Biomedical subjects

M R Adams

Publications and source records attributed to M R Adams.

At least 19 recordsLinked to original sources

PubMed1998

Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice.

Motor behavior is modulated by dopamine-responsive neurons in the striatum, where dopaminergic signaling uses G-protein-coupled pathways, including those that result in the activation of cAMP-dependent protein kinase (PKA). The RIIbeta isoform of PKA is highly enriched in the striatum, and targeted disruption of the RIIbeta gene in mice leads to a dramatic reduction in total PKA activity in this region. Although the mutant mice show typical locomotor responses after acute administration of dopaminergic drugs, they display abnormalities in two experience-dependent locomotor behaviors: training on the rotarod task and locomotor sensitization to amphetamine. In addition, amphetamine induction of fos is absent, and the basal expression of dynorphin mRNA is reduced in the striatum. These results demonstrate that motor learning and the regulation of neuronal gene expression require RIIbeta PKA, whereas the acute locomotor effects of dopaminergic drugs are relatively unaffected by this PKA deficiency.

Amphetamine↗

PubMed1998

Sex steroids increase cholesterol 7alpha-hydroxylase mRNA in nonhuman primates.

One mechanism that may account for our prior observation that oral contraceptives decrease the hepatic cholesterol concentration independently of the low-density lipoprotein (LDL) receptor in sexually intact nonhuman primates is that sex hormones increase biliary cholesterol secretion by increasing hepatic mRNA abundance for cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol into bile acids. To examine the independent effect of estrogen, progestin, and combined estrogen and progestin on the hepatic cholesterol concentration and cholesterol 7alpha-hydroxylase mRNA abundance, 34 ovariectomized adult female cynomolgus monkeys were fed a moderately atherogenic diet for 12 weeks with either oral conjugated equine estrogen ([CEE] n = 8), medroxyprogesterone acetate ([MPA] n = 9), or combined CEE + MPA (n = 9) and compared with a control group (n = 8) that did not receive exogenous sex hormones. After 12 weeks, hepatic cholesterol was significantly lower in CEE-treated (6.2 +/- 1.2 mg/g liver) and CEE + MPA-treated (6.4 +/- 0.9 mg/g liver) animals compared with the control (12.6 +/- 1.9 mg/g liver) and MPA-treated (14.6 +/- 1.6 mg/g liver) groups. Hepatic cholesterol 7alpha-hydroxylase mRNA abundance was significantly increased in CEE-treated (0.553 +/- 0.08 pg/microg RNA), MPA-treated (0.734 +/- 0.12 pg/microg RNA), and CEE + MPA-treated (0.487 +/- 0.07 pg/microg RNA) animals compared with the controls (0.318 +/- 0.03 pg/microg RNA). There was no significant difference in the plasma LDL cholesterol concentration and hepatic LDL receptor mRNA abundance between the groups. These data support but do not prove the hypothesis that low-dose oral estrogen induces an increase in cholesterol 7alpha-hydroxylase mRNA abundance, which is correlated with biliary cholesterol secretion and may result in depletion of hepatic cholesterol.

Animals↗

PubMed1998

Conjugated equine estrogens inhibit progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodeling induced by balloon catheter injury in monkeys.

OBJECTIVES: This study sought to determine the effects of estrogen treatment on atherosclerosis progression and the proliferative and structural responses of the atherosclerotic arteries to injury. BACKGROUND: Estrogen treatment suppresses the intimal response to arterial injury in nonatherosclerotic rodents and rabbits and inhibits the in vitro proliferation of smooth muscle cells. However, the effect of estrogen on the response of atherosclerotic arteries to transmural injury, as occurs in balloon catheter angioplasty in humans, is unknown. METHODS: Forty-six ovariectomized cynomolgus monkeys were fed an atherogenic diet for 30 months; 25 received 175 microg/day of conjugated equine estrogens, and 21 served as untreated control animals. All animals underwent balloon catheter injury of the left iliac artery. Subsets of animals underwent a necropsy study at 4, 7, 14 and 28 days after injury; injured and contralateral (uninjured) arteries were pressure-fixed and evaluated morphometrically. RESULTS: Estrogen treatment resulted in a 37% decrease (p < 0.05) in atherosclerosis (plaque area) in the uninjured artery. In response to injury, arterial cell proliferation increased at days 4 and 7, and intimal area was increased two- to threefold at day 28 (p < 0.05). Although estrogen treatment resulted in a trend toward decreased arterial cell proliferation at day 4, there was evidence of increased cell proliferation in both media and intima at day 7 (p < 0.05). However, there was no effect of estrogen treatment on intimal area or indexes of arterial remodeling in the injured artery at day 28 (p > 0.4). CONCLUSIONS. In contrast to previous studies of nonatherosclerotic animals, the results indicate that in the circumstance of transmural injury to arteries of primates with preexisting atherosclerosis, estrogen does not suppress arterial neointimal or structural responses to injury.

