Biomedical subjects

R M Robertson

Publications and source records attributed to R M Robertson.

At least 55 records · Page 3Linked to original sources

PubMed1997

The hypertension of autonomic failure and its treatment.

We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure > or =90 mm Hg. The prevalence of hypertension was slightly greater in females (63%) than in males (52%). Potential mechanisms responsible for this hypertension were investigated. No correlation was found between blood volume and blood pressure. Similarly, plasma norepinephrine (92+/-15 pg/mL) and plasma renin activity (0.3+/-0.05 ng/mL per hour) were very low in the subset of patients with pure autonomic failure and supine hypertension (mean systolic/diastolic pressure, 177 +/- 6/108 +/- 2 mm Hg, range 167/97 to 219/121). Supine hypertension represents a challenge in the treatment of orthostatic hypotension. We found these patients to be particularly responsive to the hypotensive effects of transdermal nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h decreased systolic blood pressure by 36+/-7 mm Hg and may effectively treat supine hypertension overnight, but the dose should be individualized and used with caution.

Aged↗

PubMed1997

Skin tone, hostility, and blood pressure in young normotensive African Americans.

Several studies have found a positive relationship between darkness of skin tone and blood pressure in African Americans. This has raised speculation about the relative contributions of genetic and/or psychosocial factors in the mediation of this relationship. Using a laboratory stress protocol, we performed cardiovascular reactivity testing with 42 male and 40 female African-American college students after pre-testing them on measures of hostility using four psychometric scales derived from the Minnesota Multiphasic Personality Inventory (MMPI). Skin tone measures were obtained with a reflectance spectrophotometer. In the combined sample of males and females, we found a weak but statistically significant positive relationship between darker skin tone and systolic blood pressure (p = 0.03). However, males were significantly darker than females (p = .005) suggesting that the skin tone and blood pressure relationship is an artifact of gender. No differences in patterns of cardiovascular habituation or levels of hostility were found between dark and light subjects. Discussion of these results focuses on the weak statistical relationship found in this and other studies and the specificity of previous findings based on educational and socioeconomic factors.

Adult↗

PubMed1997

Blood pressure response to orthostatic and mental challenge in African-American women taking oral contraceptives.

BACKGROUND: Contraceptive use among women with an elevated risk of cardiovascular disease and stroke has generated little concern among primary care physicians. African Americans in the southeastern region of the United States are particularly vulnerable to hypertension but are often neglected in research studies of cardiovascular disease. The current study examines the effect of oral contraceptive use by African-American women on blood pressure response to orthostatic and mental challenges. METHODS: One hundred African-American women between the ages of 19 and 29 years were recruited from the student populations of Meharry Medical College and Flask University in Tennessee for a study of oral contraceptive use and blood pressure. Of 95 subjects on whom complete data were collected, 31 were taking oral contraceptives (OCs). As a measure of orthostatic challenge, each subject's blood pressure was monitored by a Dinamap automated instrument while she moved from a supine to sitting to standing position. To test blood pressure reactivity to mental challenge, a subset of 34 subjects (10 OC users and 24 nonusers) were monitored while they attempted to perform a frustrating cognitive task on a computer. RESULTS: There were no differences between users and nonusers of oral contraceptives with respect to the amount of change in blood pressure associated with either the orthostatic or mental challenge. Levels of systolic blood pressure and mean arterial pressure, however, were consistently higher in subjects using oral contraceptives (P < .05) under both testing conditions. Systolic blood pressure levels were 6.7 mm Hg to 9.7 mm Hg higher in OC users during each of the three conditions of orthostatic challenge and 4.4 mm Hg to 7.4 mm Hg higher during each of the four periods of mental challenge. Among OC users, mean arterial pressure levels were 2.9 mm Hg to 4.7 mm Hg higher during orthostatic challenge and 5.0 mm Hg to 8.3 mm Hg higher during mental challenge. CONCLUSIONS: While absolute levels of systolic blood pressure never exceeded 126 mm Hg under either testing condition, the difference in blood pressure levels between the OC users and nonusers warrants concern about the long-term effects of oral contraceptive use among African-American women. Although all OC users in this study were taking low-dose formulations, OC use did not eliminate the risk of elevated blood pressure in this population. Our findings suggest that caution is warranted and that alternative birth control methods should be advised for African-American women who have additional risk factors for cardiovascular disease.

Adult↗

PubMed1996

Neural parameters contributing to temperature compensation in the flight CPG of the locust, Locusta migratoria.

