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Biomedical subjects

J M Perry

Publications and source records attributed to J M Perry.

At least 19 recordsLinked to original sources
PubMed2000

Cu2+ and Zn2+ inhibit nitric-oxide synthase through an interaction with the reductase domain.

Cu(2+) and Zn(2+) inhibit all of the NADPH-dependent reactions catalyzed by neuronal nitric-oxide synthase (nNOS) including ferricytochrome c reduction, NADPH oxidation, and citrulline formation. Cu(2+) and Zn(2+) also inhibit ferricytochrome c reduction by the independent reductase domain. Zn(2+) affects all activities of the full-length nNOS and the reductase domain to the same extent (estimated IC(50) values from 9 to 31 microm), suggesting Zn(2+) occupation of a single site in the reductase domain. Citrulline formation and NADPH oxidation by the full-length nNOS and ferricytochrome c reduction by the reductase domain are affected similarly by Cu(2+), with estimated IC(50) values ranging from 6 to 33 microm. However, Cu(2+) inhibits ferricytochrome c reduction by the full-length nNOS 2 orders of magnitude more potently, with an estimated IC(50) value of 0.12 microm. These data suggest the possibility that Cu(2+) may interact with nNOS at two sites, one composed exclusively of the reductase domain (which is perhaps also involved in Zn(2+)-mediated inhibition), and another that includes components of both domains. Occupation of the second (higher affinity) site could then promote the selective inhibition of ferricytochrome c reduction in full-length nNOS. Neither the inhibition by Cu(2+) nor that by Zn(2+) is dependent on calmodulin.

Calmodulin↗
PubMed1998

Effects of transition metals on nitric oxide synthase catalysis.

The biosynthesis of nitric oxide (NO) by the enzyme NO synthase (NOS) proceeds by the hydroxylation of L-arginine to form NG-hydroxy-L-arginine followed by the conversion of NG-hydroxy-L-arginine to L-citrulline and NO. The previously identified requirements of this relatively complicated reaction include several protein-bound cofactors: cytochrome P450-type heme, flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), and tetrahydrobiopterin (H4B). In addition to L-arginine, NOS also requires the substrates NADPH and molecular oxygen. The role of H4B in NOS catalysis has long been a subject of debate and uncertainty fueled, in part, by the failure to detect any dependence of the NOS reaction on nonheme iron, a cofactor integral to catalysis in every other H4B-dependent enzyme. Here we report the ability of NOS to bind transition metals stoichiometrically, and demonstrate that the rate of catalysis is enhanced by nonheme iron. We also show that other divalent transition metals, including Cu, Zn, Co, and Ni, inhibit NOS catalysis. Also, the addition of Cu2+ to NOS inhibits heme reduction, whereas the addition of Fe2+ does not. Overall, the results appear to connect NOS to the known H4B/nonheme iron-dependent hydroxylases, and suggest a similar, if not identical, step in the NOS reaction mechanism.

Animals↗
PubMed1998

The high-potential flavin and heme of nitric oxide synthase are not magnetically linked: implications for electron transfer.

BACKGROUND: The homodimeric nitric oxide synthase (NOS) catalyzes conversion of L-arginine to L-citrulline and nitric oxide. Each subunit contains two flavins and one protoporphyrin IX heme. A key component of the reaction is the transfer of electrons from the flavins to the heme. The NOS gene encodes two domains linked by a short helix containing a calmodulin-recognition sequence. The reductase domain binds the flavin cofactors, while the oxygenase domain binds heme and L-arginine and additionally mediates the dimerization of the NOS subunits. We investigated the origin of the unusual magnetic properties (rapid-spin relaxation) of an air-stable free radical localized to a reductase domain flavin cofactor. RESULTS: We characterized the air-stable flavin in wild-type NOS, both in the presence and absence of calcium and calmodulin, the imidazole-bound heme complex of wild-type NOS, the NOS Cys415-->Ala mutant, and the isolated reductase domain. All preparations of NOS had the same flavin electron-spin relaxation behavior. No half-field transitions or temperature-dependent changes in the linewidth of the radical spin signal were detected. CONCLUSIONS: These data suggest that the observed relaxation enhancement of the NOS flavin radical is caused by the environment provided by the reductase domain. No magnetic interaction between the heme and flavin cofactors was detected, suggesting that the flavin and heme centers are probably separated by more than 15 A.

Animals↗
PubMed1995

Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus.