Animals↗

PubMed1998

Wound healing: a paradigm for lumen narrowing after arterial reconstruction.

PURPOSE: The intimal hyperplasia hypothesis that equates lumen narrowing after arterial injury with intimal mass has recently been challenged. Evidence has emerged to suggest that lumen narrowing is caused in large part by changes in artery wall geometry rather than intimal mass per se. We have begun to explore this hypothesis in a unique nonhuman primate model of atherosclerosis. METHODS: Monkeys who were fed an atherogenic diet for 3 to 5 years underwent experimental angioplasty of the left iliac artery. The contralateral iliac artery served as an intraanimal control. Arteries were removed 2, 4, 7, 14, 28, or 112 days later for analysis (6 or 13 per time point). Angioplasty dilated arteries by fracturing atheroma and stretching or tearing the media. Cross-sections of injured arteries were analyzed for expression of extracellular matrix components and cell surface integrins that are important in wound healing. Antibodies, riboprobes, or histochemical stains specific for fibrin, hyaluronan, versican (chondroitin sulfate-containing proteoglycan), procollagen-I, elastin, and the alpha 2 beta 1 and alpha V beta 3 integrins were used. RESULTS: A thin mural thrombus was seen at sites of denudation and plaque fracture (days 2 to 7). This provisional matrix was invaded by leukocytes (days 2 to 4) and alpha-actin-positive smooth muscle cells (SMCs; days 4 to 7). Thrombus was replaced by SMCs expressing hyaluronan and the associated versican proteoglycans (day 14). Versican was expressed throughout the neointima as it enlarged (day 28), but expression later subsided (day 112). Procollagen-I expression initially increased in the adventitia (day 4) and then in the forming neointima (day 14). Procollagen-I expression was found to persist within the adventitia and in the neointima in SMCs nearest the lumen (days 28 to 112). Elastin staining was prominent within the mature neointima (day 112) but not at earlier time points. Integrin expression also increased within the injured artery wall. alpha v beta 3 staining (fibrin[ogen] receptor) increased in the injured media (days 2 to 7) and was then seen throughout the early neointima (day 7). Low level expression of alpha V beta 3 subsequently persisted within the forming neointima (day 28). alpha 2 beta 1 (collagen receptor) expression increased in the neointima in SMCs nearest the lumen (day 28). CONCLUSIONS: Lumen narrowing after angioplasty in this model of atherosclerosis is caused largely by decreased artery wall diameter. The pattern of matrix and integrin expression within the injured artery wall is in many ways analogous to that of healing wounds. These observations suggest that tissue contraction may play a role in lumen narrowing at sites of arterial reconstruction. Strategies to inhibit wound contraction may prove effective in preventing restenosis.

Angioplasty, Balloon↗

PubMed1998

Coronary artery and cultured aortic smooth muscle cells express mRNA for both the classical estrogen receptor and the newly described estrogen receptor beta.

Estrogens exhibit potent anti-atherogenic effects through mechanisms which may involve direct effects on the artery. The existence of the classical estrogen receptor (ERalpha) in vascular tissues has been established. Recently a new estrogen receptor (ERbeta) has been discovered which represents a distinct gene product with homology to the classical ERalpha. The purpose of the present study was to determine if ERbeta mRNA is expressed in vascular tissues of female and male primates. Oligonucleotide primers were developed for the specific RT-PCR amplification of ERalpha or ERbeta mRNA. RT-PCR products of the appropriate size for ERalpha and for ERbeta were observed after amplification of RNA isolated from coronary arteries of both male and female cynomolgus monkeys. Similar results were obtained from cultured aortic smooth muscle cells and from monkey reproductive tissues such as ovary and uterus. The relative expression of ERbeta to ERalpha mRNA was greatest in ovary, on the same order of magnitude in monkey vascular tissues and uterus, while the human breast cancer cell line MCF-7 exhibited a very low level of ERbeta relative to ERalpha. Sequence analysis of isolated RT-PCR products showed >95% similarity between the monkey and the published human sequences for both ERalpha and ERbeta. These findings suggest that estrogen may influence vascular gene expression not only through classical ERalpha but also through the newly described ERbeta. These findings also demonstrate the potential for targeting of these receptors in males for prevention or treatment of heart disease.

