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Biomedical subjects

R R Freedman

Publications and source records attributed to R R Freedman.

At least 19 recordsLinked to original sources
PubMed2005

Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon.

OBJECTIVE: To investigate the response of skin arterioles from control subjects and patients with scleroderma and Raynaud's phenomenon (RP/SSc) to cooling and modulators of protein tyrosine kinase (PTK) activity. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal arterioles (100-200 microm, outside diameter) from normal (n = 17) and RP/SSc (n = 17) subjects to cooling from 37 degrees to 31 degrees C. Fluorescent immunohistochemistry was used to measure tyrosine phosphorylation. RESULTS: Arterioles from control subjects exhibited dilation in response to cooling from 37 to 31 degrees C whereas those from RP/SSc subjects contracted (+4.3 +/- 1.7 vs -16.7 +/- 3.1%, P < 0.05, n = 6). In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (SOV, 10 microM), the response of arterioles from control subjects did not change; however, arterioles from RP/SSC subjects exhibited a significantly greater contraction (-72.6 +/- 19.7%; P < 0.05, n = 6). Tyrosine phosphorylation of arterioles at 37 degrees C from control and RP/SSc subjects was similar. In response to cooling to 31 degrees C, however, arterioles from RP/SSc subjects exhibited a significantly greater increase in tyrosine phosphorylation compared with those from control subjects (43 +/- 7.0% vs 10 +/- 3.8%; P < 0.01). SOV increased tyrosine phosphorylation in arterioles from both groups (73 +/- 11.6% vs 42 +/- 5.6%; P < 0.05, n = 5). Arterioles from RP/SSC subjects precontracted with norepinephrine exhibited greatly attenuated relaxation to acetylcholine compared with those from control subjects. CONCLUSION: The results of this study support the view that the hallmark of Raynaud's phenomenon associated with scleroderma, cooling-induced vasospasm, appears to be mediated by an increase in PTK activity possibly exacerbated by impaired endothelium-dependent vasodilation.

Adult↗
PubMed2001

The Raynaud's Treatment Study: biofeedback protocols and acquisition of temperature biofeedback skills.

The Raynaud's Treatment Study (RTS) compared temperature biofeedback training and a behavioral control procedure (frontalis EMG biofeedback) with nifedipine-XL and a medication placebo for treatment of primary Raynaud's phenomenon (RP) in a large (N = 313) multicenter trial. The present study describes the RTS biofeedback protocols and presents data on the acquisition of digital skin temperature and frontalis EMG responses in the RTS. The findings point to substantial problems with acquisition of physiological self-regulation skills in the RTS. Only 34.6% of the Temperature Biofeedback group (N = 81) and 55.4% of the EMG Biofeedback group (N = 74) successfully learned the desired physiological response. In contrast, 67.4% of a Normal Temperature Biofeedback group (N = 46) learned hand warming. Multivariate analysis found that coping strategies, anxiety, gender, and clinic site predicted acquisition of hand-warming skills whereas variables related to RP disease severity did not. Physiological data showed vasoconstriction in response to the onset of biofeedback and also found that performance in the initial sessions was critical for successful acquisition. These findings indicate that attention to the emotional and cognitive aspects of biofeedback training, and a degree of success in the initial biofeedback sessions, are important for acquisition.

Adult↗
PubMed2001

Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma.

OBJECTIVE: To further specify the site of vascular dysfunction in patients with Raynaud's phenomenon (RP) and scleroderma. METHODS: Ten patients with RP and scleroderma and 11 healthy control subjects received brachial artery infusions of sodium nitroprusside, an endothelium independent vasodilator, bradykinin, and substance P while bilateral finger blood flow was measured with venous occlusion plethysmography. RESULTS: Both groups showed vasodilation to sodium nitroprusside. However, in response to the endothelium dependent compounds bradykinin and substance P, the controls showed vasodilation, whereas the patients showed vasoconstriction. CONCLUSION: The vascular defect in RP and scleroderma does not lie at the site of the muscarinic receptor, but possibly in a distal signaling mechanism.

