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Biomedical subjects

C M Stein

Publications and source records attributed to C M Stein.

At least 55 records · Page 3Linked to original sources
PubMed1997

Sympathoinhibitory response to clonidine is blunted in patients with heart failure.

To determine whether alpha2-adrenergic-mediated sympathoinhibition was altered in chronic heart failure, sympathoinhibitory sensitivity was assessed using the alpha2-adrenergic agonist clonidine in 7 patients with heart failure and in 10 healthy control subjects. Basal norepinephrine spillover was significantly higher in patients with heart failure (1.3+/-0.3 microg/min) than in control subjects (0.7+/-0.1 microg/min, P=.05). Compared with control subjects, the decrement in norepinephrine spillover to cumulative doses of clonidine (1, 2, and 3 microg/kg administered intravenously) was significantly less in patients with heart failure (P<.05). Blood pressure also tended to decrease less in patients with heart failure (P=.06). The doses of clonidine required to produce a 10% decrease in blood pressure and a 25% decrease in norepinephrine spillover were significantly higher in heart failure (P<.01 and P=.05, respectively). Thus, although clonidine lowers norepinephrine spillover significantly in patients with heart failure, such patients are less sensitive to clonidine than healthy control subjects. This difference in sensitivity suggests that doses of clonidine provide effective sympathoinhibition will need to be selected for studies that will evaluate the potential therapeutic effect of clonidine in heart failure.

Adrenergic alpha-Agonists↗
PubMed1997

Norepinephrine release in the human forearm: effects of epinephrine.

It has been postulated that delayed facilitation of norepinephrine release by epinephrine is causally related to the development of hypertension. It has been proposed that a brief increase in epinephrine concentrations results in the uptake of epinephrine into the sympathetic nerve terminal. Subsequent rerelease of epinephrine stimulates presynaptic beta-adrenergic receptors, resulting in a prolonged increase in plasma norepinephrine (NE) concentrations, with amplified sympathetic responses and vasoconstriction. To determine whether such epinephrine-induced, delayed facilitation of NE release occurs in a vascular bed draining resistance vessels and, if it occurs, whether that facilitation differs in hypertension, we used a radioisotope dilution method to measure unstimulated and isoproterenol-stimulated forearm NE spillover before, during, and after a 50 ng/min infusion of epinephrine for 30 minutes directly into the brachial artery. No delayed facilitatory effects of epinephrine on forearm NE spillover were observed in either 6 normotensive (NT) or 8 borderline hypertensive (BHT) subjects (NT unstimulated forearm NE spillover preepinephrine 1.79+/-0.41 ng/min versus postepinephrine 2.36+/-0.65 ng/min, P=.38; BHT preepinephrine 2.24+/-0.70 ng/min versus postepinephrine 1.93+/-0.46 ng/min, P=.51; NT isoproterenol-stimulated forearm NE spillover preepinephrine 4.61+/-1.01 ng/min versus postepinephrine 4.4+/-0.98 ng/min, P=.9; BHT preepinephrine 4.04+/-1.36 ng/min versus postepinephrine 4.69+/-1.49 ng/min P=.5). We conclude that the short-term local infusion of epinephrine does not have a delayed facilitatory effect on forearm NE spillover in NT or BHT subjects. Therefore, the prolonged increase in NE concentrations after epinephrine infusion previously shown systemically, and not seen locally in the forearm, suggests that the delayed facilitatory response to epinephrine may occur in other organs.

Adult↗
PubMed1996

Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma.

OBJECTIVE: Free radical-induced oxidative stress with consequent lipid peroxidation and resultant tissue damage has been suggested as a potential mechanism of the pathogenesis of scleroderma. However, because reliable measurement of lipid peroxidation in vivo is difficult, it has not been possible to adequately examine this hypothesis. We have previously described a series of bioactive prostaglandin F2-like compounds, termed F2-isoprostanes, produced in vivo in humans by the non-cyclooxygenase, free radical-catalyzed, peroxidation of arachidonic acid and have shown them to be a reliable measure of lipid peroxidation in vivo. In the present study, we determined whether scleroderma is associated with enhanced oxidative stress. METHODS: As a measure of oxidative stress, we determined urinary concentrations of a tetranor-dicarboxylic acid metabolite of F2-isoprostanes (F2IP-M) by mass spectrometry in 8 patients with scleroderma (representing a wide spectrum of disease, including limited disease with refractory digital ulceration or pulmonary hypertension, and diffuse disease) and in 10 healthy control subjects. RESULTS: F2IP-M concentrations were significantly higher in patients with scleroderma (mean +/- SEM 3.41 +/- 0.64 ng/mg of creatinine) than in healthy controls (1.22 +/- 0.14 ng/mg of creatinine) (P = 0.002). These elevations occurred in patients with limited disease and in those with diffuse disease. CONCLUSION: The increased level of urinary F2IP-M supports the hypothesis that free radical-induced oxidative injury occurs in scleroderma and provides a biologic marker whose relationship to disease activity and disease therapy may be important. These findings may also provide a rationale for exploring whether antioxidant therapy may influence the natural course of the disease.