Animals↗

PubMed1998

QSARs for the effect of benzaldehydes on foodborne bacteria and the role of sulfhydryl groups as targets of their antibacterial activity.

Quantitative structure activity relationships (QSARs) were obtained describing the activity of a series of benzaldehydes against three different foodborne bacteria, Listeria monocytogenes F6861, serotype 4b, Salmonella enteritidis, Phage type 4, P167807 and Lactobacillus plantarum INT.L11. MIC values at pH 6.2 and 35 degrees C were obtained for 11 phenolic benzaldehydes to produce multiple linear regression and artificial neural network models. For each organism, the models contained a steric parameter Vw and an electronic-steric parameter for ortho substituents Es degree. The benzaldehydes did not require to partition to produce their effect, shown by the lack of a lipophilic parameter in the models. This strongly suggests that they act on the outside of the cells. Substitution ortho to the carbonyl group increased their antibacterial action. Cells were treated with 2,3-dihydroxy benzaldehyde and examined for their ability to bind radiolabelled iodoacetate to envelope sulfhydryl groups that remained available. It was shown that the accumulation of radiolabelled iodoacetate was lower after treatment, indicating possible competition between these two compounds for the same target. The order of the sensitivity to benzaldehydes (Salmonella > Listeria > Lactobacillus) correlated with the number of surface sulfhydryl groups available, being highest for Salmonella.

Anti-Bacterial Agents↗

PubMed1998

Biphasic thermal inactivation kinetics in Salmonella enteritidis PT4.

The thermal inactivation kinetics of Salmonella enteritidis PT4 between 49 and 60 degrees C were investigated. Using procedures designed to eliminate methodological artifacts, we found that the death kinetics deviated from the accepted model of first-order inactivation. When we used high-density stationary-phase populations and sensitive enumeration, the survivor curves at 60 degrees C were reproducibly biphasic. The decimal reduction time at 60 degrees C (D60 degrees C) of the tail subpopulation was more than four times that of the majority population. This difference decreased with decreasing temperature; i.e., the survivor curves became more linear, but the proportion of tail cells remained a constant proportion of the initial population, about 1 in 10(4) to 10(5). Z plots (log D versus temperature) for the two populations showed that the D values coincided at 51 degrees C, indicating that the survivor curves should be linear at this temperature, and this was confirmed experimentally. Investigations into the nature of the tails ruled out genotypic differences between the populations and protection due to leakage from early heat casualties. Heating of cells at 59 degrees C in the presence of 5 or 100 micrograms of chloramphenicol per ml resulted in reductions in the levels of tailing. These reductions were greatest at the higher chloramphenicol concentration. Our results indicate that de novo protein synthesis of heat shock proteins is responsible for the observed tailing. Chemostat-cultured cells heated at 60 degrees C also produced biphasic survivor curves in all but one instance. Cells with higher growth rates were more heat sensitive, but tailing was comparable with batch cultures. Starved cells (no dilution input) displayed linear inactivation kinetics, suggesting that during starvation a rapid heat shock response cannot be initiated.

Chloramphenicol↗

PubMed1998

Oral contraceptives and hormone replacement therapy do not increase the incidence of arterial thrombosis in a nonhuman primate model.

