Biomedical subjects

C A Hamilton

Publications and source records attributed to C A Hamilton.

At least 73 records · Page 4Linked to original sources

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↗

PubMed1994

Chronic exposure of cultured bovine endothelial cells to oxidized LDL abolishes prostacyclin release.

We investigated the effect of chronic exposure (3 days) with low-density lipoprotein (LDL) and oxidized (Ox)-LDL on the unstimulated and stimulated formation of prostacyclin (6-keto-prostaglandin [PG]F1 alpha) and total inositol phosphates (IPs) by cultured bovine aortic endothelial cells. Neither basal nor bradykinin-stimulated (1 to 10 nmol/L) formation of 6-keto-PGF1 alpha was affected by LDL, except at the highest concentration of bradykinin tested (100 nmol/L). In the presence of the antioxidants N-acetyl-L-cysteine (NAC, 10 mumol/L) or vitamin E (100 mumol/L), basal and bradykinin-stimulated formation of 6-keto-PGF1 alpha was potentiated by 20 micrograms protein/mL of LDL. Ox-LDL decreased unstimulated formation of the eicosanoid from 3.1 +/- 0.2 pg/micrograms protein in control cells to 1.6 +/- 0.1 and 0.5 +/- 0.1 pg/microgram protein after 3-day incubation with 5 and 20 micrograms protein/mL of Ox-LDL, respectively (P < .05). As in the basal state, Ox-LDL decreased bradykinin-induced 6-keto-PGF1 alpha formation. NAC or vitamin E did not influence Ox-LDL-induced endothelial cell changes in eicosanoid production. IPs formation by endothelial cells increased to a similar extent in the presence of 20 micrograms protein/mL of either LDL or Ox-LDL. However, no change was apparent in the bradykinin (10 mumol/L)-induced increase in total IPs formation after incubation with the lipoproteins. The data indicate that chronic exposure to Ox-LDL abolishes the production of prostacyclin by cultured endothelial cells. The oxidatively modified lipoprotein seems to more specifically affect the prostacyclin pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Object relations theory and pharmacopsychotherapy of anxiety disorders.

This paper provides an overview of object relations concepts, applying them specifically to combined psychoterapy-pharmacotherapy of anxiety disorders. Anxiety in this clinical theory is conceptualized as arising from threatened loss of the self- and object-relationship. At a rudimentary level, individuals can attempt to manage potential loss through splitting and projective identification. As benign and loving experiences accumulate and ego functions neurophysiologically develop, whole object relations provide alternate and more modulated ways of coping with anxiety. In anxiety disorders, these more mature coping styles break down. Treatment combining object relations approaches to psychotherapy with pharmacotherapy pay particular attention to the relationship aspects and meanings of medication and prescribing. These approaches use the concepts of empathy, containment, countertransference, splitting, projective identification, and transitional object formation to help patients come to terms with their anxiety and with the treatment relationship.

Adult↗

PubMed1994

Phosphoinositide metabolism and aging in aorta from SHR and WKY rats: effects of endothelin-1 and noradrenaline.

Inositol phosphate formation in aortic rings from SHR and WKY rats of different ages (6, 14, and 40 weeks) was examined. Both basal and agonist (noradrenaline and endothelin-1) stimulated levels of inositol phosphates were studied. No differences in basal levels of inositol phosphate formation were observed between SHR and WKY nor were differences in agonist stimulated levels found in 6 week old animals. However, at 14 and 40 weeks both noradrenaline and endothelin-1 stimulated levels were reduced in SHR compared to WKY. Both endothelin and noradrenaline stimulated inositol phosphate formation decreased with age in SHR. In WKY there was a decrease in endothelin but not noradrenaline stimulated levels with age. Age related decreases were consistently greater in SHR than WKY. Thus, both age and rat strain modulated agonist stimulated inositol phosphate formation.

Aging↗

PubMed1994

Improved detection of gadolinium enhancement using magnetization transfer imaging.

Magnetization transfer (MT) imaging is a new MR imaging technique in which off-resonance radiofrequency pulses are used to selectively saturate protons in macromolecules. This saturation effect is transferred subsequently (by dipolar and chemical exchange interactions) to protons in free water, thereby altering tissue relaxation times and modulating image contrast. Gadolinium enhancement is not significantly mediated by macromolecular interactions and is, therefore, not suppressed by MT pulses. The theory underlying the use of the MT technique is presented, with examples of its clinical usefulness in improving contrast enhancement for a variety of central nervous system diseases.

