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Biomedical subjects

D Robertson

Publications and source records attributed to D Robertson.

At least 361 records · Page 20Linked to original sources
PubMed1987

Postjunctional vascular smooth muscle alpha-2 adrenoreceptors in human autonomic failure.

Animal studies have suggested that vasoconstrictor alpha-2 adrenoreceptors exist on vascular smooth muscle cells. We tested this hypothesis in a patient with severe autonomic failure who demonstrated a pressor response to oral clonidine (a selective alpha-2 adrenoreceptor partial agonist). After clonidine 0.8 mg orally, mean arterial pressure rose by 54 mm Hg. After pretreatment with prazosin (a selective alpha-1 adrenoreceptor antagonist) and confirmation of alpha-1 blockade, clonidine 0.8 mg still raised mean arterial pressure by 43 mm Hg. After pretreatment with yohimbine (a selective alpha-2 adrenoreceptor antagonist), clonidine 0.8 mg elevated mean arterial pressure by 13 mm Hg. Since alpha-1 antagonism does not block, and alpha-2 antagonism does not block the pressor effect of clonidine, we conclude that clonidine raised blood pressure in this severely affected autonomic failure patient by vascular alpha-2 adrenoreceptor stimulation. Thus, this provides pharmacological evidence that postjunctional vascular smooth muscle alpha-2 adrenoreceptors exist in man and can modulate blood pressure.

Aged↗
PubMed1986

Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole.

In man, intravenous infusion of adenosine has been useful in inducing sustained hypotension during anesthesia. Bolus injections terminate supraventricular tachyarrhythmias by delaying AV node conduction. It has been proposed that some of its cardiovascular effects are related to inhibition of noradrenergic neurotransmission. We assessed the cardiovascular and sympathoadrenal effects of intravenous infusion of adenosine (10 to 140 micrograms/kg/min) in 7 conscious normal subjects. At the highest infusion rate achieved, adenosine increased heart rate by 33 bpm (p less than 0.005), increased systolic blood pressure by 13 mm Hg (p less than 0.02) and decreased diastolic blood pressure by 8 mm Hg (p less than 0.02). Plasma norepinephrine and epinephrine increased 44% and 213% respectively. Basal plasma renin activity was 0.7 +/- 0.09 ng AI/ml/hr and remained unchanged. Higher doses were not given due to the appearance of subjective side effects (headache, nervousness, flushing and an urge to breathe deeply). During dipyridamole administration, 4-fold lower doses were required to produce equivalent cardiovascular effects. We conclude that in conscious man, intravenous infusion of adenosine is associated with activation rather than inhibition of the sympathoadrenal system. The possible mechanisms of this sympathetic activation are discussed.

Adenosine↗
PubMed1986

Influence of yohimbine on release of anterior pituitary hormones.

We used a double-blind crossover design to study the effects of alpha 2 adrenoreceptor blockade with yohimbine on levels of anterior pituitary hormones. A dose of yohimbine was used which raised plasma norepinephrine from 379 +/- 74 (S.E.) to 730 +/- 143 pg/ml and mean arterial pressure from 83 +/- 4 to 92 +/- 5 torr (p less than 0.025). This dose (125 micrograms/kg, then 1 microgram/kg/min) also altered mood when compared to saline infusion. In spite of these changes, when prolactin, cortisol, ACTH, beta-endorphin, TSH and growth hormone were measured after 45 minutes of yohimbine infusion, no changes from baseline were noted. These data suggest that in normal man, at rest, alpha 2 adrenoreceptors in the hypothalamus, adenohypophysis or other brain areas do not tonically modulate release of these hormones into the blood.

Adrenocorticotropic Hormone↗
PubMed1986

Cross-linking of immunoglobulin E-receptor complexes induces their interaction with the cytoskeleton of rat basophilic leukemia cells.