Elevated thoracic temperature increases the wingbeat frequency of flying locusts. We investigated the extent to which temperature-induced changes in resting membrane potential and postsynaptic potential amplitude contribute to the effects of increased temperature on the frequency of the central flight rhythm. Flight neurons were hyperpolarized by changing the K+ concentration of the superfusing saline from 10 mM to 2 mM. 5 min of low-K+ superfusion hyperpolarized flight motoneurons from -42.8 mV to -50.1 mV with a concomitant decrease of the frequency of the central flight rhythm from 11.6 Hz to 10.5 Hz. The amplitude of postsynaptic potentials was halved after 10 min of zero Ca2+/high Mg2+ superfusion, but the frequency of the central rhythm did not change significantly. GABAergic inhibitory connections were reduced in amplitude using picrotoxin. This treatment increased the frequency of the central rhythm from 11.6 Hz to 12.9 Hz, and increased the thermosensitivity of the rhythm frequency. We conclude that the excitatory effect of increased temperature on rhythm frequency is not mediated by temperature effects on membrane potential and/or synaptic potential amplitude. We propose that the inhibitory effect of temperature-induced hyperpolarization of the membrane potential compensates for the excitatory effect of temperature on rhythm frequency (e.g. via increased conduction velocity). We further suggest that some measure of temperature compensation is afforded by equal effects on the amplitudes of excitatory and inhibitory postsynaptic potentials, such that the net effect on the level of excitation is zero.

Animals↗

PubMed1996

Structure of the forewing stretch receptor axon in immature and mature adult locusts.

During the first 2 weeks following imaginal ecdysis, the wingbeat frequency of Locusta migratoria doubles, and the activity of the forewing stretch receptor (fSR), in response to wing elevation, increases. We examined the three-dimensional structure of the centrally projecting axon of the fSR during adult maturation to determine if there are changes in the branching geometry. We found that changes occur in the mesothoracic projection (IISR Meso). Here, there was a significant increase in the volume of the projection from 2.3 x 10(4) +/- 0.2 x 10(4) microns 3 in immature locusts to 6.0 x 10(4) +/- 1.2 x 10(4) microns 3 in mature locusts. There were also significant increases in the total length, the number of branch points, the number of axonal swellings, and the diameters of first- and second-order branches of the projection. No significant changes were observed in the prothoracic projection (IISR Pro), and the only significant change observed in IISR Meta was negative allometric growth relative to IISR Meso. These results demonstrate that during adult maturation, growth of the fSR axon is heteromorphic between different ganglionic projections and that there is a potential increase in the connectivity of IISR Meso to other flight neurons in the mesothoracic ganglion. We suggest that this may be a mechanism for maintaining the efficacy of afferent input to flight interneurons that are also growing during maturation.

Animals↗

PubMed1996

Exposure to heat shock affects thermosensitivity of the locust flight system.

The natural habitat of the migratory locust, Locusta migratoria, is likely to result in locusts being heat stressed during their normal adult life. It is known that locusts exhibit a heat-shock response: exposure to 45 degrees C for 3 h induces thermotolerance and the expression of heat-shock proteins. We investigated the effects of exposure to heat-shock conditions on the thermosensitivity of flight rhythm generation in tethered, intact animals and in deafferented preparations. Heat shock had no effect on wingbeat frequency measured at the start of flight sequences, nor did it affect the postimaginal maturation of this parameter. During sustained flight, heat shock slowed the characteristic asymptotic reduction of wingbeat frequency. Wingbeat frequency of heat-shocked animals was less sensitive to temperature in the range 24 degrees to 47 degrees C than that of control animals, and the upper temperature limit, above which flight rhythms could not be produced, was 6 degrees to 7 degrees C higher in heat-shocked animals. These results were mirrored in the response of deafferented preparations, indicating that modifications in the properties of the flight neuromuscular system were involved in mediating the response of the intact animal. We propose that exposure to heat shock had the adaptive consequences of reducing thermosensitivity of the neural circuits in the flight system and allowing them to operate at higher temperatures.

Adaptation, Physiological↗

PubMed1996

Clinical models of cardiovascular regulation after weightlessness.

After several days in microgravity, return to earth is attended by alterations in cardiovascular function. The mechanisms underlying these effects are inadequately understood. Three clinical disorders of autonomic function represent possible models of this abnormal cardiovascular function after spaceflight. They are pure autonomic failure, baroreflex failure, and orthostatic intolerance. In pure autonomic failure, virtually complete loss of sympathetic and parasympathetic function occurs along with profound and immediate orthostatic hypotension. In baroreflex failure, various degrees of debuffering of blood pressure occur. In acute and complete baroreflex failure, there is usually severe hypertension and tachycardia, while with less complete and more chronic baroreflex impairment, orthostatic abnormalities may be more apparent. In orthostatic intolerance, blood pressure fall is minor, but orthostatic symptoms are prominent and tachycardia frequently occurs. Only careful autonomic studies of human subjects in the microgravity environment will permit us to determine which of these models most closely reflects the pathophysiology brought on by a period of time in the microgravity environment.