The neuroprotective effects of enhancing neuronal inhibition with a gamma-aminobutyric acid (GABA) uptake inhibitor were studied in gerbil hippocampus following transient ischemia. We used in vivo microdialysis to determine a suitable dosing regimen for tiagabine (NNC328) to elevate extracellular levels of GABA within the hippocampus. In anesthetized (normothermic) gerbils, tiagabine (45 mg/kg, i.p.) selectively elevated extracellular GABA levels 450% in area CA1 of the hippocampus. In gerbils subjected to cerebral ischemia via 5-min bilateral carotid occlusion, extracellular GABA levels increased 13-fold in area CA 1 returning to baseline within 30-45 min. When tiagabine was injected 10 min following onset of reperfusion, GABA levels remained elevated (200-470%) for 90 min. In addition, tiagabine significantly reduced the ischemic-induced elevation of glutamate levels in area CA1 during the postischemic period when GABA levels were elevated. There was no effect of postischemic tiagabine on aspartate or six other amino acids. Using the same dosing regimen, we evaluated the degree of neuroprotection in the hippocampus of gerbils 4 and 21 days after ischemia. Tiagabine decreased body temperature a maximum of 2.7 degrees C beginning 30 min into reperfusion and lasting 90 min. In untreated gerbils sacrificed 4 and 21 days after ischemia, there was severe necrosis (99%) of the pyramidal cell layer in area CA1. Whereas tiagabine significantly protected the CA1 pyramidal cell layer in ischemic gerbils at 4 days (overt necrosis confined to about 17% of area CA1), the protection diminished significantly 21 days postischemia. When normothermia was maintained both during and after ischemia in a separate group of tiagabine-treated animals, approximately 77% of the CA1 pyramidal cell layer was necrotic at 4 days. Based on these findings, we suggest that 1) tiagabine slows the development of hippocampal degeneration following ischemia, and 2) that mild, postischemic hypothermia is responsible, in large part, for the neuroprotective actions of this drug. We conclude that the histological outcome after administration of cerebral neuroprotectants should be assessed following long-term survival.

Animals↗
PubMed1995

Diazepam, given postischemia, protects selectively vulnerable neurons in the rat hippocampus and striatum.

Following cerebral ischemia, certain populations of neurons degenerate. Excessive accumulation of excitatory amino acids in the synaptic cleft, activation of excitatory amino acid receptors, and influx of calcium into neurons play a key role in the development of ischemia-induced neuronal death. We hypothesized that neuroprotection may be achieved by enhancing inhibitory (i.e., gamma-aminobutyric acid, GABA) neurotransmission to offset excitation. Diazepam, a drug that increases GABA-induced chloride channel opening, was administered (10 mg/kg, i.p.) to rats 1 and 2 hr following 15 min of transient global ischemia, when hippocampal GABA levels, increased during ischemia, returned to basal. Rats were maintained normothermic during ischemia and became hypothermic following the injections of diazepam. Four days later, rats were sacrificed and the brains were examined for neuronal degeneration and the presence of GABAA receptors labeled by 35S-t-butylbicyclophosphorothionate (35S-TBPS). There was substantial neuroprotection of striatal neurons and pyramidal neurons in the CA1 area of the hippocampus. In addition, diazepam prevented the loss of 35S-TBPS binding sites in the striatum and in the dendritic fields of the CA1 hippocampus following ischemia. Since hypothermia, itself, is neuroprotective, we determined if hypothermia was required for the ability of diazepam to produce neuroprotection. Diazepam was microinjected into the CA1 hippocampus 1 and 2 hr following ischemia, and rats remained normothermic. Four days later, diazepam still produced substantial protection of hippocampal neurons. Thus, postischemic hypothermia may have contributed to the neuroprotection by diazepam when it was administered systemically, but the neuroprotective effect of diazepam did not require hypothermia. We conclude that delayed enhancement of GABAergic neurotransmission directly at the site of vulnerability following an ischemic event protects the vulnerable neurons from death.

Animals↗
PubMed1991

Intercoronary connection and apical left ventricular hypertrophy: case report and review of the literature.

Cardiac catheterization in a 55-year-old man, presenting with chronic chest pain and new T wave inversion, showed apical left ventricular (LV) hypertrophy and a large intercoronary connection between the posterior descending artery (PDA) and left anterior descending (LAD). Although the LAD was normal, selective angiography of the right coronary artery (RCA) filled the LAD retrogradely. Possible mechanisms and the literature are reviewed.

Angina Pectoris↗
PubMed1991

Demonstration of myocardial reperfusion injury in humans: results of a pilot study utilizing acute coronary angioplasty with perfluorochemical in anterior myocardial infarction.