Bridging of immunoglobulin E (IgE)-receptor complexes on rat basophilic leukemia cells by polyclonal anti-IgE antibodies induces a detergent-resistant association of these complexes with the cellular cytoskeleton. In dose-response curves the extent of the cytoskeletal association appears to follow the extent of bridging, continuing to increase beyond where stimulated degranulation is maximal. This stable association is maintained after the aggregated IgE-receptor complexes have been internalized by the cell. Multivalent antigen and trimeric IgE cause less extensive receptor cross-linking than anti-IgE and stimulate degranulation; they also induce receptor association with the cytoskeleton that is revealed only after stabilization by addition of a chemical cross-linking reagent. The ability of a membrane impermeant chemical cross-linker to stabilize this association suggests that the receptor-cytoskeletal interaction may be mediated by a transmembrane protein that is exposed at the cell surface. Monomeric and dimeric IgE bound to receptors fail to induce a stable interaction with the cytoskeleton even in the presence of chemical cross-linkers and are poor (dimers) or insignificant (monomers) stimulators of cellular degranulation. These findings are consistent with a possible relationship between receptor attachment to the cytoskeleton, receptor immobilization as measured by fluorescence photobleaching recovery, and the triggering of cellular degranulation.

Animals↗
PubMed1986

Management of chronic orthostatic hypotension.

Chronic orthostatic hypotension is characterized by recurrent symptoms of cerebral hypoperfusion due to low upright blood pressure levels. The initial approach should be to identify and correct reversible causes. Persistence of orthostatic hypotension suggests autonomic failure. The goal of management is to minimize symptoms and maximize functional capacity; therefore the magnitude of blood pressure fall is not as important as the advent of symptoms. Therapy is based upon the underlying pathophysiology and the risk/benefit ratio of interventions. Patient education and nondrug measures form the cornerstone of management. Drug therapy is often limited by unacceptable supine hypertension. Rational drug use can be governed by individualized trials of therapy. Patients with moderate or severe orthostatic hypotension are difficult to treat, but can be helped toward resumption of a normal life.

Activities of Daily Living↗
PubMed1986

Atrial pressure and secretion of atrial natriuretic factor into the human central circulation.

Atrial natriuretic factor, a peptide found in mammalian cardiac atria, has natriuretic and vasodilatory properties that may be important in the regulation of intravascular volume. To study factors related to its release in human subjects, intracardiac pressures and plasma atrial natriuretic factor concentrations in the central circulation were measured in 34 patients with a variety of cardiovascular disorders. Plasma atrial natriuretic factor concentration increased from the inferior vena cava to the right atrium (76 +/- 24 to 162 +/- 37 pg/ml, p less than 0.001) and from the vena cava to the aorta (76 +/- 24 to 177 +/- 46 pg/ml, p less than 0.001). Mean right atrial pressure was positively correlated with atrial natriuretic factor concentration in the pulmonary artery (r = 0.58, p less than 0.001), and mean pulmonary capillary wedge pressure was positively correlated with concentration in the aorta (r = 0.64, p less than 0.001). In six patients whose atrial natriuretic factor concentrations were measured at two different levels of atrial pressure, increased atrial pressure was accompanied by increased atrial natriuretic factor concentration in the pulmonary artery (p less than 0.01) and aorta (p less than 0.01). Atrial natriuretic factor levels measured in fresh myocardium from a patient undergoing cardiac transplantation showed tissue concentrations in the atria 500-fold higher than tissue concentrations in the ventricles. These data document that atrial natriuretic factor is found in human atrial myocardium and suggest that it may be released in response to increased atrial pressure. Such a secretory release mechanism is consistent with the hypothesis that atrial natriuretic factor plays a role in the regulation of circulatory volume.

Adult↗
PubMed1986

Reduction of liver plasma flow by caffeine and theophylline.

Caffeine and theophylline block the vasodilating effects of adenosine and may act to enhance sympathoadrenal discharge and activate the renin-angiotensin system. To determine if these methylxanthines might thereby have effects on regional blood flow, we studied the influence of caffeine and theophylline on apparent liver plasma flow (LPF) in normal subjects as assessed by indocyanine green clearance. Oral caffeine, 250 mg, reduced LPF by 19% from 630 +/- 150 to 510 +/- 120 ml/min (P less than 0.001). Intravenous theophylline (4.3 mg/kg) reduced LPF by 15% from 550 +/- 50 to 470 +/- 90 ml/min (P less than 0.05). These methylxanthine-induced falls in LPF may alter the disposition of concomitantly administered drugs. Because of their widespread use in Western society, caffeine and theophylline may be major determinants of liver blood flow in the general population. They may therefore prolong the t1/2 and increase steady-state levels of hepatically eliminated drugs.

