Alpha-adrenergic Receptor Function Research Articles

Persistent alterations in biological profiles in women with abuse histories: Influence of premenstrual dysphoric disorder.

To examine dysregulation in biological measures associated with histories of abuse in women and whether women with premenstrual dysphoric disorder (PMDD) differ in their dysregulation. Twenty-five women meeting prospective criteria for PMDD and 42 non-PMDD controls underwent structured interview to determine abuse histories and lifetime Axis I diagnoses, excluding those with current Axis I disorders or using medications. Plasma cortisol and norepinephrine (NE), heart rate (HR), blood pressure (BP), and vascular resistance index (VRI) were assessed at rest and in response to mental stress. A greater proportion of PMDD women had prior abuse compared with non-PMDD women. Regardless of PMDD status, all abused women had lower plasma NE and higher HRs and tended to have lower plasma cortisol at rest and during stress. Abused women also reported more severe daily emotional and physical symptoms. Greater VRI and BP at rest and during stress were seen only in PMDD women with abuse. There is persistent dysregulation in stress-responsive systems in all abused women that cannot be accounted for by current psychiatric illness or medications, and PMDD women may be differentially more vulnerable to the impact of abuse on measures reflecting alpha-adrenergic receptor function.

Outcome of breech delivery at term

We studied 57 patients admitted to hospital with ischaemic heart disease, including nine patients with variant angina, to evaluate platelet reactivity and its dependence on alpha-adrenergic receptor function. The threshold concentration for biphasic platelet aggregation in response to adrenaline and adenosine diphosphate was measured in fresh platelet rich plasma. There were age related alterations in platelet responsiveness to adrenaline. In 27 age matched control subjects platelets showed adrenaline induced aggregation at a concentration higher than 0.1 mumol. The threshold concentrations for adrenaline and adenosine diphosphate were 0.91 mumol and 4.68 mumol. In 16 patients with acute infarction, 14 with old infarction, nine with effort angina, and nine with rest angina, mean values of platelet aggregation threshold for both adrenaline and adenosine diphosphate were not altered significantly when compared with control subjects. In contrast, the values for adrenaline and adenosine diphosphate in nine patients with variant angina were 0.012 mumol and 2.24 mumol and seven of them showed obvious platelet hyperactivity to adrenaline at a concentration lower than 0.1 mumol. The threshold concentration for adrenaline induced aggregation did not correlate with serum cholesterol and triglyceride levels.

Receptor function studies in specimens from the proximal human urethra obtained by transurethral resection.

During transurethral resection (TUR) for prostatic hyperplasia, specimens were taken from the proximal urethra. Muscle strips thus obtained were mounted in an organ bath and muscle contraction was induced by adding increasing concentrations of noradrenaline (NA), methoxamine (alpha 1-agonist) and clonidine (alpha 2-agonist). NA and methoxamine induced a dose-dependent muscle contraction, but clonidine had no effect. The influence of prazosin (alpha 1-antagonist) and yohimbine (alpha 2-antagonist) on the NA-induced muscle contraction was also evaluated. Both antagonists had an inhibitory effect, which was much more potent with prazosin. The specimens taken during TUR were found to be suitable for in vitro receptor function studies. The alpha-adrenergic receptor function in the proximal human urethra was found to be mainly of the alpha-type.

Arterial neuroeffector responses in early and mature spontaneously hypertensive rats.

Intramural sympathetic neuroeffector responses and presynaptic regulation of neurotransmission by amine uptake and alpha 2-adrenergic receptors were examined in young (5-week-old) and mature (12-week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar-Kyoto (WKY) control rats. Electrical field stimulation (20 V, 0.2-msec pulse width, 3-second pulse train each minute, 5-100 Hz) elicited contractile responses from isolated mesenteric arteries mounted in a myograph. There was a significant difference between the sensitivity of arteries to electrical field stimulation in the two age groups, with arteries from 12-week-old rats being more sensitive than arteries from 5-week-old animals. Also, there was a significant age-strain interaction: the sensitivity of arteries from SHR to electrical field stimulation increased dramatically with age compared with that of WKY rat arteries. Cocaine significantly increased the sensitivity to electrical field stimulation after inhibition of presynaptic alpha 2-adrenergic receptors, and had a significantly greater effect in arteries from 5-week-old SHR compared with WKY controls. This would reflect an overactive neuronal amine uptake mechanism in young SHR. At 12 weeks there was no significant interstrain difference in the effect of cocaine. Yohimbine increased the sensitivity to electrical field stimulation both before and after inhibition of neuronal amine uptake, but there was no difference in its effect with age or strain. Therefore, although sensitivity to sympathetic nerve stimulation varies with age in the SHR, there is no evidence that this can be ascribed to alpha 2-adrenergic receptor function.

