5-HT1D alpha and 5-HT1D beta receptor DNA sequences, respectively. Similar analyses of postmortem human trigeminal ganglia revealed the presence of 5-HT1D alpha, but not 5-HT1D beta, receptor message. Inasmuch as one recent report found that mRNA encoding only the 5-HT1D beta receptor subtype was expressed by vascular smooth muscle of the central nervous system, the present findings suggest the importance of developing selective 5-HT1D alpha receptor agonists as a strategy to reduce the risk of myocardial infarction and possibly stroke that complicates the acute treatment of migraine headache.

Animals↗
PubMed1994

Pretreatment with intraventricular basic fibroblast growth factor decreases infarct size following focal cerebral ischemia in rats.

Basic fibroblast growth factor is a polypeptide with potent multipotential trophic effects on central nervous system cells, including neurons, glia, and endothelial cells. In particular, it promotes the survival of a wide variety of brain neurons in vitro, and protects these neurons against the effects of several neurotoxins, including excitatory amino acids, hypoglycemia, and calcium ionophore. Since lack of substrate delivery, excitatory amino acid toxicity, and calcium entry into cells appear to be important processes in neuronal death after ischemia, we tested the hypothesis that pretreatment with basic fibroblast growth factor limits infarct size in a model of focal cerebral ischemia in vivo. Mature male Long-Evans rats received either continuous intraventricular infusion of basic fibroblast growth factor (1.2 micrograms/day; with or without heparin, added to stabilize the growth factor) or vehicle alone for 3 days before focal ischemic infarcts were made in the right lateral cerebral cortex by permanent distal middle cerebral artery occlusion and temporary (45-minute) bilateral carotid occlusion. Intraoperative measurements of core temperature, arterial blood pressure and blood gases, blood glucose concentration, and hematocrit, and postoperative measurements of temperature revealed no differences among vehicle- versus basic fibroblast growth factor-treated animals. Twenty-four hours later, animals were killed, brains were removed and stained to visualize cortical infarcts, and infarct volume was determined by image analysis. Overall, we found a 25% reduction in infarct volume in basic fibroblast growth factor- (N = 25) versus vehicle-treated (N = 23) animals (p < 0.01). This reduction was not enhanced by the addition of heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Dual role of nitric oxide in focal cerebral ischemia.

The importance of nitric oxide (NO) in the pathophysiology of cerebral ischemia was examined following middle cerebral artery occlusion in rats. A significant increase in infarct size developed following inhibition of NO synthase (NOS) activity by L-arginine analogues whereas intravenous L-arginine dose-dependently decreased infarct volume in the same models. Protection after L-arginine administration was associated with enhanced blood flow within the perinfarct zone as demonstrated by simultaneous recording of rCBF and electrocorticogram activity within subjacent brain. Selective NOS inhibition by 7-nitroindazole (7-NI) significantly reduced infarct volume at doses of 25 and 50 mg kg and in amounts that did not decrease the response of pial vessels to topical acetylcholine. Together these data suggest that enhanced NO production within the cerebrovasculature protects brain tissue during focal ischemia via hemodynamic mechanisms whereas neuronal overproduction may facilitate or mediate neurotoxicity. Recent data using transgenic animals lacking NOS activity support the latter conclusion.

Acetylcholine↗
PubMed1994

Basic fibroblast growth factor dilates rat pial arterioles.

Basic fibroblast growth factor (bFGF) is a polypeptide that promotes the survival and differentiation of brain neurons, glia, and endothelial cells. It has been shown recently that intravenously administered bFGF lowers blood pressure by systemic vasodilation; this effect is mediated, in part, by nitric oxide (NO)-dependent mechanisms. In the current study, we directly evaluated the effect of bFGF on pial arterioles of pentobarbital-anesthetized Sprague-Dawley rats (n = 18) using the closed cranial window technique. Basic FGF (5-200 ng/ml) produced dose-dependent vasodilation; maximal vessel diameter (approximately 120% of control) was reached at 100 ng/ml. No vasodilation was found when bFGF was heat inactivated, or preincubated with blocking antibody. Moreover, bFGF-induced vasodilation was attenuated by coadministration of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), consistent with an NO-dependent mechanism. These results suggest that bFGF may play an important role in the regulation of cerebrovascular tone and cerebral blood flow.

Administration, Topical↗
PubMed1994

The NOS inhibitor, 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels.

