Biomedical subjects

C A Hamilton

Publications and source records attributed to C A Hamilton.

At least 19 recordsLinked to original sources

PubMed1995

Imidazoline receptors, subclassification, and drug-induced regulation.

Overall, as summarized in TABLE 6, a variety of responses to chronic drug treatment were observed depending on the drug, the tissue, and the ligand. Taken together these studies support the concept that the three ligands bind to distinct sites. In addition, they suggest that idazoxan and possibly yohimbine act as agonists at the I2 site in kidney. Finally, the lack of regulation of the I1 site in hindbrain is consistent with the low incidence of withdrawal symptoms reported with imidazoline-preferring drugs.

Animals↗

PubMed1995

Near-resonance spin-lock contrast.

Spin-lock and spin-tip excitations are the two magnetization components created by the preparatory RF pulse of an MRI contrast enhancement sequence. Only spin-lock is inherently adiabatic, preserving spin alignment so that tissue-specific relaxation can generate desired saturation contrasts. Spin-tip is the rotating-frame oscillating excitation, and generally causes nonadiabatic loss of all detectable magnetization. Relative levels of spin-lock and spin-tip are important to understand as a function of the preparatory B1 delta amplitude, resonance frequency offset, delta, and the pulse waveform. These MR responses can be accurately analyzed theoretically and numerically by using Torrey's tipped coordinates to formulate Bloch's equations. At near-resonance offsets, (delta/gamma B1) less than 2.0, spin-lock contrast (SLC) depends strongly on T2, due to the nature of spin-lock T1 rho relaxation in the RF pulse interval. The relaxation rates 1/T1 rho and 1/T2 rho apply for active B1 delta, but remain linear combinations of ordinary (1/T1) and 1/T2) for motionally narrowed MR. The SLC increases rapidly as delta decreases below 2000 Hz; carefully chosen B1 delta rise times avoid spin-tip losses down to 150 Hz or less. The SL saturation enhances or multiplies any other indirect saturation effects that may be also present, such as magnetization transfer. A strong near-resonance SLC multiplier is advantageous for clinically practical MRI sequences that use short B1 delta pulses and fast SE multislice scan modes. Simulations based upon spin-lock/spin-tip theory and measured (T1,T2) yield excellent agreement with real MRI results for clinically practical fast multislice scans.

Computer Simulation↗

PubMed1995

Regulated expression of a contractile protein gene correlates with recovery of contractile function after reversible metabolic inhibition in cultured myocytes.

Little is known of the relation between recovery of contraction and the regulation of contractile protein gene expression in ventricular myocytes after severe ATP depletion. We have examined alterations in activation of an MLC-2 luciferase fusion gene in cultured neonatal rat ventricular myocytes produced by exposure to 2 mM Na CN and 20 mM 2-deoxyglucose, and after recovery is serum or serum free medium. The effects of metabolic inhibition followed by recovery on expression on an RSV-luciferase activity were also investigated. Myocytes were co-transfected with a CMV beta-galactosidase fusion gene, and luciferase activities were normalized relative to beta-galactosidase activity to control for transfection efficiency. Two hours of metabolic inhibition produced significant cell injury, as documented by disorganization of myofilaments, and reduction in luciferase and beta-galactosidase activity within transfected cells. Cells allowed to recover for 48 h in serum free hormone supplemented medium showed a further decline in corrected luciferase activity, consistent with a marked reduction in MLC-2 gene transcription. Cells recovered from severe metabolic inhibition in serum free medium also showed failure to redevelop contractile activity, and failure of redevelopment of organized myofibrils. In contrast, myocytes exposed to serum during the 48 h recovery period had a marked increase in luciferase activity, resumed contractile activity and re-established organized myofilaments. There were no significant differences between RSV luciferase activities in cells recovered in serum versus serum free media. In ventricular myocytes in which contraction was inhibited by exposure to 10 microM verapamil, MLC-2 luciferase activity declined by 87%. However, even when contractile activity was inhibited by exposure to verapamil during recovery from metabolic inhibition, exposure to serum containing medium caused a significantly greater increase in MLC-2 luciferase activity than did serum free medium. Thus, the effects of serum on MLC-2 gene expression were not solely due to an effect of serum on recovery of contractile activity. Verapamil had no consistent effect on expression of RSV luciferase. These results suggest that expression of the MLC-2 gene is markedly reduced following recovery from severe metabolic inhibition, an effect largely due to cessation of myocyte contractile activity. Resupply of growth factors present in fetal calf serum reactivate expression of this gene, and this is associated with resumption of contractile activity and redevelopment of organized myofibrils. These results suggest that reactivation of contractile protein gene expression during recovery from metabolic inhibition may be beneficial in allowing cells to recover from this insult.