Autonomic Nervous System↗

PubMed1995

Hydrophobic amino acid residues of human anticoagulation protein C that contribute to its functional binding to phospholipid Vesicles.

The contributions to functional phospholipid (PL) binding of the cluster of amino acid side chains of human protein C (PC) comprising F4, L5, and L8 have been assessed by construction of mutants of PC and activated protein C (APC) designed wherein a hydrophilic side chain replaced the wild-type hydrophobic groups at these positions. The PL-dependent plasma-based anticoagulant activities of [F4Q]-r-APC and [L8Q]r-APC were severely reduced to 5% and < 2%, respectively, of wild-type r-APC. Activity losses of the mutants toward inactivation of coagulation factor VIII, measured in the complete in vitro tenase system, have also been observed. As evidenced through Ca(2+)-induced intrinsic fluorescence changes, both [F4Q]r-PC and [L8Q]r-PC were able to adopt Ca(2+)-dependent conformations that appeared similar to that of wtr-PC, ruling out shortcomings associated with such Ca(2+)-induced transitions as the basis for their anticoagulant activity losses. However, despite this, [L8Q]r-PC showed greatly defective macroscopic binding properties to PL vesicles, as did to a lesser extent [F4Q]r-PC. These findings were similar to those reported previously for [L5Q]r-PC/APC [Zhang, L., & Castellino, F. J. (1994) J. Biol. Chem. 269, 3590-3595]. We thus propose that the PL-dependent activity losses of these mutants are related to their suboptimal binding to PL or to their misorientation on the PL surface leading to poor alignment of the active sites of the r-APC mutants with the complementary cleavage sites on fVIII/fVIIIa and fV/fVa.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1995

Outbreak of cryptosporidiosis associated with a disinfected groundwater supply.

In an outbreak of cryptosporidiosis in Warrington, a town in North-West England, 47 cases were recorded between November 1992 and February 1993, most within the first month. There was a strong statistical association between cases and residence in an area supplied from two groundwater sources. In a case-control study, a strong association between having drunk unboiled tap water from these sources, and a dose-response relationship were found. Oocysts were not detected in the water supply. During very heavy rainfall one source of water was found to drain surface water directly from a field containing livestock faeces, thereby bypassing natural sandstone filtration. Exceptionally heavy rainfall occurred at the probable time of infection. After withdrawal of the original water supply, the outbreak rapidly subsided. It was concluded that there was very strong evidence that this outbreak was waterborne. This, the second documented outbreak of cryptosporidiosis attributable to a groundwater supply, demonstrates that infection can be transmitted from a disinfected groundwater source despite apparently satisfactory treated water quality. We recommended that guidelines for protection of groundwater are implemented, raw groundwater should be routinely monitored for microbiological contamination, and the structure of all sources and waterworks should be assessed in risk surveys of water catchment areas.

Adult↗

PubMed1995

Contraction of isolated porcine coronary arteries is inhibited by high concentrations of propranolol.

Isometric tension responses of isolated porcine coronary artery rings were studied in the presence of concentrations of propranolol higher than those necessary to block effects mediated by beta-adrenergic receptors. Propranolol (50-300 microM) inhibited contractions induced by 30 mM KCl and by histamine, norepinephrine, and acetylcholine in a concentration-dependent, noncompetitive fashion. The (+) propranolol isomer and the racemic mixture were equipotent inhibitors of contraction. Propranolol inhibition was partly reversed by increased extracellular Ca++. These effects of propranolol thus appeared to be independent of beta-blockade and could be relevant to some of the drug's observed but still unexplained in vivo actions.

Acetylcholine↗

PubMed1994

Causes of chronic orthostatic hypotension.

OBJECTIVE: To determine the frequency of various causes of orthostatic hypotension. DESIGN: Survey. SETTING: Tertiary referral center. PATIENTS: One hundred patients with moderate to severe orthostatic hypotension. RESULTS: Twenty-seven percent of the patients had primary autonomic failure, 35% had secondary autonomic failure, and 38% had hypotension without evidence of generalized autonomic degeneration. CONCLUSIONS: In a tertiary referral center, only a minority of patients with severe orthostatic hypotension will have Shy-Drager syndrome or Bradbury-Eggleston syndrome as their primary disease. Occasional patients who initially appear to have Bradbury-Eggleston syndrome ultimately prove to have Shy-Drager syndrome or paraneoplastic autonomic failure. Antidepressant drugs, even in low doses, remain a major overlooked cause of orthostatic hypotension.