We examined whether 7-nitroindazole (7-NI), a putative inhibitor of neuronal nitric oxide synthase (nNOS), decreases cerebral infarction 24 h after proximal middle cerebral artery (MCA) occlusion. In preliminary experiments, we determined that 7-NI (25, 50, and 100 mg/kg i.p.) decreased nitric oxide synthase (NOS) activity within cerebral cortex by 40-60% when measured up to 120 min, but not 240 min after administration. At 25 or 50 mg/kg, 7-NI did not alter the systemic arterial blood pressure or the dilation of pial arterioles after topical acetylcholine (10 and 100 microM). To examine the effect of 7-NI on infarct size, 55 Sprague-Dawley halothane-anesthetized rats were subjected to proximal MCA occlusion (modified Tamura method). Five minutes after occlusion, 7-NI (25 or 50 mg/kg i.p.) or vehicle was injected. Animals treated with 25 or 50 mg/kg showed 25 and 27% reductions in infarct volume, respectively. Coadministration of L-arginine (300 mg/kg i.p.) plus 7-NI (25 mg/kg i.p.) reversed the effect. If, indeed, the effects of 7-NI are mediated by inhibition of nNOS activity, these results suggest that enzymatic products of the neuronal isoform promote ischemic injury and that they do so at least within the first few hours after permanent occlusion. The results also emphasize the importance of developing strategies to selectively inhibit the neuronal isoform inasmuch as we observed previously that administering the less selective NOS inhibitor, N omega-nitro-L-arginine (L-NA), in the same model either caused no change or increased the volume of ischemic injury.

Acetylcholine↗
PubMed1994

Cerebral blood flow changes during cortical spreading depression are not altered by inhibition of nitric oxide synthesis.

CBF increases concomitantly with cortical spreading depression (CSD). We tested the hypothesis that CBF changes during CSD are mediated by nitric oxide (NO). Male Wistar rats (n = 23) were subjected to KCl-induced CSD before and after administration of nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine (L-NNA) or N-nitro-L-arginine methyl ester (L-NAME) and in nontreated animals. CBF, CSD, and mean arterial blood pressure were recorded. Brain NOS activity was measured in vitro in control, L-NNA, and L-NAME-treated rats by the conversion of [3H]arginine to [3H]citrulline. Our data show that the NOS inhibitors did not significantly change regional CBF (rCBF) during CSD, even though cortical NOS activity was profoundly depressed and systemic arterial blood pressure was significantly increased. Our data suggest that rCBF during CSD in rats is not regulated by NO.

Amino Acid Oxidoreductases↗
PubMed1994

Nitric oxide synthase inhibition and cerebrovascular regulation.

There is increasing evidence that nitric oxide (NO) is an important molecular messenger involved in a wide variety of biological processes. Recent data suggest that NO is also involved in the regulation of the cerebral circulation. Thus, NO participants in the maintenance of resting cerebrovascular tone and may play an important role in selected vasodilator responses of the cerebral circulation. Furthermore, evidence has been presented suggesting that NO participates in the mechanisms of cerebral ischemic damage. Despite the widespread attention that NO has captured in recent years and the large number of studies that have been published on the subject, there is considerable controversy regarding the role of this agent in cerebrovascular regulation and in ischemic damage. In this paper the results of investigations on NO and the cerebral circulation are reviewed and the evidence for and against a role of NO is critically examined.

Amino Acid Oxidoreductases↗
PubMed1994

Importance of nitric oxide synthase inhibition to the attenuated vascular responses induced by topical L-nitroarginine during vibrissal stimulation.

We assessed the regional cerebral blood flow (rCBF) response to vibrissal stimulation before and after nitric oxide synthase (NOS) inhibitors were topically applied through a closed cranial window placed over the cortical barrel fields in anesthetized Sprague-Dawley rats. In the presence of L-nitroarginine (1 mM), both the maximum and total responses became reduced, but only in those animals demonstrating > 50% inhibition of NOS activity as determined by the conversion of [3H]arginine to [3H]citrulline within homogenates taken from cortical gray matter under the cranial window. The degree of enzyme inhibition depended in part, upon duration after topical application of NOS inhibitor. When > 50%, enzyme inhibition correlated with the decrease in maximum and total rCBF response (p < 0.01). These findings emphasize the merits of assessing enzyme activity after administering NOS inhibitors, and suggest that NO generated from parenchymal NOS activity plays an important role in the cerebrovascular response to physiologic somatosensory stimulation under the stated conditions.