Reperfusion may limit the amount of potentially salvageable myocardium through the introduction of cellular elements into previously ischemic but viable myocardium (reperfusion injury). It has been demonstrated that intracoronary infusion of a 20% intravascular perfluorochemical emulsion (Fluosol) significantly reduces infarct size and results in improved left ventricular function in the canine model. This pilot study was performed to explore the existence of myocardial reperfusion injury in humans. Utilizing Fluosol as a probe in conjunction with emergency coronary angioplasty, 26 patients presenting within 4 h with a first anterior myocardial infarction were randomized to emergency angioplasty or angioplasty followed by a 30-min intracoronary infusion of Fluosol at 40 ml/min. Global and regional ventricular function were assessed immediately and a mean of 12 days after successful angioplasty with contrast ventriculography. Infarct size was semiquantitated with thallium-201 single-photon emission computed tomography (SPECT) images before discharge. Twelve patients (six undergoing angioplasty alone, six treated with angioplasty and Fluosol) had an occluded infarct-related vessel (Thrombolysis in Myocardial Infarction [TIMI] grade 0 to 1) at the time of emergency catheterization and were included in the final analysis. At 12 days after successful angioplasty, the improvement in regional ventricular function was greater in patients receiving adjunctive therapy with intracoronary Fluosol versus those undergoing angioplasty alone utilizing both the radial shortening and centerline method, respectively (23 +/- 3.1% vs. 8 +/- 2.3%, p less than 0.02; and -1.6 +/- 0.4 vs. -2.9 +/- 0.2 SD/chord, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1988

Intracoronary verapamil for reversal of refractory coronary vasospasm during percutaneous transluminal coronary angioplasty.

Coronary artery spasm unresponsive to intracoronary nitroglycerin was observed in eight patients undergoing percutaneous transluminal coronary angioplasty for unstable ischemic symptoms (unstable angina or recent nontransmural infarction, or both). All patients manifested eccentric lesions angiographically with the right coronary artery involved in four, circumflex artery in two and left anterior descending in two. Severe coronary spasm was documented angiographically in all patients after angioplasty and resulted in symptomatic and electrocardiographic evidence of ischemia. Multiple sites of spasm were present in the dilated vessel in three patients. Coronary artery spasm persisted despite the infusion of large doses of intracoronary nitroglycerin (200 to 2,000 micrograms, mean 850 micrograms) over 10 min. Administration of intracoronary verapamil (1 to 1.5 mg over 10 min) resulted in complete relief of spasm with restoration of brisk anterograde flow in all patients. These findings suggest that intracoronary verapamil may be a useful agent for the relief of coronary spasm occurring in the setting of coronary angioplasty.

Adult↗
PubMed1987

Iatrogenic pseudoanaphylaxis.

A nurse exposed accidentally to chymopapain by ocular exposure was treated vigorously for chymopapain anaphylaxis. Retrospective analysis of the case indicates that there was no evidence of IgE antibody against chymopapain, and the clinical events were inconsistent with anaphylaxis and could be explained by a vasovagal reaction and the cardiorespiratory effects of repeated intravenous epinephrine. Our assessment is that the nurse is currently in a state of good health; however, she did not accept our absence of allergic disease diagnosis and has sought "clinical ecology therapy." Although no litigation in this case has arisen, the legal implications of this case report are reviewed.

Adult↗
PubMed1986

Determinants of left ventricular aneurysm formation after anterior myocardial infarction: a clinical and angiographic study.

To determine factors involved in left ventricular aneurysm formation after transmural anterior myocardial infarction, 79 patients with a first myocardial infarction who underwent cardiac catheterization within 6 months of infarction were evaluated. Patients who had received thrombolytic therapy were excluded. Patients were divided into four groups depending on the status of the left anterior descending artery and the presence or absence of a left ventricular aneurysm: Group I (n = 25): aneurysm with occluded left anterior descending artery; Group II (n = 27): no aneurysm and occluded left anterior descending artery; Group III (n = 23): no aneurysm and patent left anterior descending artery; and Group IV (n = 4): aneurysm with patent left anterior descending artery. Single vessel disease was more common in Group I (aneurysm) compared with Groups II and III (no aneurysm) (chi 2(4) = 12.8; probability value equal to 0.012). Collateral blood supply in the presence of an occluded left anterior descending artery was significantly less in Group I (aneurysm) compared with Group II (no aneurysm) (0.9 versus 2.4, p less than 0.001). The extent of coronary artery disease and collateral blood supply in Groups I and II were directly related (p = 0.012). Neither age, sex nor risk factors for coronary disease correlated with aneurysm formation. At a mean follow-up of 48 months, no differences were observed in the incidence of recurrent angina, new myocardial infarction, embolic events or sudden death. More patients in Group II underwent coronary artery bypass surgery. Total occlusion of the left anterior descending artery in association with inherent poor collateral blood supply is a significant determinant of aneurysm formation after anterior myocardial infarction. Multivessel disease with either good collateral circulation or a patent left anterior descending artery is uncommonly associated with the development of left ventricular aneurysm.