Blood Flow Velocity↗
PubMed2001

Effect of temperature and modulators of protein tyrosine kinase activity on the reactivity of isolated venules in secondary Raynaud's phenomenon.

OBJECTIVE: To investigate the response of skin venules from healthy controls and scleroderma patients with Raynaud's phenomenon (RP/SSc) to cooling and to modulators of protein tyrosine kinase (PTK) activity at normal and reduced temperature. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal venules (200-400 microm outside diameter) from normal (n = 10) and RP/SSc (n = 8) subjects to cooling and to contractile agents at 37 and 31 degrees C. RESULTS. The response to clonidine at 37 degrees C was less in venules from patients with RP/SSc compared to controls; the contraction to serotonin was greater in venules from RP/SSc patients versus controls; at 31 degrees C, venules from RP/SSc patients contracted to both clonidine and serotonin to a greater extent versus controls; and contraction to these agonists was reversed by cumulative addition of genistein (1-100 microM). Venules from controls and patients with RP/SSc exhibited slight vasodilation to cooling from 37 to 31 degrees C. In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (10 microM), venules from controls now exhibited a small contraction (-5.1 +/- 3.2%) and venules from RP/SSC subjects a significantly greater contraction (-38.7 +/- 9.0%; p < 0.05). CONCLUSION: Our study supports the view that RP/SSc is the result of defects in the peripheral vasculature.

Adult↗
PubMed2000

Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women.

OBJECTIVE: To determine the effects of clonidine, which reduces central sympathetic activation, on the sweating threshold in postmenopausal women with and without hot flashes. DESIGN: Laboratory physiologic study. SETTING: University medical center. PATIENT(S): 12 healthy postmenopausal women reporting frequent hot flashes and 7 reporting none. INTERVENTION(S): In two separate sessions, participants received a blind intravenous injection of clonidine HCl (2 microg/kg of body weight) or placebo, followed by body heating. MAIN OUTCOME MEASURE(S): Core body temperature, mean skin temperature, sweat rate, sternal skin conductance level, and blood pressure. RESULT(S): Symptomatic women had significantly lower core body temperature sweating thresholds than asymptomatic women after receiving placebo. Clonidine significantly increased this threshold in symptomatic women but lowered it in asymptomatic women. CONCLUSION(S): These results support the hypothesis that elevated brain norepinephrine levels reduce the sweating threshold in symptomatic women, thereby contributing to the initiation of menopausal hot flashes.

Adrenergic alpha-Agonists↗
PubMed2000

Effects of menstrual cycle and race on peripheral vascular alpha-adrenergic responsiveness.

Gender differences in the incidence of many cardiovascular diseases may be due to the effects of sex hormones. Both alpha(1)- and alpha(2)-adrenergic receptors produce vasoconstriction in peripheral blood vessels and have demonstrated gender effects in previous studies. In addition, race has been shown to influence the effects of some alpha-adrenergic stimuli. We therefore sought to determine the effects of the menstrual cycle and race on peripheral blood flow responses to the intra-arterial infusion of phenylephrine (alpha(1)-agonist) and clonidine (alpha(2)-agonist). Ten white and 8 black women were studied during the early luteal phase and the follicular phase; these phases were verified in each woman through measurements of plasma estradiol and progesterone. Plasma norepinephrine was measured with HPLC. During phenylephrine infusion, there was significantly greater vasoconstriction in the luteal phase versus the follicular phase (P<0.05). There were no differences (P>0.8) between white and black women. During clonidine infusion, white women showed significantly more vasoconstriction in the follicular phase than during the luteal phase (P<0.006). For black women, the responses for both phases did not differ (P>0.9). Blood pressures were significantly higher in the black women (diastolic P<0.005, systolic P<0.05). The luteal-phase elevation of alpha(1)-adrenergic responses may be due to elevated levels of estradiol, progesterone, or both. The lack of luteal-phase reduction in alpha(2)-adrenergic vasoconstriction in black women may contribute to their increased pressor responses to adrenergic stimuli.

Adrenergic alpha-Agonists↗
PubMed1999

Reduced thermoregulatory null zone in postmenopausal women with hot flashes.