Older oral contraceptive (OC) formulations containing high doses of potent synthetic estrogens and progestins are associated with increased risk of thrombosis. To examine the effects of current low-dose OC and hormone replacement therapy (HRT) regimens on arterial thrombosis, premenopausal and surgically postmenopausal cynomolgus monkeys were divided into four treatment groups. Premenopausal monkeys were given either no OCs or ethinyl estradiol and levonorgestrel as an OC at a dose equivalent to that currently given to women. Postmenopausal monkeys were given either no HRT or conjugated equine estrogens and medroxyprogesterone as an HRT at a dose equivalent to that currently given to women. The monkeys were fed an atherogenic diet containing these treatments for 27 to 30 months. At the end of this time, arterial thrombosis was evaluated with a standardized stenosis/injury procedure in the left carotid artery. Blood flow velocity was monitored for cyclic or permanent occlusive thrombosis. The current OC and HRT regimens did not increase the susceptibility of the artery wall to develop an occlusive thrombus following injury and stenosis. In fact, there was a reduction in the incidence of thrombosis in the OC animals compared with untreated controls. Increased amounts of atherosclerosis were associated with an increased incidence of occlusive arterial thrombosis. Several selected coagulation parameters [von Willebrand factor, protein C, lipoprotein(a), and platelet aggregation] did not appear to be associated with either the amount of atherosclerosis or incidence of arterial thrombosis.

Animals↗

PubMed1997

Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice.

The antipsychotic drug, haloperidol, elicits the expression of neurotensin and c-fos mRNA in the dorsal lateral region of the striatum and produces an acute cataleptic response in rodents that correlates with the motor side effects of haloperidol in humans. Mice harboring a targeted disruption of the RIIbeta subunit of protein kinase A have a profound deficit in cAMP-stimulated kinase activity in the striatum. When treated with haloperidol, RIIbeta mutant mice fail to induce either c-fos or neurotensin mRNA and the acute cataleptic response is blocked. However, both wild-type and mutant mice become cataleptic when neurotensin peptide is directly injected into the lateral ventricle, demonstrating that the kinase deficiency does not interfere with the action of neurotensin but rather its synthesis and release. These results establish a direct role for protein kinase A as a mediator of haloperidol induced gene induction and cataleptic behavior.

Animals↗

PubMed1997

Contrasting effects of conjugated estrogens and tamoxifen on dilator responses of atherosclerotic epicardial coronary arteries in nonhuman primates.

BACKGROUND: Estrogens have been shown to improve dilator responses of atherosclerotic coronary arteries. Tamoxifen is a mixed estrogen agonist/antagonist with as yet unexplored effects on vascular function. Therefore, the goal of this study was to compare the effects of conjugated equine estrogens (CEEs) with those of tamoxifen on epicardial coronary artery dilator responses in atherosclerotic, ovariectomized monkeys. METHODS AND RESULTS: Fifty ovariectomized cynomolgus monkeys were fed an atherogenic diet for 34 months. During this time, monkeys were assigned to one of three treatment groups: (1) control, no hormone replacement (n=15); (2) CEEs mixed in the diet at a dose of 0.043 mg x kg(-1) x d(-1) (n=14); or (3) tamoxifen mixed in the diet at a dose of 1.3 mg x kg(-1) x d(-1) (n=21). Quantitative angiography was used to measure coronary artery dilator responses to intracoronary infusions of acetylcholine (10(-8), 10(-7), and 10(-6) mol/L) and nitroglycerin (15 microg/min). Coronary arteries of the tamoxifen-treated group constricted in response to high-dose acetylcholine (-5.4+/-2.3%, P<.05 versus control), whereas those of the CEE group did not (P>.05 versus control). Conversely, arteries from the CEE group dilated in response to nitroglycerin (9.1+/-2.1%, P<.05 versus control), whereas those from the tamoxifen group did not (P>.05 versus control). Statistical adjustments for variations in plaque extent (determined subsequently after necropsy) and plasma lipoproteins did not alter the results. CONCLUSIONS: Tamoxifen has primarily estrogen-antagonistic effects on epicardial coronary artery dilator responses in atherosclerotic monkeys. Results implicate the estrogen receptor as a modulator of coronary artery dilator responses in ovariectomized, atherosclerotic monkeys.

Acetylcholine↗

PubMed1997

Differences in the effect of cigarette smoking on endothelial function in chinese and white adults.