Angiography↗
PubMed1985

Correlation of saphenous vein bypass graft angiograms with histologic changes at necropsy.

Previous studies of saphenous vein (SV) bypass grafts have been either angiographic or morphologic, and few have correlated angiograms with histology. Nine necropsy patients who had received 21 SV implants 12 to 120 months (mean 67 +/- 42) before death were studied. All patients had severe coronary artery disease. Three types of histologic changes were found: atherosclerosis in 9 grafts, fibrointimal proliferation in 8 and total occlusion with fibrosis in 4. All patients had premortem angiograms 0 to 3 months (mean 0.7 +/- 1.1) before death. In 14 of 21 grafts, premortem angiograms accurately reflected the postmortem findings. In 7 grafts, the premortem angiograms either overestimated (4 grafts) or underestimated (3 grafts) the extent of luminal narrowing. Six of the 7 SV implants incorrectly assessed by angiography had fibrointimal proliferation and 1 had atherosclerosis. The presence of smooth muscle in SV implants with fibrointimal proliferation may be a mechanism of spasm or relaxation during angiography, which could cause errors in estimating the degree of stenosis. Nitrates or calcium antagonists may be useful in both assessing the degree of underlying vasomotion in SV grafts and as a therapeutic modality.

Aged↗
PubMed1984

Effect of tyramine on myocardial catecholamine release in coronary heart disease.

The influence of tyramine on myocardial catecholamine release and on coronary blood flow has not previously been determined in man. Therefore, the effect of tyramine was measured on coronary and systemic hemodynamics and on norepinephrine (NE) and epinephrine levels in blood from the aorta and coronary sinus in 9 patients with coronary artery disease. Tyramine produced a striking increase in coronary sinus NE, from a baseline of 344 +/- 56 to a peak level of 1416 +/- 310 pg/ml (p less than 0.01) 2 minutes after tyramine. The increase in aortic NE was less striking, from 265 +/- 32 to 421 +/- 63 pg/ml (difference not significant). Therefore, the net release of NE from the heart was increased by tyramine from 12,007 +/- 393 to 139,357 +/- 46,156 pg/ml/min (p less than 0.03). There was no release of epinephrine across the coronary bed. There was a variable response of coronary blood flow and resistance after tyramine. Thus, the rich innervation of the heart by sympathetic nerve endings can result in marked NE release into the coronary sinus.

Adult↗
PubMed1983

Evaluation of left ventricular performance using digital subtraction angiography.

Cardiac applications for digital subtraction angiography appear promising, but few correlative studies with contrast ventriculography have been done. Left ventricular volume, ejection fraction, and regional wall motion by digital subtraction angiography were evaluated after intravenous injection of 40 ml of iodinated contrast medium and after left ventricular injection of 5 to 10 ml of contrast medium. A film-based system of the authors' own design was used. Results were compared with those after direct left ventricular injection of 40 ml of contrast medium. The ventriculograms after intravenous injection were of diagnostic quality in 9 of 12 studies, and there were close correlations between intravenous and direct-injection studies for left ventricular ejection fraction (r = 0.89, n = 9, and p = 0.001) and for left ventricular volume (r = 0.91, n = 18, and p less than 0.001). Regional wall motion scores showed close correspondence in 83% of sectors. After small-volume left ventricular injections, the ventricular image was enhanced considerably by digital subtraction. Correlations between small- and large-volume ventriculograms were close for left ventricular ejection fraction (r = 0.91, n = 8, and p = 0.002) and for left ventricular volume (r = 0.96, n = 16, and p less than 0.001). There was close correspondence of wall motion scores in 87% of sectors. Thus, digital subtraction angiography improves the visibility of the left ventricle after either intravenous or small-volume direct left ventricular injection. Digital images produce excellent estimates of left ventricular volume and should have considerable usefulness for the study of cardiac performance and anatomy.

Adult↗
PubMed1983

Epithelial polyps of the prostatic urethra. A light-microscopic and immunohistochemical study.

Epithelial polyps of the prostatic urethra are an uncommon and histologically heterogeneous group of lesions. We review the clinical and histologic features of a series of seven such polyps. Six were composed of prostatic-type epithelium. In five instances the epithelium was entirely histologically identical to that of normal prostate. One case contained foci of stratified, mitotically active cells, suggesting adenomatous transformation. All six stained intensely for both prostatic acid phosphatase and prostatic specific antigen. The seventh polyp was cytologically different. It was composed of flattened to cuboidal cells that did not stain for either antigen. All patients were treated by transurethral excision, and none of the six with follow-up developed a recurrence.

Acid Phosphatase↗