Adolescent↗

PubMed1994

Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure.

It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.

Autonomic Nervous System Diseases↗

PubMed1994

The head and neck discomfort of autonomic failure: an unrecognized aetiology of headache.

Information concerning the frequency, severity, character, location, duration, diurnal pattern of headache and ancillary symptoms were obtained in 25 patients with autonomic failure and 44 control subjects. Precipitating and ameliorating factors were identified. Autonomic failure patients had more head and neck discomfort than controls. Their discomfort was much more likely to localize in the occiput, nape of the neck and shoulder, compared with controls. There was a greater tendency for the discomfort to occur in the morning and after meals. It was sometimes less than 5 min in duration and was often associated with dimming, blurring, or tunnelling of vision. It was provoked by upright posture and relieved by lying down. Patients with severe autonomic failure and orthostatic hypotension often present with a posture-dependent headache or neck pain. Because the relationship of these symptoms to posture is often not recognized, the fact that these findings may signal an underlying autonomic disorder is underappreciated, and the opportunity to consider this aetiology for the headache may be missed.

Autonomic Nervous System Diseases↗

PubMed1994

A sensitive radioimmunoassay for fludrocortisone in human plasma.

Fludrocortisone has been a mainstay of therapy for orthostatic hypotension for many years. Clinical experience suggests that there exists a substantial interindividual variation in responsiveness to the drug. To assess this, we have developed an assay that permits measurement of the low concentrations of fludrocortisone found in human plasma. Fludrocortisone was detected by radioimmunoassay. A polyclonal rabbit antibody, raised against dexamethasone which cross-reacts strongly with fludrocortisone, was reacted with either standard or unknown samples in the presence of [125I]fludrocortisone-3-TyrNH2 (synthesized by coupling tyrosine amide to fludrocortisone-3-oxime and iodinating with chloramine T oxidation). The ED10, ED50, and ED80 were 0.34, 5.0, and 30 ng/mL of plasma, respectively. The cross reactivity with other 9-fluorinated steroids was found as follows: dexamethasone, 340%; betamethasone, 230%; and triamicinolone, 8%. To preclude an erroneous result, subjects who were pregnant or receiving any steroid medication were excluded from the study. The percent cross-reactivity with the main naturally occurring steroids was as follows: 11-desoxycortisol 3.2%, cortisol 1.1%, DOC 0.3%, pregnenolone 0.1%, corticosterone 0.06%, progesterone 0.05%, and aldosterone < 0.05%. The only compound with potential for interference, because of its high level in the circulation in the early morning, was cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

Fludrocortisone↗

PubMed1993

The diagnosis and treatment of baroreflex failure.

BACKGROUND: Baroreflexes originate in the great vessels of the neck and thorax and prevent arterial pressure from rising or falling excessively. METHODS: This study was undertaken to clarify the cause, clinical spectrum, and therapy of this disorder. We studied 11 patients with baroreflex failure presenting as severe, labile hypertension and hypotension, often with headache, diaphoresis, and emotional instability, and characterized by the failure of exogenous vasoactive substances to alter heart rate. Each underwent hemodynamic monitoring and biochemical, physiologic, and pharmacologic testing. RESULTS: The patients' maximal systolic blood pressures ranged from 164 to 280 mm Hg, and their minimal systolic pressures ranged from 58 to 96 mm Hg. Plasma norepinephrine and epinephrine concentrations were sometimes many times normal during blood-pressure surges. All the patients had excessive pressor and tachycardia responses to the mental-arithmetic and cold pressor tests and marked hypersensitivity to clonidine. The underlying causes of baroreflex failure included the familial paraganglioma syndrome, neck surgery or radiation therapy for pharyngeal carcinoma, bilateral lesions of the nucleus tractus solitarii, and surgical section of the glossopharyngeal nerves; in two patients the cause was unknown. Therapy with clonidine reduced the frequency of attacks by 81 percent and attenuated the elevated blood pressure and heart rate in the attacks that occurred. CONCLUSIONS: The syndrome of baroreflex failure should be considered in patients with otherwise unexplained labile hypertension. Clonidine attenuates the pressor and tachycardic surges in baroreflex failure.