OBJECTIVE: Most menopausal hot flashes are preceded by small elevations in core body temperature. If the thermoneutral zone between the thresholds for sweating and shivering is reduced in women with symptoms, the triggering mechanism for hot flashes could be explained. STUDY DESIGN: We studied 12 postmenopausal women with symptoms and 8 without symptoms. We measured body temperatures with a rectal probe, an ingested telemetry pill, and a weighted average of rectal and skin temperatures. Each woman underwent 3 experimental sessions: determination of the sweating threshold by body heating, determination of the shivering threshold by body cooling, and replication of the sweating threshold with exercise. RESULTS: The women with symptoms had significantly smaller interthreshold zones than did the symptom-free women for all 3 measures of body temperature: rectal temperature, 0.0 degrees C +/- 0.06 degrees C versus 0.4 degrees C +/- 0.18 degrees C (P <.005); telemetry pill temperature, 0.0 degrees C +/- 0.11 degrees C versus 0.4 degrees C +/- 0.18 degrees C (P <.005); and mean body temperature, 0.8 degrees C +/- 0.09 degrees C versus 1.5 degrees C +/- 0.20 degrees C (P <. 0006). Sweat rates were significantly higher among the women with symptoms (0.06 +/- 0.002 mg. cm(-2). min(-1)) than among the women without symptoms (0.03 +/- 0.001 mg. cm(-2). min(-1), P <.05). Sweating thresholds during exercise did not significantly differ from those during body heating. During exercise all the women with symptoms and none of the women without symptoms had hot flashes. CONCLUSIONS: Menopausal hot flashes in women with symptoms may be triggered by small elevations in body temperature acting within a reduced thermoneutral zone.

Body Temperature↗
PubMed1999

Behavioral and pharmacologic interventions: the Raynaud's Treatment Study.

The Raynaud's Treatment Study (RTS) exemplified clinical trials with treatments that differ qualitatively both in their modes and in their methods of delivery. The RTS compared finger-temperature biofeedback to slow-release nifedipine, a calcium channel blocker, in patients with primary Raynaud's disease. Factors influencing the study design were the nature of the interventions and control measures of the protocol, the possibility of perceived differences by the patients between the treatments once the final protocol was developed, and concern on the part of the investigators over the fact that the primary endpoint was self-reported. This paper presents the final statistical model: a double parallel design with both a placebo group and a nonspecific behavioral control group.

Biofeedback, Psychology↗
PubMed1999

A thermal vascular test for distinguishing between patients with Raynaud's phenomenon and healthy controls. Raynaud's Treatment Study Investigators.

This study tested the reliability and validity of a diagnostic thermal vascular test (TVT) for patients with Raynaud's Phenomenon (RP). The TVT examined digital blood pressure responses to combined cooling and occlusion and was developed as part of the Raynaud's Treatment Study, a multicenter clinical trial comparing the efficacy of biofeedback and pharmacological treatment. A computerized system permitted efficient, accurate, and uniform testing at different geographical sites. A comparison of 199 patients with RP and 52 healthy controls is reported. The TVT showed a sensitivity of 79% and a specificity of 88%. Test-retest reliability was acceptable (r = .80). Addition of a psychological challenge failed to improve the discrimination between patients with RP and controls. The TVT separated patients with RP and controls as well as or better than existing tests and did so with enhanced ease of operation.

Diagnosis, Differential↗
PubMed1999

Feasibility and psychometrics of an ambulatory hot flash monitoring device.