Adult↗
PubMed1996

Angiotensin converting enzyme inhibition and sympathetic activity in healthy subjects.

BACKGROUND: One suggested mechanism for the reduction in mortality rates resulting from the use of angiotensin converting enzyme inhibitors in congestive heart failure is the inhibition of the angiotensin II-mediated norepinephrine release. Direct evidence for this mechanism is lacking in humans. SUBJECTS AND METHODS: We examined the effects of captopril, 25 mg three times a day, or matched placebo for 7 days on sympathetic activity during a 10 mEq/day sodium diet in seven healthy male subjects aged 30 +/- 3 (SEM) years. A tritiated norepinephrine radioisotope dilution technique was used to measure sympathetic activity, both at rest and during isometric handgrip exercise. RESULTS: Captopril blunted the increase in mean arterial pressure during isometric handgrip exercise (placebo, from 81 +/- 4 to 112 +/- 2 mm Hg; captopril, from 78 +/- 3 to 101 +/- 2 mm Hg; p < 0.01). However, the increase in systemic norepinephrine spillover during isometric handgrip exercise was not blunted by captopril. Captopril had no effect on resting mean arterial pressure or systemic norepinephrine spillover. CONCLUSIONS: Captopril did not attenuate baseline or static exercise-stimulated sympathetic activity in healthy subjects. These findings would indicate that angiotensin converting enzyme inhibition does not decrease sympathetic activity at rest or during the stimulus of isometric handgrip exercise.

Adult↗
PubMed1996

Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with rheumatoid arthritis receiving cyclosporine.

INTRODUCTION: Cytochrome P4503A (CYP3A) is primarily responsible for the metabolism of cyclosporine and that of many other drugs. Several substrates of CYP3A have been investigated for use as pharmacologic probes to predict the CYP3A-metabolizing capacity of an individual and, therefore, the disposition of other CYP3A substrate drugs. One such measure of CYP3A activity is the 14C erythromycin breath test, which has been applied to the prediction of cyclosporine disposition. However, the test has practical limitations. Because of this, the 0- to 8-hour urinary dapsone recovery ratio has been studied as an alternative and more practical probe of CYP3A activity. METHODS: The dapsone recovery ratio and the 14C erythromycin breath test were correlated with cyclosporine concentrations in 16 patients with rheumatoid arthritis to determine the usefulness of the dapsone recovery ratio as an alternative to the 14C erythromycin breath test. The erythromycin breath test showed a fourfold variation between subjects and correlated weakly with trough cyclosporine concentrations (r = -0.50, p < 0.05), whereas the dapsone recovery ratio varied only approximately twofold between subjects and did not correlate with trough cyclosporine concentrations (r = 0.02, p = 0.94). The correlation between the dapsone recovery ratio and the erythromycin breath test (r = 0.22, p = 0.41) was not significant. CONCLUSIONS: These data suggest that results obtained with one probe in vivo may not apply to another CYP3A substrate. The poor quantitative relationship between cyclosporine concentrations and the erythromycin breath test limits its usefulness in the prediction of an individual's cyclosporine dose requirement.

Adult↗
PubMed1996

Immunodeficient states and associated rheumatic manifestations.

The molecular mechanisms of the primary immunodeficiencies have been further explored and provide insights into the regulation of the immune response and its role in autoimmune disease, infection, and malignancy. The critical role of CD40-CD40 ligand-mediated effects in T cell-dependent B cell activation, shown through the study of patients with common variable immunodeficiency and hyper IgM syndrome, suggests a potential narrow target for immunomodulatory therapy. A mouse model for chronic granulomatous disease has been developed and promises to be a source of future information. Optimal cost-effective therapy for primary immunodeficiencies continues to be defined, with the results of a large series of patients treated with subcutaneous immunoglobulin infusions reported. Further experience with polyethylene glycol adenosine deaminase and interleukin-2 conjugates is discussed.