The mechanisms of action of lithium. I. Effects on serotoninergic and noradrenergic systems in normal subjects.

The effects of 2 weeks of lithium carbonate administration at therapeutic plasma levels were examined in 11 normal volunteers. Serotoninergic function before and after lithium administration was assessed using low-dose intravenous clomipramine hydrochloride challenge, while urinary and plasma metabolites of norepinephrine (NE) were used to assess noradrenergic systems. Long-term lithium administration in normal subjects did not significantly or consistently enhance serotonin-mediated neuroendocrine responses but did increase measures related to neuronal release of NE. No statistically significant effects of lithium on prolactin, corticotropin, or cortisol responses to serotoninergic challenge could be detected. The probability of a type II error was assessed, and a doubling of prolactin level was unlikely to have been missed, although more modest increases (less than 75%) could have been overlooked. After 2 weeks of lithium administration, there were significant increases in 24-hour urinary excretion of NE, normetanephrine, and fractional NE release, compatible with increased neuronal release of NE and a lithium-induced subsensitivity in alpha 2-adrenergic receptor function. These changes were not statistically significant after 1 week of administration, suggesting that increased NE release is characteristic of long- rather than short-term lithium administration. Since previous reports have demonstrated enhanced prolactin responses after short- but not long-term lithium use, the present study points to temporal specificity in lithium's effects on both serotoninergic and noradrenergic function. Lithium's effects on NE release were consistent but small (a 16% increase), while its effects on serotoninergic responses were larger (a 50% increase in prolactin responses) but quite inconsistent, suggesting that neither of these systems is the primary site of action of lithium.

Alpha-2 adrenergic receptor function in post-stroke depression

The growth hormone (GH) response to desipramine was measured in ten patients meeting criteria for post-stroke depression (PSD), eight age-matched post-stroke (PS) non-depressed patients and eight healthy controls. Responses were significantly blunted in patients with PSD. These findings suggest diminished alpha-2 adrenoceptor function may be an important marker for PSD.

Species differences in regulation of alpha-adrenergic receptor function

The effects of alpha-adrenergic receptor stimulation with norepinephrine and phenylephrine after beta-adrenergic and muscarinic receptor blockades were compared in conscious baboons, calves, dogs, and rats in which left ventricular (LV) pressure. LV maximum rate of pressure development (dP/dt), and heart rate were measured. Autonomic receptor density was examined in crude sarcolemmal preparations from the hearts. The major physiological differences were observed in rats, where alpha 1-adrenergic receptor stimulation resulted in the greatest (P less than 0.05) increases in LV dP/dt (29 +/- 2%) in response to phenylephrine, 5.0 micrograms/kg, in comparison with responses in dogs (12 +/- 4%), calves (3 +/- 3%), and baboons (1 +/- 2%). This was associated with the greatest (P less than 0.05) alpha 1-adrenergic receptor density in the rat heart (73 +/- 5 fmol/mg) compared with values in the baboon (6 +/- 1 fmol/mg), calf (21 +/- 3 fmol/mg), or dog (10 +/- 3 fmol/mg) myocardium. Thus there are major differences among mammalian species in alpha-adrenergic receptor density and physiological responsiveness to alpha-adrenergic agonists.

Intravenous Yohimbine Selective Enhancer of Norepinephrine and Cortisol Secretion and Systolic Blood Pressure in Humans

Yohimbine hydrochloride was administered intravenously to nine normal volunteers to assess alpha 2-adrenergic receptor function. Plasma catecholamines, cortisol, and psychophysiological parameters (blood pressure, pulse, somatic symptoms checklist, and visual analogue scales assessing mood) were used as dependent variables. Plasma norepinephrine and plasma cortisol increased significantly after yohimbine administration, while epinephrine remained unchanged. Systolic blood pressure and somatic symptoms were also significantly increased by yohimbine. These findings suggest that low-dose intravenous yohimbine is an effective probe for alpha 2-adrenergic receptors and the hypothalamic-pituitary-adrenal axis.

Effects of preoperative calcium entry blocker therapy on alpha-adrenergic responsiveness in patients undergoing coronary revascularization.