OBJECTIVE: To assess the feasibility and psychometric properties of a lightweight, automated, ambulatory sternal skin conductance monitor to measure frequency of hot flashes (HFs) among breast cancer survivors (BCSs). DESIGN: A total of 19 postmenopausal BCSs and 5 premenopausal healthy comparison women participated by wearing the monitor for 24 h during their normal daily activities, including sleep. HFs were assessed using subjective (diaries, event markers) and objective (skin conductance) methods. RESULTS: Problems with subjective reporting of HFs were reported by 35% of BCSs. Technological problems and discomfort related to wearing the monitor were minimal. A total of 243 HFs were recorded using the skin conductance monitor by 17 BCSs and 5 premenopausal women (BCS group M = 13.4; range, 1-30). Subjective reporting of HFs was associated with a 31-33% false-positive rate. Skin conductance monitoring during waking hours was associated with a 30% false-negative rate. CONCLUSIONS: The monitor is a feasible method for objectively assessing HFs in BCSs. Data support continued use of sternal skin conductance as an objective measure of HF frequency. This technology should prove useful as an objective measure of HFs in future intervention research aimed at alleviating the symptom and improving quality of life among BCSs.

Adult↗
PubMed1999

Endothelial and adrenergic dysfunction in Raynaud's phenomenon and scleroderma.

OBJECTIVE: To investigate the involvement of endothelial and adrenergic mechanisms in patients with Raynaud's phenomenon (RP) and scleroderma. METHODS: Ten patients with RP and scleroderma and 10 healthy volunteer controls were studied. Intraarterial methacholine, sodium nitroprusside, and clonidine were administered while bilateral finger blood flow was measured with venous occlusion plethysmography. RESULTS: Compared to the controls, the patients showed diminished responses to methacholine, an endothelium dependent vasodilator, and to clonidine, an alpha2-adrenergic agonist. However, both groups showed similar responses to sodium nitroprusside, an endothelium independent vasodilator. CONCLUSION: The findings were consistent with previous histological evidence of endothelial damage in scleroderma blood vessels. Failure to release nitric oxide from vascular endothelium may play a role in RP in patients with scleroderma.

Adrenergic Agonists↗
PubMed1998

Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes.

OBJECTIVE: To determine if increases in core body temperature preceding most hot flashes are caused by increased metabolic rate, peripheral vasoconstriction, or central noradrenergic activation. DESIGN: Laboratory physiological study. SETTING: University medical center. PATIENT(S): Fourteen healthy, postmenopausal women reporting frequent hot flashes. INTERVENTION(S): Data were recorded for 3 hours in a temperature- and humidity-controlled room. MAIN OUTCOME MEASURE(S): Core body temperature, mean skin temperature, respiratory exchange ratio, sternal skin conductance, plasma 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid. RESULT(S): Twenty-nine physiologically defined hot flashes were recorded. Increases in core body temperature, measured with an ingested radiotelemetry capsule, preceded 76% of the flashes. Increased metabolic rate began after increased core temperature. Peripheral vasoconstriction did not occur. Plasma levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of brain norepinephrine, increased significantly, whereas vanillylmandelic acid, a peripheral metabolite, did not. CONCLUSION(S): Core body temperature elevations preceding menopausal hot flashes are not driven by peripheral vasoconstriction or increased metabolic rate, but probably by a central noradrenergic mechanism.

Analysis of Variance↗
PubMed1998

Effect of modulators of protein tyrosine kinase activity on gender-related differences in vascular reactivity at reduced temperature.

We used the isolated-muscle-bath technique to examine the effect of protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) inhibitors on the response of rings of tail artery from male and female rats to cooling and reduced temperature in the absence and presence of two PTK-dependent (clonidine and serotonin) and one PTK-independent (phenylephrine, PE) agonists. At 37 degrees C, reactivity to clonidine, serotonin, and PE was the same in tail artery from female and male rats. At 25 degrees C, reactivity to clonidine and serotonin, but not PE, was greater in tail artery from female rats compared with those from male rats. Sodium orthovanadate (SOV) eliminated the gender-related difference in the contractile effect of clonidine and serotonin at 25 degrees C. The sensitivity to relaxation by genistein was considerably greater for clonidine and serotonin at both temperatures as compared with PE. At 25 degrees C the sensitivity to genistein was greater for the clonidine and serotonin-contracted rings from female rats. In the presence of SOV, temperature reduction led to contraction of rat-tail artery. This effect was greater in rings from female rats. Our results strongly implicate differences in the activity of the PTK transduction pathway as the cause of the observed gender-related differences in agonist-mediated contraction at 25 degrees C and in cold-induced vasoconstriction.