Analysis of Variance↗

PubMed1995

Inducible L-arginine/nitric oxide pathway in human internal mammary artery and saphenous vein.

To characterize the L-arginine/nitric oxide (NO) pathway in human vascular smooth muscle (VSM), contractile responses of isolated internal mammary arteries (IMA) and saphenous veins (SV) were observed after induction of NO synthase by interleukin-1 beta (IL-1 beta) or by lipopolysaccharide (LPS). In IL-1 beta-treated endothelium-denuded rings, contractile responses to phenylephrine were reduced in SV rings only. Maximum phenylephrine-induced contraction was depressed by approximately 50%. This was not modified by the presence of indomethacin, NG-nitro-L-arginine methyl ester (L-NAME), or methylene blue (MeB). In LPS-treated vessels, contractile responses were depressed in both SV and IMA rings (40%), and this was not affected by indomethacin. In SV, L-NAME, NG-monomethyl-L-arginine, or MeB did not affect the inhibitory effect of LPS, whereas the effect was reversed in IMA by these inhibitors. In LPS-treated IMA, but not in SV, exogenous L-arginine evoked significant vasodilation (20%). We conclude that VSM of the human IMA possesses an L-arginine/NO pathway inducible by LPS. In SV, LPS or IL-1 beta treatment inhibits contraction by an unidentified system that is not dependent on NO synthase or on guanylate cyclase activities.

Aged↗

PubMed1995

Development and progression of atherosclerosis in aorta from heterozygous and homozygous WHHL rabbits. Effects of simvastatin treatment.

This study was conducted to define progression of atherosclerosis in both homozygous and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits and to investigate the ability of the HMG CoA reductase inhibitor simvastatin to attenuate progression of the disease. We examined contractile responses to phenylephrine and endothelium-dependent relaxation in response to carbachol in thoracic aorta at 3, 6, 9, and 12 months in control New Zealand White (NZW) rabbits, homozygous WHHL rabbits, and heterozygous WHHL rabbits. Homozygous and heterozygous rabbits were treated with simvastatin (10 mg/kg per day) from 3 to 6 months and from 9 to 12 months of age. Simvastatin significantly reduced serum cholesterol levels in young heterozygotes, with a nonsignificant trend toward a reduction in older heterozygotes. In homozygotes, no significant fall was observed. Contractile function declined progressively with age in all groups--most in homozygotes and least in NZW rabbits. Relaxation was unaffected by age in NZW rabbits; relaxation declined in the heterozygotes and declined to a greater extent in homozygotes. Simvastatin retarded the loss of function in the young heterozygotes. Similar trends were observed in young homozygotes and older heterozygotes, with no effect in older homozygotes. Histological studies revealed the progressive development of early atherosclerosis in heterozygotes, and more advanced atherosclerosis was observed in homozygotes. Simvastatin did not inhibit development of atheroma. A correlation was observed between vascular function and structure. However, functional changes preceded the development of atheroma. In addition, we have demonstrated that simvastatin can help to reduce the loss of vascular function associated with the progression of atherosclerosis in the heterozygous WHHL rabbit.