Animals↗
PubMed1996

Arthritis associated with HIV infection in Zimbabwe.

OBJECTIVE: To document the clinical and immunogenetic features of arthritis associated with heterosexually acquired human immunodeficiency virus (HIV) infection. METHODS: All patients were assessed by a rheumatologist and standard laboratory tests were performed. RESULTS: There were 3 common clinical presentations. (1) Oligo/polyarticular arthritis (22 men, 4 women). HIV infection had not previously been diagnosed in 24 of these patients but persistent generalized lymphadenopathy (85%) and weight loss (42%) were present. Joints commonly involved were ankles (65%) and knees (54%), often with associated enthesitis (31%) and dactylitis (23%). Followup data in 18 patients showed that arthritis resolved completely in 9 patients (one subsequently recurred), improved by >50% in 5 patients, was unremitting in 3 patients, and recurred frequently in one patient. None of 7 patients tested were HLA-B27 or B7 positive. (2) Reiter's syndrome (RS) (21 men, 3 women; incomplete RS 18 patients,complete RS 6 patients). Lymphadenopathy was present in 19 patients (79%) and 4 patients were previously known to have HIV infection. Involvement of knees (80%) and ankles (58%) was common, as were enthesitis (29%) and dactylitis (13%). Followup data in 21 patients showed that 14 resolved (5 with recurrences), 2 improved by >50%, and 5 had continued arthritis. HLA-B27 was not found in 13 patients tested but a cross reacting antigen was found in 6 patients. (3) Symmetrical polyarthritis (4 men, 4 women). Symmetrical arthritis of the wrists (8 patients) and peripheral interphalangeal (PIP) and metacarpophalangeal (MCP) joints (7), as well as lymphadenopathy (5), nodules (4), rheumatoid factor (3), and erosive radiographic changes (one patient) were seen. (4) Miscellaneous. Other types of arthritis included 3 patients with psoriasis and arthritis and one patient each with Behcet's disease, Salmonella septic arthritis, and secondary syphilis. CONCLUSION: Arthritis associated with HIV in this population is most commonly characterized by oligoarticular, asymmetrical, large joint arthritis, with or without features of Reiter's syndrome, and is not associated with HLA-B27.

AIDS-Related Opportunistic Infections↗
PubMed1995

Attenuation of isoproterenol-mediated vasodilatation in blacks.

BACKGROUND: The mechanism of enhanced vascular reactivity in young blacks, which may play a part in the development of hypertension, has not been defined. To determine the contribution of blunted vasodilatation mediated by beta 2-adrenergic receptors to this phenomenon, we compared forearm blood-flow responses to isoproterenol in young black and white normotensive men. METHODS: We used venous-occlusion plethysmography to measure the responses of blood flow in the forearm to the intraarterial administration of isoproterenol (10 to 400 ng per minute) in 9 normotensive black men (mean [+/- SD] age, 31.3 +/- 8.0 years) and 13 normotensive white men (mean age, 32.9 +/- 5.6 years). Sympathetic activity in the forearm was measured simultaneously by isotope-dilution techniques. RESULTS: Base-line blood flow in the forearm was similar in blacks and whites, but the degree of vasodilatation in response to isoproterenol was markedly lower in blacks. Isoproterenol at an infusion rate of 400 ng per minute produced a 9-fold increase in blood flow in whites but only a 3.5-fold increase in blacks (P < 0.001). The base-line rate of norepinephrine spillover in the forearm was higher in blacks (2.0 +/- 1.3 ng per minute [11.8 +/- 7.7 nmol per minute]) than in whites (0.6 +/- 0.5 ng per minute [3.5 +/- 3.0 nmol per minute], P = 0.002), but there was no difference between the groups after isoproterenol stimulation. CONCLUSIONS: Forearm blood-flow responses to isoproterenol were markedly attenuated in normotensive blacks, indicating a blunting of vasodilatation mediated by beta 2-adrenergic receptors. Sympathetic activity in the forearm was greater in blacks than in whites, but isoproterenol-stimulated presynaptic beta 2-adrenergic responses (which facilitated norepinephrine release) did not differ significantly between blacks and whites. Our findings suggest that the mechanisms responsible for blunted vasodilatation in response to the administration of isoproterenol may contribute to enhanced vascular reactivity in blacks and may play a part in the pathogenesis of hypertension in blacks.

Adult↗
PubMed1995

Dietary sodium intake modulates systemic but not forearm norepinephrine release.