Brain↗

PubMed1993

Down-regulation of imidazoline sites in rabbit kidney.

The effects of 6 days treatment with guanabenz, clonidine, rilmenidine and idazoxan on [3H]idazoxan and [3H]clonidine binding to imidazoline sites on rabbit kidney membranes were compared. Guanabenz and rilmenidine treatment resulted in a decrease in Bmax for [3H]clonidine binding and guanabenz treatment for [3H]idazoxan binding consistent with the compounds in vitro affinities for the imidazoline binding sites. [3H]Idazoxan binding was also decreased by idazoxan treatment suggesting that idazoxan may act as an agonist at this site. These results show that imidazoline sites in kidney may be modified during chronic drug treatment and provide further evidence for differences between the sites labelled by the two ligands.

Adrenergic alpha-Agonists↗

PubMed1993

Vasorelaxant properties of isolated human internal mammary arteries and saphenous veins: comparative effects of milrinone and sodium nitroprusside.

Internal mammary arteries (IMA) and saphenous veins (SV) are vessels currently used in human coronary artery bypass surgery. In addition to late complications, the vessels may develop spasm perioperatively. We studied isolated IMA and SV from patients undergoing coronary artery bypass graft to reproduce in vitro the phenomenon of vasospasm. Vascular rings were constricted with phenylephrine in a classic organ bath. The effects of two vasodilator agents, milrinone and sodium nitroprusside (SNP), on phenylephrine precontracted vessels and as a pretreatment to reverse or prevent the contraction, respectively, were studied. When added to a precontracted vessel, milrinone had the same vasorelaxant effect as SNP in artery rings (EC50: 7.4 x 10(-7) +/- 0.8 x 10(-7) vs. 5.9 x 10(-7) +/- 0.8 x 10(-7) M, milrinone vs. SNP). In veins, milrinone was less effective in relaxing the rings than SNP (EC50: 15 x 10(-7) +/- 3 x 10(-7) vs. 1.5 x 10(-7) +/- 0.1 x 10(-7) M, milrinone vs. SNP, p < 0.05). If milrinone or SNP was added as a pretreatment, using the EC50 values, the inhibitory effect of milrinone on phenylephrine-induced contractions was greater in arteries than in veins (71 +/- 4 vs. 36 +/- 11% inhibition of maximum contraction to phenylephrine, artery vs. vein, p < 0.05). In arteries, milrinone caused a greater inhibitory effect than SNP (71 +/- 4 vs. 52 +/- 9% inhibition, milrinone vs. SNP, p < 0.05), but similar inhibition in veins (36 +/- 11 vs. 42 +/- 16%, milrinone vs. SNP).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1993

Effects of a xanthine oxidase/hypoxanthine free radical and reactive oxygen species generating system on endothelial function in New Zealand white rabbit aortic rings.

We investigated the effects of the xanthine oxidase (XO)/hypoxanthine (HX) free radical (FR) generating system on the relaxant properties of aortic rings from New Zealand White rabbits. This system generates superoxide anions, hydroxyl radicals, and H2O2. We wished to identify which of these species is responsible for impairment of vascular function. After obtaining dose-response curves to phenylephrine (PE) and carbachol or sodium nitroprusside (SNP), we exposed rings to the FR generating system or H2O2 for 30 min, either with or without a range of potentially protective agents. Dose-response curves to carbachol or SNP were then repeated. Exposure to the XO/HX system impaired endothelium-dependent, carbachol-induced relaxation. The hydroxyl radical scavengers mannitol, N-(2-mercaptopropionyl)-glycine (MPG), and captopril offered no protection. Superoxide dismutase (SOD) increased the impairment of response, catalase provided partial protection, and a combination of SOD and catalase completely prevented impairment of the response. H2O2 mimicked the effects of XO/HX system. H2O2 appears to be the primary species involved in mediating the toxic effects of the XO/HX FR generating system, but the superoxide anion is probably responsible for some of the loss of relaxation and a role for intracellular generation of hydroxyl radicals cannot be excluded.

Animals↗

PubMed1993

Comparison of endothelin-1 and noradrenaline stimulated inositol phosphate formation in cultured aortic smooth muscle cells from spontaneously hypertensive and Wistar Kyoto rats.