Amino Acid Oxidoreductases↗
PubMed1994

Blockade by oral or parenteral RPR 100893 (a non-peptide NK1 receptor antagonist) of neurogenic plasma protein extravasation within guinea-pig dura mater and conjunctiva.

1. The ability of an NK1 receptor antagonist, RPR 100893, and its enantiomer, RPR 103253 to block neurogenic plasma protein extravasation in guinea-pig dura mater and conjunctiva was assessed following 125I-labelled bovine serum albumin ([125I]-BSA, 50 muCi kg-1, i.v.) and unilateral electrical stimulation of the trigeminal ganglion (0.6 mA, 5 ms, 5 Hz, 5 min) or capsaicin administration (150 micrograms kg-1, i.v.). 2. When administered p.o. 60 min prior to electrical stimulation, RPR 100893 (> or = 0.1 microgram kg-1) decreased plasma protein extravasation in dura mater in a dose-dependent manner, whereas the enantiomer (10 or 100 micrograms kg-1, p.o.) was inactive. 3. When given i.v. 30 min prior to electrical stimulation, RPR 100893 (> or = 0.5 ng kg-1) significantly inhibited plasma protein extravasation in the dura mater evoked by electrical stimulation in a dose-dependent manner. 4. RPR 100893 (100 micrograms kg-1, p.o.) also reduced the leakage when given 45 min before the guinea-pigs were killed and 10, 40 and 80 min after electrical trigeminal stimulation. 5. RPR 100893 given p.o. dose-dependently inhibited capsaicin-induced plasma protein extravasation with ID50S of 7.4 micrograms kg-1 and 82 micrograms kg-1 for dura mater and conjunctiva, respectively. 6. These results are consistent with the contention that NK1 receptors mediate neurogenic plasma protein leakage following trigeminal stimulation, and suggest that NK1 receptor antagonists of the perhydroisoindolone series may be useful for treating migraine and cluster headaches.

Administration, Oral↗
PubMed1994

The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia.

Nitrogen monoxide (NO) has recently emerged as an important mediator of cellular and molecular events which impacts the pathophysiology of cerebral ischemia. Although tempting to ask whether NO is "good or bad" for cerebral ischemia, the question underestimates the complexities of NO chemistry and physiology as well as oversimplifies the pathophysiology of focal cerebral ischemia. Important vascular and neuronal actions of NO have been defined which both enhance tissue survival and mediate cellular injury and death, and these will be reviewed. Strategies which modify NO synthesis and/or metabolism may someday assume therapeutic importance, but not until the tissue compartments generating NO, the activities of the enzymes that are inducibly and constitutively expressed, and the redox state of NO during the stages of ischemic injury, are defined with greater precision. Our knowledge of these processes is rudimentary. This review will summarize the evidence from animal models which supports an emerging role for NO in ischemic pathophysiology. Important aspects of NO synthesis and inhibitors of this process will also be discussed.

Amino Acid Oxidoreductases↗
PubMed1994

Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia.

The reduction in focal infarct volume after L-arginine has been attributed to an increase in regional cerebral blood flow (rCBF) within ischemic tissue. We tested the hypothesis that L-arginine-induced rCBF increases precede the recovery of spontaneous electrical activity [electrocorticogram (ECoG)] in spontaneously hypertensive rats subjected to middle cerebral artery (MCA) occlusion. ECoG was recorded from the penumbral region of parietal cortex by a glass microelectrode inserted into 1-mm3 cortical tissue from which blood flow was sampled by laser-Doppler flowmetry. rCBF dropped to 21 +/- 8% of the preischemic level, and ECoG was depressed by 64 +/- 13% after distal MCA occlusion. L-Arginine infusion (300 mg/kg i.v.) increased rCBF in 14 out of 18 rats, and ECoG significantly recovered in seven rats in which rCBF exceeded 31% of preischemic flow. Increases in rCBF anticipated the functional improvement in every case. Saline (n = 6) or D-arginine (n = 5) administration was ineffective. These data demonstrate that increasing rCBF can promote functional recovery in the ischemic brain and suggest that early administration of L-arginine or other vasodilators may enhance tissue survival by increasing rCBF.

Animals↗
PubMed1994

L-NNA decreases cortical hyperemia and brain cGMP levels following CO2 inhalation in Sprague-Dawley rats.