INTRODUCTION: Sodium intake has profound effects on systemic and renal sympathetic activity, but its effects on sympathetic activity in skeletal muscle vascular beds, a site at which local regulatory mechanisms could alter vascular tone directly, are unclear. METHODS: To determine the effect of dietary sodium intake on basal and isoproterenol-stimulated systemic and forearm norepinephrine kinetics, we studied seven healthy male volunteers twice, 4 weeks apart, while they were receiving a low-sodium (10 mmol sodium/24 hours) diet and a high-sodium diet (250 mmol sodium/24 hours). Forearm blood flow, measured by plethysmography, and systemic and forearm norepinephrine spillover, measured by radioisotope dilution, were determined before and after intra-arterial infusion of 60 and 400 ng/min isoproterenol. RESULTS: Baseline (before isoproterenol) systemic norepinephrine spillover was higher when subjects received the low-sodium diet (448.1 +/- 55.7 ng/min) compared with the high-sodium diet (269.7 +/- 42.7 ng/min; p < 0.05). In contrast, sodium intake did not affect local forearm norepinephrine spillover, either at baseline (low-sodium diet, 2.05 +/- 0.48 ng/min versus high-sodium diet, 2.63 +/- 0.79 ng/min; p = 0.50) or after stimulation with isoproterenol in doses of 60 ng/min (low-sodium diet, 8.84 +/- 2.2 ng/min versus high-sodium diet, 6.1 +/- 1.9 ng/min; p = 0.38) or 400 ng/min (low-sodium diet, 16.4 +/- 4.5 ng/min versus high-sodium diet, 16.7 +/- 2.5 ng/min; p = 0.93). CONCLUSIONS: Under conditions of low sodium intake, systemic norepinephrine spillover was increased but forearm norepinephrine spillover was not, suggesting that alteration in sodium intake may produce a differential effect on norepinephrine spillover in different tissues but that decreased local sympathetic activity in skeletal muscle is not the likely mechanism by which a low-sodium diet may lower blood pressure or attenuate stress-induced pressor responses.

Adrenergic beta-Agonists↗
PubMed1995

Dietary sodium intake modulates vasodilation mediated by nitroprusside but not by methacholine in the human forearm.

Studies in animals suggest that nitric oxide production is increased under conditions of salt loading and that this increase protects against the development of salt-induced hypertension. To determine the effect of dietary sodium intake on nitric oxide-mediated vascular responses, we studied seven healthy male volunteers twice 4 weeks apart while they were receiving a diet containing 10 or 250 mmol Na+ per 24 hours. Methacholine (0.25 to 8 micrograms/min) and sodium nitroprusside (0.25 to 8 micrograms/min) were infused intra-arterially in incremental doses, and forearm blood flow was measured. The response of forearm blood flow to sodium nitroprusside was greater when subjects received a high sodium diet than when they received a low sodium diet (F = 7.11, P < .05); however, the response to methacholine was not altered by sodium intake (F = 0.57, P = NS). Plasma renin activity was significantly higher (3.99 versus 1.0 ng angiotensin I/mL per hour) when subjects received a low salt diet (P < .05). Systolic pressure, diastolic pressure, heart rate, and baseline forearm blood flow were not affected by sodium status. We conclude that under conditions of salt loading, vasodilation in response to sodium nitroprusside was enhanced, whereas the response to methacholine was not affected, suggesting a differential effect of sodium intake on endothelium-dependent and endothelium-independent responses after the administration of methacholine and sodium nitroprusside, respectively.

Adult↗
PubMed1995

Tachyphylaxis of human forearm vascular responses does not occur rapidly after exposure to isoproterenol.