Age Factors↗

PubMed1995

Role of superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats.

We undertook these studies to determine whether a deficient nitric oxide production in genetically hypertensive rats could result from its being scavenged by an excess production of superoxide. In one study we used a porphyrinic microsensor to measure nitric oxide concentrations released by cultured endothelial cells from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). SHRSP cells released only about one third the concentration of nitric oxide as did WKY cells. Treatment of cells with superoxide dismutase increased nitric oxide release, demonstrating that normally nitric oxide is scavenged by endogenous superoxide. The increase in nitric oxide release in response to superoxide dismutase treatment was more than twice as great from SHRSP as from WKY cells, demonstrating the greater amount of superoxide in the hypertensive rats. A direct measure of superoxide with the use of lucigenin demonstrated the presence of 68.1 +/- 7.1 and 27.4 +/- 3.5 nmol/L of this anion in SHRSP and WKY endothelial cells, respectively. The presence of superoxide in the rat aorta was also estimated by quantification of its effect on carbachol relaxation. This relaxation was diminished when endogenous superoxide dismutase was blocked by diethyldithiocarbamic acid. This blockade reduced the relaxation by 51.2 +/- 5.2% in SHRSP aortas and by only 22.0 +/- 8.2% (P = .015) in WKY aortas. Data from these diverse systems are in agreement that superoxide production is excessive in SHRSP tissues. This excess superoxide, by scavenging endothelial nitric oxide, could contribute to the increased vascular smooth muscle contraction and hence to the elevated total peripheral resistance of these rats.

Animals↗

PubMed1995

Emergency physicians. Accuracy in the diagnosis of stroke.

BACKGROUND AND PURPOSE: The role of emergency physicians in trials of acute stroke therapy is expanding. We investigated the ability of emergency physicians to accurately identify patients with stroke. METHODS: We reviewed all 446 patients who were evaluated in the emergency department and had an inpatient admitting or discharge diagnosis of ischemic or hemorrhagic stroke from May 1, 1992, to June 30, 1993. The final admitting diagnosis made by the emergency physician was compared with the final hospital discharge diagnosis, 95% of which were made by neurologists or neurosurgeons. RESULTS: All 76 patients with a final discharge diagnosis of intracerebral or subarachnoid hemorrhage were correctly diagnosed by the emergency physicians (sensitivity, 100%; positive predictive value, 100%). Of the 351 patients with a final discharge diagnosis of ischemic stroke or transient ischemic attack, 346 were correctly identified by the emergency physicians (sensitivity, 98.6%; positive predictive value, 94.8%). Nineteen patients were diagnosed with stroke or transient ischemic attack by the emergency physician but had a final discharge diagnosis other than stroke. Discharge diagnoses included paresthesia or numbness of unknown causes (3), seizure (2), complicated migraine (2), peripheral neuropathy (2), cranial nerve neuropathy (2), psychogenic paralysis (1), and other (7). CONCLUSIONS: Emergency physicians at a large urban teaching hospital with a comprehensive stroke intervention program can accurately identify patients with stroke, particularly hemorrhagic stroke. If similar accuracy can be documented in other types of hospitals, emergency physicians may become key providers of urgent stroke intervention.

Adult↗

PubMed1995

Combined effects of magnetization transfer and gadolinium in cranial MR imaging and MR angiography.

Magnetization transfer (MT) imaging is an MR technique in which image contrast is altered by applying RF pulses that saturate a restricted pool of hydrogen protons associated with cell membranes, proteins, and other macromolecules. Protons in this restricted pool, unlike those in tissue-free water, are not visible on MR due to their short T2 relaxation times. However, these restricted protons modulate the observed signal from free water by dipolar and chemical exchange interactions. In MT imaging, specifically tailored RF pulses are applied to saturate selectively the restricted macromolecular pool. This saturation is "transferred" to the free protons, causing their signal amplitude to decrease [1]. Increased signal intensity due to T1 shortening caused by gadolinium administration does not depend upon macromolecular interactions and is not appreciably suppressed by MT pulses (Fig. 1). Consequently, MT pulses act synergistically with gadolinium to increase the visibility of enhancing lesions by preferentially suppressing nonenhancing background tissue [2]. The purpose of this paper is to demonstrate the principles underlying the synergistic effects of MT saturation and paramagnetic contrast agents and to illustrate these effects in clinical MR imaging and MR angiography.