BACKGROUND: The prevalence of coronary artery disease in southern China is approximately one fifth that in "westernized" countries, even though approximately 70% of Chinese men smoke cigarettes and Chinese women have substantial passive exposure to cigarette smoke. OBJECTIVES: Endothelial dysfunction is an early event in atherosclerosis and occurs in young white active and passive smokers; we compared endothelial physiology in healthy young Chinese and white smokers and nonsmokers. PATIENTS: 144 healthy adults who were 16 to 45 years of age: 72 Chinese persons in a village in southern China and 72 white persons in Australia and England who were matched for exposure to cigarette smoke. Each ethnic group comprised 36 controls (lifelong nonsmokers with no regular exposure to cigarette smoke; 16 men and 20 women) and 36 active or passive smokers (15 men and 21 women). MEASUREMENTS: Arterial endothelial function was tested with high-resolution external vascular ultrasonography, and brachial artery diameter was measured at rest, after flow increase (which causes endothelium-dependent dilatation), and after administration of sublingual nitroglycerin (an endothelium-independent dilator). RESULTS: Endothelium-dependent dilatation was similar in Chinese (7.9%) and white (8.4%) nonsmokers (P > 0.2). Among white persons, endothelium-dependent dilatation was lower in active or passive smokers (3.9%) than in nonsmokers (8.4%) (P < 0.001). Among Chinese persons, dilatation was not significantly lower in active or passive smokers (7.3%) than in nonsmokers (7.9%) (P > 0.2). Dilatation was higher in Chinese active or passive smokers (7.3%) than in white active or passive smokers (3.9%) (P < 0.001). Dilatation responses to nitroglycerin were similar in all groups (P = 0.17). CONCLUSION: Young Chinese adults have less evidence of arterial endothelial dysfunction than young white adults with similar direct or indirect exposure to cigarette smoke.

Adolescent↗

PubMed1997

Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease.

L-Arginine is the physiological substrate for nitric oxide synthesis by the vascular endothelium. In hypercholesterolaemic rabbits, oral L-arginine reduces atheroma, improves endothelium-dependent dilatation and reduces monocyte/endothelial cell adhesion. The effect of oral L-arginine on endothelial physiology is unknown, however, in humans with established atherosclerosis. In a prospective, double-blind, randomised crossover trial, ten men aged 41 +/- 2 years with angiographically proven coronary atherosclerosis took L-arginine (7 g three times per day) or placebo for 3 days each, with a washout period of 10 days. After L-arginine, compared to placebo, plasma levels of arginine were increased (318 +/- 18 vs. 124 +/- 9 mumol/l, P < 0.01) and endothelium-dependent dilatation of the brachial artery (measured as the change in diameter in response to reactive hyperaemia, using external vascular ultrasound) was improved (4.7 +/- 1.1 vs. 1.8 +/- 0.7%, P < 0.04). No changes were seen in endothelium-independent dilatation of the brachial artery (measured as the change in diameter in response to sublingual nitroglycerine), blood pressure, heart rate or fasting lipid levels. Serum from six of the ten subjects after L-arginine and placebo was then added to confluent monolayers of human umbilical vein endothelial cells for 24 h, before human monocytes obtained by countercurrent centrifiguation elutriation were added and cell adhesion assessed by light microscopy. Adhesion was reduced following L-arginine compared to placebo (42 +/- 2 vs. 50 +/- 1%, P < 0.01). In young men with coronary artery disease, oral L-arginine improves endothelium-dependent dilatation and reduces monocyte/endothelial cell adhesion.

Administration, Oral↗

PubMed1997

Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: reversibility with oral L-arginine but not vitamin C.