Calcium entry blocking drugs (CaEBs) produce vasodilation and, in high doses, modify alpha adrenergic receptor function. Previous laboratory data suggested that CaEBs might alter the response to alpha-adrenergic stimulation. The authors tested the hypothesis that CaEB therapy altered alpha-adrenergic responsiveness in patients chronically treated with CaEBs. Twenty-six consenting patients with coronary artery disease were given a phenylephrine challenge before anesthesia induction and during cardiopulmonary bypass while the aorta was cross-clamped. A log dose response curve was constructed for each patient, and the ED30 (dose producing 30% increase in systemic vascular resistance) was calculated. Nine patients not treated with CaEB served as controls, and 17 patients were treated with nifedipine (n = 7) or diltiazem (n = 10). Mean ED30 was increased approximately three-fold in the CaEB treated groups compared to the control group. However, there was no statistical difference in the ED30 or phenylephrine dose response slopes between CaEB treated and untreated patients. In awake patients, ED30 correlated with nifedipine levels (R = 0.953, P = 0.01). There was a significant (P less than .02) shift in the ED30 from prior to anesthesia to during aortic cross-clamp and cardiopulmonary bypass; ED30 was approximately 50% less and correlated with CaEB level (R = 0.713, P = 0.03). Hemodynamic variables were not different between groups at any interval. Our data suggest that vascular responsiveness to phenylephrine in patients treated with CaEBs is diminished, but similar to that in untreated patients. Vascular responsiveness decreases in awake patients with increasing nifedipine levels.

Alpha 2-adrenergic receptor function in patients with unipolar and bipolar affective disorders

Alpha 2-adrenergic receptor function was measured in platelets from unipolar (UP) depressed, bipolar (BP) depressed, and bipolar euthymic patients and normal control subjects. Only the platelets from UP depressed patients were different from control in having an increased number of α 2-receptors, a decreased percent norepinephrine inhibition of prostaglandin E 1 (PGE 1)-stimulated cyclic AMP (cAMP) production, and a decrease in PGE 1 stimulation of cAMP production. Platelets from BP patients, depressed or euthymic, were not significantly different from control subjects. These preliminary data suggest that α 2-adrenergic receptor function and PGE 1 stimulation of cAMP production are diminished in UP patients.

Neuroendocrine effects of clonidine in chronic schizophrenic patients under long-term neuroleptic therapy and after drug withdrawal: relations to psychopathology.

The sensitivity of the alpha-adrenergic hypothalamic pituitary system, as indicated by growth hormone (GH) release after clonidine (0.15 mg i.v.), was studied in nine chronic schizophrenic in-patients (study 1) under long-term neuroleptic (NL) therapy and after 5 days' drug withdrawal and in 17 chronic schizophrenic in-patients (study 2) under long-term NL therapy and after 12 days' drug withdrawal. GH response after 5- and 12-day drug-free periods did not differ significantly from that under NL treatment; however, it was significantly lower after 12 days' drug withdrawal (AUC: 319.9 +/- 445.5 ng/ml X min) compared to age- and sex-matched normal controls (579 +/- 611 ng/ml X min). The basal norepinephrine (NE) plasma levels under long-term NL therapy were significantly elevated in both studies (study 1:894 +/- 553 pg/ml; study 2:432 +/- 268 pg/ml) compared to controls (study 1:253 +/- 55 pg/ml, study 2:234 +/- 126 pg/ml), and were decreased significantly after 5 days' drug withdrawal compared to NL treatment. There was no significant correlation between age, duration of NL therapy, last daily dosage, psychopathology, and NE plasma levels and GH response. The data presented suggest hyposensitivity of alpha-adrenergic receptor function in the hypothalamic-pituitary axis after 12 days' drug withdrawal in chronic schizophrenics. The significantly elevated NE plasma levels under NL therapy indicate that there is no adaption mechanism, even after long-term treatment.

Alpha-adrenergic receptors in orthostatic hypotension syndromes.

Alpha-adrenergic receptor function was measured in platelets from patients with orthostatic hypotension and normotensive controls. Patients with idiopathic orthostatic hypotension (IOH) or multiple system atrophy (MSA) had more alpha-receptors than controls. Patients with IOH, but not MSA, produced less prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) than controls. Patients with sympathotonic orthostatic hypotension (SOH) were similar to controls in receptor number and cAMP production. The percent norepinephrine (NE) inhibition of PGE1-stimulated cAMP production was similar in patients and controls. An increase in alpha-receptor number may result from decreased peripheral NE secretion in IOH and MSA. Increased alpha-receptor number and decreased cAMP production, which accompany essential hypertension, may contribute to the supine hypertension of IOH, and an increase in alpha-receptor number may contribute to the supine hypertension of MSA. SOH patients appear to have no abnormalities of alpha-receptor function.

Clonidine-induced growth hormone secretion in chronic schizophrenia.