Brain↗

PubMed1995

Pertussis toxin sensitive endothelin-1 coupling to inositol phosphate formation via a GTP-binding protein: comparison in SHR and WKY cultured aortic smooth muscle cells.

The effects of pertussis toxin on endothelin-1 and noradrenaline coupling to inositol phosphate (IP) formation was investigated in cultured aortic smooth muscle cells from 14 week SHR and WKY rats. Endothelin-1 (10(-6) M) stimulated IP formation was decreased in cells from SHR compared to WKY (WKY 1117 +/- 157, SHR 668 +/- 85% of basal). Pre-incubation with pertussis toxin produced a significant and similar reduction in endothelin stimulated IP production in both SHR (54% reduction) and WKY (55%). However, the observed reduction in endothelin-1 stimulated IP accumulation was still apparent in SHR when compared to WKY. Pertussis toxin preincubation followed by removal of extracellular calcium reduced further the endothelin responses by similar amounts in SHR and WKY cells, but SHR stimulated IP formation remained significantly decreased compared to WKY. The extent of pertussis toxin ADP-ribosylation of Gi alpha was similar in both SHR and WKY cells. Endothelin-1 produced a reduction in the extent of ADP-ribosylation of Gi alpha and this was of similar magnitude in both SHR and WKY cell membranes. In contrast, noradrenaline stimulated IP formation was unaffected by pertussis toxin pre-incubation. It was concluded that SHR cells do not appear to have an alteration in endothelin-1 activated, pertussis toxin sensitive G-protein coupling to IP formation or in the dependence of inositol phosphate formation on extracellular calcium.

Animals↗

PubMed1995

The effects of perindopril on vascular smooth muscle polyploidy in stroke-prone spontaneously hypertensive rats.

OBJECTIVE: To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. DESIGN: The following experimental groups were used: young (age < 20 weeks) and old (age > 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. METHODS: Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. RESULTS: The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. CONCLUSIONS: ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Signal transduction mechanisms of the vasoconstriction in hypertension.

We tested the hypothesis that vascular smooth muscle in genetic hypertension is characterised by hypereactivity to vasoactive agonists, by abnormalities in Ca2+ handling and the phosphoinositide signalling system. Activation of these signal transduction mechanisms by noradrenaline and endothelin-1 was compared in isolated perfused tail arteries from adult hypertensive and normotensive Wistar Kyoto rats. Basal cytosolic Ca2+ was greater in arteries from hypertensive rats, but basal perfusion pressure and basal inositol phosphate accumulation were unchanged. Contractile responses and Ca2+ mobilisation after noradrenaline, but not endothelin-1, were enhanced in arteries from hypertensive rats. Total inositol phosphates accumulation was similar in hypertensive and normotensive rats after either noradrenaline or endothelin-1 stimulation. In both hypertensive and normotensive rats, for a given Ca2+ mobilisation, higher contractile responses and higher levels of inositol phosphates were observed after endothelin-1 than noradrenaline stimulation. In conclusion, changes in contractility associated with modifications in the Ca2+ handling between hypertensive and normotensive rats suggested that alterations in the signal-transduction system occur with hypertension. The different effects of endothelin-1 and noradrenaline could be related to interactions with other signalling pathways.

Animals↗

PubMed1994

Chronic exposure of bovine aortic endothelial cells to native and oxidized LDL modifies phosphatidylinositol metabolism.