The role of nitric oxide (NO) in the response to 5% CO2 inhalation was investigated by measuring 1) regional cerebral blood flow (rCBF) by laser-Doppler flowmetry and pial vessel diameter through a closed cranial window after topical NG-nitro-L-arginine (L-NNA, 1 mM), and 2) the time-dependent changes in brain guanosine 3',5'-cyclic monophosphate (cGMP) levels after L-NNA (10 mg/kg ip). When L-NNA (but not NG-nitro-D-arginine) was applied topically for 30 or 60 min, the response to hypercapnia was significantly attenuated. A correlation was found between inhibition of brain NO synthase (NOS) activity and the rCBF response (r = 0.77; P < 0.01). However, L-NNA applied 15 min before hypercapnia did not attenuate the increase in rCBF but did attenuate the dilation to topical acetylcholine. Inhalation of CO2 (5%) elevated brain cGMP levels by 20-25%, and L-NNA reduced this response. These data from the rat suggest that 1) a product of NOS activity is associated with hypercapnic hyperemia and the attendant increase in brain cGMP levels, and 2) hypercapnic blood flow changes may not be dependent on endothelial NOS activity within pial vessels.

Acetylcholine↗
PubMed1994

L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat.

BACKGROUND AND PURPOSE: We previously reported that L-arginine infusion increased pial vessel diameter by nitric oxide-dependent mechanisms, improved regional cerebral blood flow (rCBF) distal to middle cerebral artery (MCA) occlusion, and reduced infarction volume in spontaneously hypertensive rats when administered intraperitoneally before and after MCA occlusion. In this report we extend our findings (1) by examining the time course of L-arginine on rCBF and pial vessel diameter under basal conditions and on rCBF after MCA occlusion and (2) by reproducing the protective effect of L-arginine on infarct volume when given intravenously immediately after the onset of MCA occlusion in both normotensive and hypertensive models of focal cerebral ischemia. METHODS: Changes in pial vessel diameter (closed cranial window) and rCBF (laser-Doppler flowmetry) were measured over time after L-arginine infusion into anesthetized Sprague-Dawley rats. rCBF was also measured distal to MCA occlusion in a brain region showing rCBF reductions in the range of 80% of baseline. The effects of infusing L-arginine (300 mg/kg for 10 minutes beginning 5 minutes after occlusion) were assessed on infarction volume in Sprague-Dawley rats after proximal MCA occlusion and in spontaneously hypertensive rats after common carotid artery plus distal MCA occlusion. RESULTS: L-Arginine (300 mg/kg IV) elevated rCBF by 20% when measured in the dorsolateral cortex of Sprague-Dawley rats and caused L-nitroarginine-methyl ester-inhibitable increases in pial vessel diameter. L-Arginine (> or = 30 mg/kg IV) increased blood flow distal to MCA occlusion by 50%. These effects were sustained throughout the observation period (70 to 105 minutes). Changes in mean arterial blood pressure were not observed. L-Arginine (300 mg/kg IV) reduced infarction volume by 35% and 28% in Sprague-Dawley and spontaneously hypertensive rats, respectively, when examined 24 hours after vessel occlusion. CONCLUSIONS: These studies extend our previous findings by demonstrating that exogenous L-arginine induces sustained rCBF increases in normal brain as well as in a marginally perfused brain region distal to MCA occlusion. Our data in Sprague-Dawley rats support the conclusion that L-arginine-induced increases in rCBF can decrease infarction volume. We conclude that nitric oxide-mediated mechanisms increase rCBF and decrease infarction volume after MCA occlusion in both normotensive and hypertensive animals.

Amino Acid Oxidoreductases↗
PubMed1993

Comparing the status of women and men in academic medicine.

OBJECTIVE: To explore the status and academic productivity of women compared with men in academic internal medicine. DESIGN: Mail survey done in 1986. SETTING: A total of 107 major teaching hospitals in the United States. PARTICIPANTS: Full-time (1693 of 2510) faculty in cardiology, rheumatology, and general internal medicine; 67% of eligible men and 70% of eligible women. MEASUREMENTS: Academic productivity defined as research grants awarded, abstracts accepted, and papers published in refereed journals; academic advancement as determined by academic rank and tenure status; and monetary compensation. RESULTS: Women entered academic medicine with shorter periods of fellowship training and were less likely to be members in the Alpha Omega Alpha honor society, but they had job descriptions similar to those of men, with similar allocation of work between research, clinical, and teaching activities. After adjustment, women and men were similar in the numbers of research grants funded as principal investigator (1.9 compared with 2.0), abstracts accepted (6.8 compared with 6.1), and papers published in refereed journals (28.8 compared with 29.2; all with P > 0.20). Women were as likely as men to have tenure, but they had lower academic rank (full or associate professor; 33% compared with 47%, P < 0.001) and received less compensation ($72,000 compared with $79,600 annually; P < 0.001). CONCLUSION: Although women do similar professional tasks and achieve similar levels of academic productivity, they receive fewer rewards for their work, both in academic rank and monetary compensation.