In vitro and limited in vivo data suggest that rapid desensitization of beta-adrenoceptor responses occurs after exposure to agonist. Tachyphylaxis to a beta-adrenoceptor agonist would represent a potentially important mechanism for the short-term regulation of vascular tone. The effects of a 4-hour infusion of 400 ng/min intra-arterial isoproterenol on forearm blood flow and presynaptic beta-adrenoceptor-mediated norepinephrine release were determined in eight healthy volunteers. Intra-arterial isoproterenol at 400 ng/min resulted in a significant increase in forearm blood flow in all eight subjects at all time points, with no evidence of tachyphylaxis. In fact, forearm blood flow after 4 hours of the isoproterenol infusion (22.8 +/- 3.3 mL/100 mL per minute) was significantly greater than after 7 minutes (14.6 +/- 2.8 mL/100 mL per minute), 15 minutes (15.4 +/- 2.4 mL/100 mL per minute), and 30 minutes (17.4 +/- 3.0 mL/100 mL per minute) of the infusion (P < .05). Similarly, presynaptic beta-adrenoceptor responses showed no evidence of tachyphylaxis, so forearm norepinephrine spillover values after 7 minutes (6.6 +/- 0.94 ng/min), 15 minutes (7.6 +/- 1.5 ng/min), and 4 hours (8.8 +/- 1.1 ng/min) of isoproterenol infusion were increased and similar. Minimal systemic effects were observed, and there was no evidence of tolerance, there being no difference in heart rate after 7 minutes (70.7 +/- 2.7 beats per minute) and 4 hours (72.2 +/- 3.6 beats per minute) of isoproterenol infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Cyclosporine impairs vasodilation without increased sympathetic activity in humans.

Hypertension and nephrotoxicity frequently complicate treatment with cyclosporine; two suggested mechanisms are increased sympathetic activity and altered vascular reactivity. It is difficult to assess these mechanisms in patients receiving cyclosporine after transplantation because of the accompanying major physiological alterations. Therefore, we studied 12 patients with rheumatoid arthritis twice--while they were taking and not taking cyclosporine. We measured vascular response in the dorsal hand vein using the linear variable differential transformer technique. Cyclosporine treatment significantly attenuated vasodilation induced by 60 ng/min isoproterenol (no cyclosporine, 19.8 +/- 3.5% versus cyclosporine, 7.9 +/- 2.2%; P = .02) and prostaglandin E1 at 1000 pg/min (no cyclosporine, 72.6 +/- 10.2% versus cyclosporine 45.6 +/- 9.0%) and 2000 pg/min (no cyclosporine, 100.8 +/- 14.7% versus cyclosporine, 68.6 +/- 8.0%; F = 5.47, P = .047). However, neither vascular response to phenylephrine or nitroglycerin nor sympathetic activity assessed by measurement of norepinephrine spillover with a radioisotope dilution technique was affected by cyclosporine (no cyclosporine, 516.1 +/- 47.9 ng/min versus cyclosporine, 476.6 +/- 51.8 ng/min; P = .42). Cyclosporine impaired venodilation in response to two agonists that act through adenylate cyclase without altering alpha-agonist-induced venoconstriction or sympathetic activity. Therefore, in humans impaired vasodilation rather than sympathetic activation or enhanced vasoconstriction may be an important mechanism for the alterations of vascular tone that occur after long-term cyclosporine administration.

Adult↗
PubMed1995

Forearm beta adrenergic receptor-mediated vasodilation is impaired, without alteration of forearm norepinephrine spillover, in borderline hypertension.

Impaired beta adrenoceptor-mediated vasodilation associated with enhanced sympathetic activity has been reported in established hypertension. We examined whether altered beta adrenoceptor-mediated vasodilation occurs early in the disease process, when structural vascular changes are likely to be less marked, by measurement of forearm blood flow by strain gauge plethysmography after the intraarterial administration of increasing doses of a beta receptor agonist, isoproterenol, in eight subjects with borderline hypertension (BHT) and 13 normotensive (NT) controls. To determine the role of sympathetic activation in the regulation of responsiveness, we measured local sympathetic activity in the forearm by a radioisotope dilution technique. Vasodilation in response to isoproterenol, measured either as changes in forearm blood flow or forearm vascular resistance, was impaired in the BHT group so that flow at the highest dose of isoproterenol (400 ng/min) increased less (15.2 +/- 1.5 ml/100 ml per min) than in the NT group (24.4 +/- 2.4 ml/100 ml per minute) (P < 0.001). Although, systemic norepinephrine spillover was significantly greater in BHT, the difference in blood flow response to isoproterenol was not accounted for by increased local sympathetic activity since forearm norepinephrine spillover at baseline (BHT 1.0 +/- 0.4 ng/min vs. NT 0.64 +/- 0.13 ng/min) and after the administration of isoproterenol 60 ng/min (BHT 5.2 +/- 1.4 ng/min vs. NT 6.0 +/- 1.5 ng/min) and 400 ng/min (BHT 13.5 +/- 2.9 ng/min vs. NT 16.5 +/- 2.7 ng/min) did not differ between the two groups. We therefore conclude that vasodilation in response to isoproterenol is impaired in subjects with BHT and that this impairment is not explained by locally increased basal, or stimulated, sympathetic activity.

Adult↗