The aim of this study was to investigate the effects of chronic exposure to low density lipoprotein (LDL) and oxidised LDL (OXLDL) on phosphatidylinositol metabolism in bovine aortic endothelial cells. Basal levels of total inositol phosphates and inositol 1,4,5-trisphosphate were increased after both 18 and 66 h exposure to OXLDL 20 micrograms/ml. Levels also tended to be increased after exposure to LDL but this only reached significance for LDL 20 micrograms/ml after 18 h exposure. Absolute levels of inositol phosphates after stimulation with ATP were unaffected by incubation with LDL or OXLDL. However, when expressed as a percentage of basal levels, stimulated levels of inositol phosphates were reduced for ATP 10(-3) and 10(-4)M. Uptake of [3H]inositol into the phosphatidylinositol cycle was reduced after incubation with LDL and OXLDL for either 18 or 66 h. The effect of OXLDL was greater than that of LDL. The antioxidants EDTA and N-acetylcysteine attenuated the effects of LDL but not OXLDL. In addition, catalase but not mannitol or superoxide dismutase modified the effect of LDL on [3H]inositol uptake. These studies show that chronic exposure to OXLDL and to a lesser extent LDL can modify phosphatidylinositol metabolism in bovine aortic endothelial cells and that the effects of LDL may be attenuated by antioxidants and free radical scavengers. We hypothesise that the decreased uptake of [3H]inositol could be related to an alteration in membrane structure and integrity and may reflect alteration in transport of a number of ions and molecules.

Animals↗

PubMed1994

Correction of partial volume inaccuracies in quantitative phase contrast MR angiography.

The phase difference method of phase contrast MR angiography provides a means of measuring the average velocity in each voxel of an MR scan. When static tissue is present in a voxel containing flow, the measured velocity is not the average velocity of the flow alone, but is lower due to the partial volume effect of the static tissue. We present a preprocessing technique that removes the contribution of static tissue in each voxel prior to calculation of average velocity, resulting in more accurate velocity measurements and better lumen definition. Results of flow tube experiments are presented which confirm the improvement in measurement accuracy.

Algorithms↗

PubMed1994

Effects of ACE inhibitors on oxidation of human low density lipoprotein.

Oxidation of low density lipoprotein (LDL) may be instrumental in the development of atherosclerosis. We have examined the effect of the angiotensin converting enzyme (ACE) inhibitors captopril and quinaprilat and the -SH containing compound N-acetylcysteine on LDL oxidation. Oxidation of isolated human LDL was initiated with CuCl2. Conjugated diene formation (monitored spectrophotometrically at 234 nm) gave a measure of LDL oxidation. Captopril inhibited LDL oxidation but quinaprilat did not. The lag phase to the rapid increase in absorbance at 234 nm determined was 109 (65-157) min median and range for control samples and rose to 209 (168-305) min with captopril 10 microM, a ratio of 2.1:1 for drug to control (P = 0.01). N-acetylcysteine had a similar effect to captopril (drug to control lag time ratio 2.0:1, with NAC 10 microM), i.e. suggesting resistance to oxidation was due to the -SH group of both drugs. Captopril may have a potentially anti-atherosclerotic property not shared by other ACE inhibitors.

Acetylcysteine↗

PubMed1994

Agonist desensitisation of alpha 1 adrenoceptors and endothelin-1 receptors coupled to phosphatidylinositol metabolism.