Achievement↗
PubMed1993

Conformationally restricted sumatriptan analogues, CP-122,288 and CP-122,638 exhibit enhanced potency against neurogenic inflammation in dura mater.

CP-122,288 and CP-122,638 blocked plasma protein extravasation response within dura mater following trigeminal ganglion stimulation. The threshold (1 and 0.1 pmol/kg, respectively) was remarkably lower than for sumatriptan (7 nmol/kg), as was the dose at maximum response. As with sumatriptan, substance P-induced plasma leakage was unaffected by either compound, and metergoline only partially (27%) reversed the effects of CP-122,288. The data suggest the importance of modifications at the aminoethyl side chain to the actions of sumatriptan and possibly to the treatment of migraine headache.

Animals↗
PubMed1993

Predicting the occurrence of adverse events after coronary artery bypass surgery.

OBJECTIVE: To determine whether adverse events occurring after coronary artery bypass surgery in Medicare patients can be predicted from clinical variables representing illness severity at admission. DESIGN: Retrospective analysis of clinical data abstracted from hospital charts, with development and validation using half-samples of the database. A logistic model was developed using illness severity at admission to predict the occurrence of an adverse event after bypass surgery. SETTING: Hospitals in seven states. PATIENTS: Random sample of 2213 Medicare patients 65 years of age or more who underwent bypass surgery between January 1985 and June 1986. OUTCOME MEASURE: The occurrence of death within 30 days of admission or any of 13 nonfatal postoperative adverse events (for example, myocardial infarction, congestive heart failure, and wound infection). RESULTS: Thirty-three percent of patients had one or more postoperative adverse events or died within 30 days of admission. Mortality within 30 days of admission was 6.6%; each adverse event was associated with increased mortality (range, 7.5% to 66.7%). Admission predictors of the occurrence of an adverse event included a history of bypass surgery, emergent surgery, a history of chronic obstructive pulmonary disease, the presence of an infiltrate on admission chest radiograph, a pulse of 110 beats/min or more, age, blood urea nitrogen of 10.7 mmol/L (30 mg/dL) or more, acute myocardial infarction at admission, and a history of myocardial infarction; the presence of one- or two-vessel disease was negatively associated with the occurrence of an adverse event. The model c-statistic was 0.64. CONCLUSIONS: Severity of illness at admission has modest predictive power with respect to adverse-event occurrence in Medicare patients who undergo bypass surgery.

Aged↗
PubMed1993

Screening flexible sigmoidoscopy: patient attitudes and compliance.

OBJECTIVE: To measure patients' expectations and attitudes about screening flexible sigmoidoscopy and their discomfort during the procedure, and to identify factors affecting compliance among patients scheduled for sigmoidoscopy. DESIGN: Patient survey at the time sigmoidoscopy was ordered and again one week after the procedure was performed. SETTING: An academic general internal medicine practice. PATIENTS: 105 consecutive patients scheduled for screening flexible sigmoidoscopy. MAIN RESULTS: Seventy-five percent of patients (79/105) scheduled for sigmoidoscopy complied with the procedure. Compliance was higher among men and among patients who had family histories of colon cancer. Although many patients experienced moderate to extreme embarrassment (27%), discomfort (42%), and pain (31%), patients experienced less embarrassment (p = 0.03) and pain (p = 0.02) than they had expected. Patients aged 65 years and older were twice as likely as younger ones (52% versus 25%) to experience moderate to extreme pain (p = 0.04). Only 1.4% of patients reported that they would probably not have the test again. CONCLUSION: Although flexible sigmoidoscopy is an uncomfortable procedure for some patients, especially those aged 65 and older, in general it is not as bad as patients expect and most would have the test again. Therefore, rather than assuming sigmoidoscopy is too uncomfortable for all patients to tolerate as a screening test, clinicians should inform their patients about the potential benefits and risks of sigmoidoscopy and about what the patient can expect during the procedure, thus enabling the patient to make an informed decision about whether to undergo screening sigmoidoscopy.

Aged↗