Animals↗
PubMed1996

Familial aggregation of primary Raynaud's disease.

OBJECTIVE: To determine the occurrence of familial aggregation of primary Raynaud's disease. METHODS: Twenty-three patients with primary Raynaud's disease and their first-degree relatives were assessed by questionnaire and, when possible, by physical examination. The same procedures were performed on the patients' spouses and the spouses' first-degree relatives, who served as the control group. RESULTS: The prevalence of Raynaud's disease was significantly higher in the families of the probands than in the control families when assessed by questionnaire (26.1% versus 5.5%; P < 10(-5)), and by physical examination (11.2% versus 2.8%; P = 0.015). CONCLUSION: These findings demonstrate that there is significant familial aggregation of primary Raynaud's disease.

Adult↗
PubMed1996

Core body temperature during menopausal hot flushes.

OBJECTIVE: To measure core body temperature by ingested radiotelemetry pill and rectal temperature during menopausal hot flushes under controlled laboratory conditions. DESIGN: Patients were recorded during sleep using both methods in a sound-proofed, temperature and humidity-controlled laboratory room. SETTING: University medical center. PATIENTS: Eight postmenopausal women who were amenorrheic for > or = 1 year and reported frequent hot flushes. RESULTS: Thirty-seven hot flushes were detected by criterion increases in sternal skin conductance level. Significant increases in telemetered but not rectal temperature occurred before 24 of the hot flushes. CONCLUSIONS: Core body temperature elevations precede a majority of menopausal hot flushes and serve as one trigger of this heat-loss phenomenon.

Body Temperature↗
PubMed1995

Blockade of vasospastic attacks by alpha 2-adrenergic but not alpha 1-adrenergic antagonists in idiopathic Raynaud's disease.

BACKGROUND: Idiopathic Raynaud's disease is characterized by cold-induced digital vasospasms, but its origin has not been established. Previous research has shown that peripheral vascular alpha 2-adrenergic receptors are hypersensitive to local cooling in these patients, but the role of alpha 1-adrenergic receptors is not clear. Moreover, the role of adrenergic receptors in the production of actual vasospastic symptoms has not been investigated. METHODS AND RESULTS: We studied 23 patients with idiopathic Raynaud's disease who were screened using conservative criteria. They were randomly assigned to receive brachial artery infusions of an alpha 1-antagonist, an alpha 2-antagonist, or both while vasospastic attacks were induced by cooling in the laboratory. Each patient's hands were photographed, and the number of attacks in the infused hand was compared with the number in the contralateral hand. The number of fingers (mean +/- SEM) with attacks in infused hands was yohimbine 0.3 +/- 0.3, prazosin 2.3 +/- 0.3, and both drugs 0.6 +/- 0.2. The difference between prazosin and the other two drug groups was significant (P < .001). CONCLUSIONS: These findings demonstrate that activation of alpha 2-adrenergic receptors but not alpha 1-adrenergic receptors is necessary for the production of vasospastic attacks in idiopathic Raynaud's disease.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

Core body temperature and circadian rhythm of hot flashes in menopausal women.

Postmenopausal hot flashes are characterized by sweating and peripheral vasodilation and occur more frequently during increased heat loads. The circadian rhythm of core body temperature (TC) is well known and suggests that hot flashes will be most frequent when core temperature is highest. This hypothesis has not been tested previously. Ten symptomatic and six asymptomatic postmenopausal women were recruited from advertisements and screened. Each received 24-h ambulatory monitoring of sternal skin conductance levels to detect hot flashes, ambient temperature, skin temperature, and TC. The last measure was recorded using an ingested radiotelemetry pill. Cosinor analysis demonstrated a circadian rhythm (P < 0.02) of hot flashes with a peak at about 1825 h. TC values of the symptomatic women were lower than those of the asymptomatic women (P < .05) from 0000-0400 h and at 1500 and 2200 h. The majority of hot flashes were preceded by elevations in TC. Thus, elevated TC may serve as one trigger of menopausal hot flashes.

Body Temperature↗