Agonist desensitisation of responses coupled to phosphatidylinositol metabolism were studied. Responses mediated by two different agonists, endothelin-1 and noradrenaline were investigated. In vivo pressor responses were examined in conscious male New Zealand white rabbits, while effects on inositol phosphate formation were studied in rings of freshly isolated aorta and in cultured aortic vascular smooth muscle cells. No desensitisation of responses to noradrenaline were observed in vivo despite a 10-day infusion under conditions which cause desensitisation of alpha 2 and beta-adrenoceptor mediated responses. In contrast, responses to endothelin-1 were attenuated within 5 min of commencing endothelin-1 infusions. No reduction in noradrenaline stimulated inositol phosphate was observed in cultured vascular smooth muscle cells after pre-incubation with noradrenaline up to 10(-4) M, whereas with endothelin-1 pre-incubation a dose and time-related reduction in endothelin-1 stimulated inositol phosphate formation was observed. Thus, differences in the pattern of desensitisation of both pressor responses and phosphatidylinositol metabolism were observed for noradrenaline and endothelin-1 suggesting that the nature of the 2nd messenger involved in signal transduction is not the only determinant of agonist desensitisation. In addition, differences in the rate of desensitisation and sensitivity to endothelin-1, but not noradrenaline, were observed when responses in cultured cells were compared with in vivo responses or responses to freshly isolated tissues. These differences are discussed in relation to possible modifications of the endothelin receptor or its coupling to phosphatidylinositol metabolism during culture.

Animals↗

PubMed1994

Cranial tissues: appearance at gadolinium-enhanced and nonenhanced MR imaging with magnetization transfer contrast.

PURPOSE: To determine the relative contrast of normal cranial tissues at magnetization transfer (MT) spin-echo magnetic resonance (MR) imaging. MATERIALS AND METHODS: MR imaging at 1.5 T was performed with conventional spin-echo techniques without and with off-resonance MT saturation pulses. The signal intensities of normal cranial tissues were measured in 10 healthy volunteers on spin-density- and T2-weighted images and in 10 patients on T1- weighted images obtained before and after administration of gadopentetate dimeglumine. RESULTS: MT saturation produced a significant (P < .01) reduction in signal from all tissues except cerebrospinal fluid and fat. Several gray matter structures had higher signal intensity than white matter on T1-weighted MT images. After administration of gadopentetate dimeglumine, imaging with the MT sequence increased visualization of normally enhancing structures. CONCLUSION: MT saturation pulses produce new patterns of tissue contrast that differ substantially from those seen on conventional spin-echo images.

Adult↗

PubMed1994

Cerebral infarction: effects of dose and magnetization transfer saturation at gadolinium-enhanced MR imaging.

PURPOSE: To determine contrast enhancement after cerebral infarction at T1-weighted magnetic resonance (MR) imaging with delayed, gadolinium-enhanced, and magnetization transfer (MT) techniques. MATERIALS AND METHODS: Ten patients aged 40-81 years with recent infarctions (< 7 days) were prospectively studied at MR imaging. Gadoteridol (0.1 mmol/kg [standard dose] and an additional 0.2 mmol/kg [high dose]) was administered before imaging with and without MT saturation and after a 15-minute delay. Two neuroradiologists ranked enhancement conspicuity. RESULTS: interobserver concordance was excellent (kappa = .86). Pairwise comparisons revealed high-dose MT images were ranked highest, followed by high-dose delayed non-MT images (P < .01). Standard-dose MT images and initial high-dose non-MT images were ranked intermediately but were not distinguishable from each other (P > .05). Initial and delayed standard-dose MT images were ranked lowest (P < .01) and were not distinguishable from each other. CONCLUSION: MT saturation and high-dose gadoteridol individually and synergistically improve the depiction of contrast enhancement.

Adult↗

PubMed1994

"Crisscross" MR imaging: improved resolution by averaging signals with swapped phase-encoding axes.

At conventional magnetic resonance imaging, the number of phase-encoding steps is often chosen to be less than the number of readout samples, resulting in reduced spatial resolution in the phase-encoding direction. Signal averaging improves the signal-to-noise ratio of the image but does not affect this asymmetry in resolution. By swapping the phase- and frequency-encoding directions between excitations and averaging the resultant data sets ("crisscross" imaging), equal spatial resolution can be obtained in both principal directions. Increased spatial resolution can be obtained with this method with no increase in imaging time, and the method can potentially be applied in echo-planar and three-dimensional Fourier transform imaging.

Brain↗