Adenosine↗
PubMed1986

Sodium loading and posture modulate human atrial natriuretic factor plasma levels.

Atrial natriuretic factor is postulated to act through atrial stretch receptors as a volume regulatory hormone that stimulates diuresis and natriuresis in response to increased atrial pressure. To characterize the stimuli associated with the release of atrial natriuretic factor in humans, we studied 14 normal subjects, both in the supine position and after 10 minutes in an upright posture, while they were on a regular diet (Day 0) and during 3 days of supplemental sodium chloride intake (8 g/day). Radioimmunoassay of plasma atrial natriuretic factor was performed with rabbit antibody to the human hormone amino acids (102-126). Urinary sodium excretion increased from 111 +/- 13 mEq/day (mean +/- SEM) on Day 0 to 275 +/- 15 mEq/day by the third day (Day 3) of high sodium intake. The level of atrial natriuretic factor in the supine position rose from 17 +/- 4 pg/ml (Day 0) to 76 +/- 13 pg/ml on Day 3 (p less than 0.001) and after 10 minutes in an upright posture on Day 3, the level fell to 32 +/- 10 (p less than 0.005). Plasma concentrations of atrial natriuretic factor correlated positively with spot and 24-hour urinary sodium excretion and weight gain, and correlated negatively with plasma aldosterone and renin activity. We conclude that the response of atrial natriuretic factor to sodium loading and posture change in humans is appropriate for a volume regulatory hormone.

Adult↗
PubMed1986

Plasma catecholamine modulation of alpha 2 adrenoreceptor agonist affinity and sensitivity in normotensive and hypertensive human platelets.

We measured alpha 2-adrenoreceptor density as well as affinity for and sensitivity to agonist on intact platelets of normotensive and hypertensive subjects before and after physiological increases in plasma catecholamines. In normotensives, posture-induced rises in plasma catecholamines correlated with reduced alpha 2-adrenoreceptor agonist affinity and fewer high affinity state receptors. Platelet aggregation and inhibition of adenylate cyclase by L-epinephrine also was reduced. Hypertensive subjects had similar rises in plasma catecholamines with upright posture, but showed no change in receptor affinity or sensitivity. No change in platelet alpha 2-adrenoreceptor number occurred in these studies. In vitro incubation with L-epinephrine revealed that platelets from hypertensives had slower desensitization than those from normotensives. Binding studies at different temperatures and with varying sodium concentrations found no thermodynamic or sodium-dependent differences between normotensive and hypertensive groups. These studies demonstrate that platelets from hypertensive subjects exhibit a defect in the ability of physiological concentrations of agonist to desensitize the alpha 2-adrenoreceptor.

Adenosine Diphosphate↗
PubMed1986

Use of alpha 2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system.

We studied the effects of clonidine, an alpha 2-adrenoreceptor agonist, and yohimbine, an alpha 2-adrenoreceptor antagonist, on blood pressure, heart rate, and plasma catecholamines in 12 patients with autonomic dysfunction. Clonidine (0.1 mg, orally) lowered blood pressure 18 +/- 3 torr in six subjects and raised it 5 +/- 1 torr in six. The change in blood pressure in response to this dose of clonidine was inversely proportional to the supine level of norepinephrine (P less than 0.05). Yohimbine (4-64 micrograms/kg) raised plasma norepinephrine and blood pressure in six patients with degenerative autonomic dysfunction. Yohimbine also attenuated by 50% (P less than 0.05) the hypotensive response to head-up tilt of patients with degenerative autonomic dysfunction. Clonidine depends upon postjunctional hypersensitivity and the degree of autonomic insufficiency to elicit its pressor response. In contrast, the pressor response to yohimbine is related to the capacity of the sympathetic nervous system to be activated and release norepinephrine. If plasma norepinephrine levels following yohimbine administration are monitored, the biochemical and hemodynamic response to the drug may provide a sensitive indication of the capacity of the sympathetic nervous system to be activated in patients with autonomic dysfunction.