Total [3H]-inositol phosphate formation was measured in cultured aortic smooth muscle cells from 6 and 14 week spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) normotensive rats. Basal inositol phosphate formation was significantly increased in cells cultured from SHR compared to WKY at both 6 and 14 weeks as was basal phosphatidylinositol formation. This difference in basal values was apparent after 9 h or more incubation with [3H]-myoinositol. Both endothelin-1 and noradrenaline stimulated inositol phosphate formation was unchanged in cultured smooth muscle cells from 6-week SHR compared to WKY. In cultured smooth muscle cells from 14-week SHR a decrease was observed in endothelin-1 stimulated inositol phosphate formation compared to controls. Noradrenaline stimulated inositol phosphate formation was increased in cultured cells from 14 week SHR. Endothelin-1 and noradrenaline stimulated inositol phosphate formation does not appear to be involved in the development (at 6 weeks) of hypertension in this model. However, in established hypertension (14 weeks) cells from SHR have altered total [3H] inositol phosphate formation in response to stimulation with noradrenaline and endothelin-1 although these changes are in opposite directions. Therefore, in cultured smooth muscle cells from 14-week rats noradrenaline and endothelin-1 appear to be regulated independently with regard to their effects on the phosphatidylinositol cycle.

Age Factors↗

PubMed1992

The role of imidazoline receptors in blood pressure regulation.

Using the ligands [3H] clonidine and [3H] idazoxan, nonadrenergic imidazoline preferring binding sites have been identified in a range of tissues from several species including man. These sites may represent a new family of receptors. An endogenous ligand and potential clonidine displacing substance has been identified. There is strong evidence for an involvement of the nonadrenergic imidazoline [3H] clonidine labelled sites in the nucleus reticularis lateralis in blood pressure regulation, and some evidence for a role in sodium regulation in the kidney for the [3H] idazoxan labelled sites. Some drugs which were previously thought to act via alpha 2-adrenoceptors, may mediate their effects in part via these imidazoline sites.

Adrenergic alpha-Antagonists↗

PubMed1992

Adrenergic and nonadrenergic effects of imidazoline and related antihypertensive drugs in the brain and periphery.

In radioligand binding studies the alpha 2-adrenoceptor antagonist ligand [3H]yohimbine binds exclusively to adrenergic sites. However, in addition to binding to alpha 2-adrenoceptor sites, two other ligands, [3H]clonidine and [3H]idazoxan, also bind at nonadrenergic imidazoline sites. Many of the compounds with a high affinity for these imidazoline sites are centrally acting antihypertensive drugs and there is some evidence that these sites are involved in blood pressure regulation. With chronic treatment of rabbits with guanabenz, clonidine, and rilmenidine, down regulation of alpha 2 but not imidazoline sites occurred in forebrain and hindbrain with guanabenz treatment, and in hindbrain with clonidine treatment. However, no change in either imidazoline or alpha 2-adrenoceptor binding site number occurred in animals given chronic rilmenidine treatment. This rank order of effect, guanabenz greater than clonidine greater than rilmenidine, is consistent with the alpha 2-adrenoceptor activation by the three drugs in the periphery. In contrast, chronic treatment with guanabenz, clonidine, and rilmenidine had similar effects on blood pressure, heart rate, and responses to intracisternal clonidine. We suggest that stimulation of alpha 2-adrenoceptors cannot account for all the changes in cardiovascular responses observed on chronic treatment and that activation of nonadrenergic imidazoline-preferring sites may contribute to the antihypertensive properties of imidazoline and related compounds.

Animals↗

PubMed1992

Do centrally-acting antihypertensive drugs act at non-adrenergic as well as alpha-2 adrenoceptor sites?

Rabbits were treated with guanabenz, clonidine and rilmenidine for 6 days via osmotic minipumps. Blood pressure, heart rate and responses to intracisternal clonidine were measured after 1 and 6 days treatment. Radioligand binding to forebrain and hindbrain membranes after 6 days treatment was examined using [3H]yohimbine to measure the number of adrenergic binding sites and [3H]clonidine and [3H]idazoxan to assess nonadrenergic imidazoline sites. No change in nonadrenergic imidazoline binding was observed but adrenergic binding was decreased in forebrain and hindbrain by guanabenz and in hindbrain by clonidine treatment. Resting heart rate was decreased after 1 day's treatment with partial recovery by day 6. At this time heart rate significantly reduced in the clonidine and rilmenidine treated groups but not the guanabenz group. No significant change in baseline blood pressure was observed in normotensive rabbits. Both depressor and bradycardia responses to intracisternal clonidine were attenuated after 1 day's dosing but only depressor responses were influenced after 6 days. Blood pressure and heart rate thus appeared to be regulated independently. It is possible that imidazoline receptors predominate in the central control of blood pressure while central alpha-2 adrenoceptors play a greater part in heart rate regulation.

Animals↗