Adult↗

PubMed1993

Effects of temperature on synaptic potentials in the locust flight system.

1. Neuronal circuitry in the locust flight system operates normally within a temperature range of 24-42 degrees C. I investigated the effects of temperature on parameters of postsynaptic potentials generated in different neurons following action potentials of the forewing stretch receptor. 2. Increases in temperature reduced latency, time-to-peak and duration (Q10s = 0.51, 0.70, and 0.68, respectively; 24-34 degrees C) and increased the slope (Q10 = 1.13; 24-34 degrees) of the excitatory postsynaptic potential (EPSP). However, increases in temperature increased EPSP amplitude below room temperature (Q10 = 1.25; 14-24 degrees C) but decreased EPSP amplitude above room temperature (Q10 = 0.80; 24-34 degrees C). 3. I conclude that neuronal and synaptic function were affected by temperature in ways predictable by well-established thermal effects on channel conductance and kinetics and on membrane properties. Thus temperature compensation of the output of the flight system must be mediated in some way by the operation of the circuitry. 4. I propose that below room temperature EPSP amplitude was increased by predominant effects on channel conductance and membrane time constant, and above room temperature EPSP amplitude was decreased by a predominant effect on the amplitude and duration of the presynaptic action potential. Further, I suggest that the frequency of the output rhythm is unaffected by the amplitude of single EPSPs, within permissive limits.

Animals↗

PubMed1993

Endothelin as a neuropeptide. Cardiovascular effects in the brainstem of normotensive rats.

The relevance of endothelin in central cardiovascular function was studied in urethane-anesthetized Sprague-Dawley rats. Blood pressure (BP) was monitored intra-arterially, and cerebrospinal fluid (CSF) was collected through an intracisternal catheter for radioimmunoassay of endothelin-1 (ET-1). Endothelin levels in the CSF were significantly higher (39 +/- 3 pg/ml) than in plasma (10 +/- 3 pg/ml, n = 11). ET-1 in CSF or plasma was not affected by systemic infusion of saline, but its levels significantly decreased when a sustained increase in BP was elicited with phenylephrine (14 +/- 7 pg/ml in the CSF and 6 +/- 4 pg/ml in plasma, n = 5). In sinoaortic-denervated animals, phenylephrine failed to reduce CSF endothelin levels. In different experiments, intracisternal administration of ET-1 (10 pmol) evoked an initial decrease in BP and heart rate (HR), followed by pronounced hypertension, bradycardia, and, in 70% of the animals, death from cardiorespiratory failure. Intracisternal administration of endothelin-3 (ET-3, 80 pmol, n = 11) evoked only a modest hypotensive and bradycardic response without cardiorespiratory impairment. Microinjection of ET-1 (0.5, 1, 2, 4, and 6 pmol/60 nl) into the nucleus of the solitary tract or area postrema produced a decrease in BP and HR. On the other hand, injection of low concentrations of ET-3 into the nucleus of the solitary tract increased BP and HR (at 2 pmol, 17 +/- 3 mm Hg, 14 +/- 6 beats per minute, n = 7), whereas ET-3 in the area postrema produced a prominent dose-related decrease in BP and HR. In the rostroventrolateral medulla, the lowest doses of ET-1 first modestly increased BP and renal sympathetic nerve activity. These effects were followed by hypotension, bradycardia, increase in respiratory frequency, and further enhancement of sympathetic nerve traffic. In 29% of the animals, these effects were followed by cardiorespiratory arrest. The specificity of the cardiovascular response to endothelin was demonstrated by the inhibitory effects of the receptor antagonist BQ-123. These results demonstrate that endothelin has specific cardiovascular effects in the brainstem of the rat and support a role for endothelin in cardiovascular regulation.

Animals↗

PubMed1992

Administration of dexfenfluramine in pregnant rats: effect on brain serotonin parameters in offspring.

Dexfenfluramine (DFEN) was infused SC at doses of either 6 or 12 mg/kg/day during the last week of pregnancy in rats. Compared with untreated controls, weight gain of dams was attenuated by DFEN without effect on the number or birth weight of offspring. Brain serotonin (5-HT) concentration and/or paroxetine binding to the 5-HT uptake carrier was reduced by 20% on the day after birth in one study but not in two other studies. No decreases in brain 5-HT parameters were observed on or after the sixth postnatal day. In contrast, mothers sustained large depletions of brain 5-HT when measured at least 3 weeks after giving birth. These data indicate that fetal brains either are protected from or recover rapidly from the 5-HT-depleting actions of high-dosage regimens of DFEN in rats.

Animals↗