OBJECTIVES: This study sought to assess the effect of cigarette smoking on adhesion of human monocytes to human endothelial cells and to measure the effect of L-arginine and vitamin C supplementation on this interaction. BACKGROUND: Cigarette smoking has been associated with abnormal endothelial function and increased leukocyte adhesion to endothelium, both key early events in atherogenesis. Supplementation with both oral L-arginine (the physiologic substrate for nitric oxide) and vitamin C (an aqueous phase antioxidant) may improve endothelial function; however, their benefit in cigarette smokers is not known. METHODS: Serum was collected from eight smokers (mean [+/-SD] age 33 +/- 5 years) with no other coronary risk factors and eight age- and gender-matched lifelong nonsmokers. The serum was added to confluent monolayers of human umbilical vein endothelial cells and incubated for 24 h. Human monocytes obtained by counterflow centrifugation elutriation were then added to these monolayers for 1 h, and adhesion then was measured by light microscopy. To assess reversibility, monocyte/ endothelial cell adhesion was then measured for each subject 2 h after 2 g of oral vitamin C and 2 h after 7 g of oral L-arginine. RESULTS: In smokers compared with control subjects, monocyte/ endothelial cell adhesion was increased (46.4 +/- 4.5% vs. 27.0 +/- 5.2%, p < 0.001), endothelial expression of intercellular adhesion molecule (ICAM)-1 was increased (0.31 +/- 0.02 vs. 0.22 +/- 0.03, p = 0.004), and vitamin C levels were reduced (33.7 +/- 24.1 vs. 53.4 +/- 11.5 mumol/liter, p = 0.028). After oral L-arginine, monocyte/ endothelial cell adhesion was reduced in smokers (from 46.4 +/- 4.5% to 35.1 +/- 4.0%, p = 0.002), as was endothelial cell expression of ICAM-1 (from 0.31 +/- 0.02 to 0.27 +/- 0.01, p = 0.001). After vitamin C, there was no significant change in monocyte/ endothelial cell adhesion or ICAM-1 expression from baseline in the smokers despite an increase in vitamin C levels (to 115 +/- 7 mumol/liter). CONCLUSIONS: Cigarette smoking is associated with increased monocyte-endothelial cell adhesion when endothelial cells are exposed to serum from healthy young adults. This abnormality is acutely reversible by oral L-arginine but not by vitamin C.

Adult↗

PubMed1997

L-arginine reduces human monocyte adhesion to vascular endothelium and endothelial expression of cell adhesion molecules.

BACKGROUND: Monocyte adhesion to endothelial cells is a key early event in atherogenesis. Because L-arginine has been shown to reduce atheroma and to decrease monocyte-endothelial cell adhesion in an animal model of atherosclerosis, we studied the effects of L-arginine on human monocyte adhesion to human endothelial cells and endothelial expression of cell adhesion molecules. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were grown to confluence, then incubated for 24 hours with arginine-deficient media to which was added saline (control), 100 or 1000 mumol/L L-arginine, 100 mumol/L D-arginine, 100 mumol/L NG-monomethyl-L-arginine (L-NMMA), or 100 mumol/L L-arginine with 100 mumol/L L-NMMA. Human monocytes obtained by elutriation were incubated for 1 hour with HUVECs, and adhesion was measured by light microscopy. Compared with control, monocyte adhesion was reduced by L-arginine (59 +/- 10%, P = .01) and increased by L-NMMA (123 +/- 20%, P = .01). Surface expression of cell adhesion molecules by HUVECs was assessed by an ELISA under the above conditions with and without stimulation with interleukin-1 beta. Expression of ICAM-1 was reduced with both concentrations of L-arginine compared with control in both the basal (43 +/- 12%, P < .01), and stimulated (46 +/- 15%, P < .01) states, which correlated with decreased levels of mRNA. Expression of VCAM-1 was reduced only in the stimulated state and only in the presence of 1000 mumol/L L-arginine (72 +/- 24%, P = .02). CONCLUSIONS: L-Arginine reduces human monocyte adhesion to endothelial cells and decreases expression of certain endothelial cell adhesion molecules.

Arginine↗

PubMed1997

EEDQ reduces the striatal neurotensin mRNA response to haloperidol.

Haloperidol is believed to induce neurotensin/neuromedin N (NT/ N) gene expression in the dorsolateral striatum (DLST) of the rat brain via dopamine D2 receptor blockade, but is also known to interact with other receptors as well. To further characterize haloperidol's effects, rats were treated with the irreversible monoaminergic receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2 hydroxyquinolone (EEDQ). In situ hybridization was performed for NT/N mRNA. D2-like and sigma receptor autoradiography was performed using 125I-sulpride and 3H-1,3-di-o-tolylguanidine (DTG), respectively. Despite antagonism of D2 receptors, pretreatment with EEDQ failed to significantly reduce the NT/N mRNA response when given 3 days prior to the haloperidol challenge. These data suggest that the acute effects of haloperidol on NT/N mRNA expression in large part result from D2 receptor antagonism. Nonetheless, a contribution of other receptors can not be excluded.

Animals↗

PubMed1997

Arterial reactivity is enhanced in genetic males taking high dose estrogens.