Adult↗
PubMed1986

[Alpha 2-adrenoreceptor regulation in the human body].

The affinity of platelet alpha-2-adrenoreceptors for adrenaline is decreased in vivo and in vitro exposure of platelets to catecholamines at physiological concentrations in normal subjects. The direction of these alterations is consistent with the direction of the desensitization phenomena observed in the intact platelet. Hypertensive subjects display an abnormality characterized by an inability to reduce the affinity of their platelet alpha-2-adrenoreceptors in response to increased circulating levels of catecholamines. The potential importance of this defect in the etiology and clinical manifestations of essential hypertension remains to be ascertained.

Adenosine Diphosphate↗
PubMed1986

Induction of ligand carrying "natural liposomes" in cancer cells.

N-ethyl-maleimide (NEM) induced plasma membrane vesiculation of human cancer cell line EJ was studied in vitro using immunoelectromicroscopic methods. We have demonstrated the presence of plasma membrane glycoconjugates and antigens on these vesicles. The effect of NEM or Ricin-antiRicin antibody complex internalisation was also followed. It was revealed that NEM is able to block the internalisation and stimulate the recycling arm of the complex-traffic. Multivesicular endosome-derived plasma membrane vesicles play import role in this recycling. According to the presented evidences it is possible to produce ligands carrying "natural liposomes".

Antigen-Antibody Complex↗
PubMed1986

Biochemical aspects of inner ear fluids and possible implications for pharmacological treatment.

Inner ear fluids are in dynamic equilibrium with surrounding fluids, namely blood and cerebrospinal fluid. It is known that substances injected into the blood stream or cerebrospinal fluid are transported into the inner ear fluids. The rate of transport from blood into perilymph is inversely related to the molecular weight or molecular size. There appears to exist a blood-labyrinth barrier. In general, the morphology of capillaries in the spiral ligament and stria vascularis is similar to that of brain capillaries which contribute to formation of the blood-brain barrier. Information on the volume of the inner ear fluids is necessary for estimating the toxicity of the drugs as well as the effective concentration of systemically injected substances. Recently, alteration of the levels of arachidonic acid metabolites, especially the prostaglandins, in perilymph under experimental conditions has been reported. The responses of prostaglandin levels in perilymph to these experimental conditions (aspirin injection, antidiuretic hormone or epinephrine infusion) suggest that prostaglandins may play an important role under physiological conditions. Possible mechanisms of auditory dysfunction due to abnormal prostaglandin metabolism in the auditory system are discussed.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Hemodynamic and humoral effects of caffeine in autonomic failure. Therapeutic implications for postprandial hypotension.

We examined the effects of caffeine and meals on blood pressure and heart rate in 12 patients with autonomic failure. The influence of caffeine on plasma norepinephrine, epinephrine, and renin activity was also studied. Caffeine 250 mg, raised blood pressure by 12/6 mm Hg, from 129 +/- 25/78 +/- 12 (mean +/- S.D.) to a maximum of 141 +/- 30/84 +/- 16 mm Hg at 45 minutes (P less than 0.01), but did not change heart rate, levels of norepinephrine, or epinephrine, or plasma renin activity. Blood pressure fell by 28/18 mm Hg after a standardized meal, from 133 +/- 32/80 +/- 15 to a minimum of 105 +/- 21/62 +/- 12 mm Hg at 60 minutes (P less than 0.01). After pretreatment with 250 mg of caffeine, the standardized meal induced a fall of only 11/10 mm Hg, from 140 +/- 33/79 +/- 7 to 129 +/- 31/69 +/- 13 mm Hg at 60 minutes (P less than 0.05 vs. values after the control per day for seven days) in five patients, postprandial blood pressures remained higher after caffeine than after placebo (P less than 0.05). We conclude that caffeine is a pressor agent and attenuates postprandial hypotension in autonomic failure, and that this effect is not primarily due to elevations in sympathoadrenal activity or activation of the renin-angiotensin system. Caffeine may be useful in the treatment of orthostatic hypotension due to autonomic failure, especially in the postprandial state.

Aged↗