OBJECTIVES: We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. BACKGROUND: Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. METHODS: We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. RESULTS: Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). CONCLUSIONS: Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.

Adult↗

PubMed1997

Chinese adults are less susceptible than whites to age-related endothelial dysfunction.

OBJECTIVES: We sought to assess the effects of aging on the endothelial physiology of a group of Chinese adults. BACKGROUND: Several studies have documented an association between aging and progressive arterial endothelial dysfunction in white subjects. We hypothesized that age-related endothelial dysfunction, an important event in atherosclerosis, might be less marked in southern Chinese subjects, in whom the prevalence of coronary heart disease is only approximately 20% of that in industrialized countries. METHODS: We studied endothelial function in 76 healthy adults aged 16 to 70 years: 38 Chinese from a village of 3,000 people in southern China and 38 white subjects from Sydney, Australia. In each ethnic group, there were 19 younger persons (16 to 40 years) and 19 older adults (55 to 70 years). None had evidence of diabetes, hypertension or clinical vascular disease or had ever been regular cigarette smokers. With the use of high resolution external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). RESULTS: Endothelium-dependent dilation was similar in young Chinese (mean +/- SD 8.3 +/- 2.5%), young whites (7.9 +/- 2.0%) and older Chinese (6.8 +/- 2.9%), but it was significantly impaired in older whites (1.8 +/- 2.5%, p < 0.001 by analysis of variance). On multivariate analysis, older age was associated with impaired endothelium-dependent dilation (p < 0.001) (independent of the effects of serum cholesterol, gender and vessel size) in the white but not in the Chinese subjects (p = 0.83). Nitroglycerin-induced dilation was not significantly different with aging in either ethnic group. CONCLUSIONS: Endothelium-dependent dilation is similar in the arteries of healthy young Chinese and white adults. With older age, however, Chinese subjects are less susceptible to impaired endothelial function.

Adolescent↗

PubMed1997

Structural determinants of lumen narrowing after angioplasty in atherosclerotic nonhuman primates.

PURPOSE: The relationship between lumen narrowing, intimal hyperplasia, and wall remodeling after angioplasty was explored in a nonhuman primate model of atherosclerosis. METHODS: Cynomolgus monkeys (n = 37) used in long-term atherosclerosis studies underwent left iliac artery balloon injury. The uninjured right iliac artery served as a reference segment for intraanimal comparisons. One month later iliac arteries were fixed by perfusion (100 mm Hg) and removed for cross-sectional analysis to determine mean values for lumen area (LA), intimal area (IA), internal elastic lamina area (IELA), plaque burden (IA/IELA), and depth of wall injury. Values for each balloon-injured iliac artery were normalized to the contralateral uninjured iliac artery (percent of control), and linear regression analysis was performed comparing LA with IA, with IELA, and with depth of injury. Comparisons were also made between those arteries that remained dilated 1 month after balloon injury (LA > or = 140%; n = 13) and those that renarrowed (LA < or = 100%; n = 14). RESULTS: For all 37 animals, LA 1 month after balloon injury correlated well with IELA (r = 0.72; p < 0.001) but not with IA (r = 0.10; p = 0.54), suggesting that changes in artery size rather than neointimal mass determined lumen caliber. When comparing arteries that remained dilated (n = 13) with those that renarrowed (n = 14), there were no differences in depth of wall injury (injury depth: 0, no injury; 1, intima; 2, IEL; 3, media; 4, EEL; 2.1 +/- 0.3 vs 1.6 +/- 0.3; p = 0.12), neointimal accumulation (IA, 507% +/- 118% vs. 421% +/- 81% of control; p = 0.55), or plaque burden (IA/IELA, 0.39 +/- 0.04 vs 0.37 +/- 0.06; p = 0.71), respectively. However, wall size defined as IELA was significantly smaller in arteries that renarrowed than in those that remained dilated (IELA, 115% +/- 14% vs 230% +/- 19% of control; p < 0.001). CONCLUSIONS: Restenosis after angioplasty has been attributed to intimal hyperplasia, equating loss of lumen caliber with neointimal mass. The data presented herein suggest that lumen narrowing after arterial wall injury may have little to do with intimal mass per se, but rather that a change in wall caliber or wall narrowing is the cause of restenosis.

Angioplasty, Balloon↗