Clonidine (0.15 mg intravenously), an alpha-adrenergic receptor agonist, was administered to 13 male chronic schizophrenics, who had been withdrawn from chronic neuroleptic therapy, and to 18 normal male controls. There was no significant difference in growth hormone (GH) response between the two groups. There was no significant correlation between duration of psychosis, duration of neuroleptic therapy or length of neuroleptic withdrawal and GH response. These results suggest that postsynaptic alpha-adrenergic receptor function in the hypothalamic-pituitary axis is unaltered in chronic schizophrenia or by prior chronic neuroleptic therapy.

Alpha-Adrenergic receptor function in schizophrenia. Receptor number, cyclic adenosine monophosphate production, adenylate cyclase activity, and effect of drugs.

alpha-Adrenergic receptor function was assessed in platelets from drug-free schizophrenic patients and control subjects. The number of alpha-receptors was similar in platelet membranes from schizophrenic patients and control subjects. In intact platelets from schizophrenic male, but not female, patients, prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) level was less than in control subjects. This defect may be due, at least in part, to decreased adenylate cyclase activity. In platelet lysates from schizophrenic patients, but not from normal control subjects, adenylate cyclase activity was diminished and PGE1-stimulated adenylate cyclase activity could be restored partially by the addition of guanosine triphosphate. Treatment with neuroleptic drugs or lithium carbonate did not change alpha-receptor number or cAMP production in platelets from schizophrenic patients, but high doses of propranolol hydrochloride increased cAMP production without affecting the number of alpha-receptors. If the production of cAMP in neurons is similar to that in platelets, diminished cAMP production may be associated with a vulnerability to schizophrenia.

Prenatal phenobarbital treatment and temperature-controlling dopamine receptors.

Pregnant mice were fed a phenobarbital-containing diet on days nine through 18 of pregnancy. Following parturition, the offspring of such animals were allowed to reach adulthood and then were tested for their response to an acute injection of apomorphine. Male offspring were less sensitive, while female offspring were more sensitive than matched controls to apomorphine-induced hypothermia. The witnessed differences in apomorphine-induced hypothermia could not be attributed to differences in brain apomorphine levels, alterations in the thermoregulation following non-drug challenges to the mouse's thermoregulatory ability, or changes in alpha-adrenergic receptor function. Our results suggest that prenatal phenobarbital administration produces changes in the function of dopamine receptors which regulate body temperature, and that the prenatally-induced changes last well into adulthood.

Platelet reactivity and its dependence on alpha-adrenergic receptor function in patients with ischaemic heart disease.

We studied 57 patients admitted to hospital with ischaemic heart disease, including nine patients with variant angina, to evaluate platelet reactivity and its dependence on alpha-adrenergic receptor function. The threshold concentration for biphasic platelet aggregation in response to adrenaline and adenosine diphosphate was measured in fresh platelet rich plasma. There were age related alterations in platelet responsiveness to adrenaline. In 27 age matched control subjects platelets showed adrenaline induced aggregation at a concentration higher than 0.1 mumol. The threshold concentrations for adrenaline and adenosine diphosphate were 0.91 mumol and 4.68 mumol. In 16 patients with acute infarction, 14 with old infarction, nine with effort angina, and nine with rest angina, mean values of platelet aggregation threshold for both adrenaline and adenosine diphosphate were not altered significantly when compared with control subjects. In contrast, the values for adrenaline and adenosine diphosphate in nine patients with variant angina were 0.012 mumol and 2.24 mumol and seven of them showed obvious platelet hyperactivity to adrenaline at a concentration lower than 0.1 mumol. The threshold concentration for adrenaline induced aggregation did not correlate with serum cholesterol and triglyceride levels.

Reduced cyclic AMP production in the blood platelets from schizophrenic patients

The authors assessed alpha-adrenergic receptor function in blood platelets from chronic schizophrenic patients and normal control subjects. The number of receptors was measured by the specific binding of the alpha-adrenergic antagonist [3H]dihydroergocryptine to the platelets. A physiological response of the platelets to agonist occupancy of the alpha-adrenergic receptors was measured by the norepinephrine inhibition of prostaglandin E1(PGE1)-stimulated cyclic AMP (cAMP) production. cAMP production in male schizophrenic patients was lower than in normal male subjects. alpha-Adrenergic receptor function was similar in patients and normal control subjects of both sexes. Normal male subjects had about 1.5 times the number of alpha-adrenergic receptors as normal females and generated about 1.8 times the quantity of PGE1-stimulated cAMP.

The Inhibitory Effect of Coli-Endotoxin on Alpha-Adrenergic Receptor Functions in the Lower Urinary Tract

The effects of endotoxin from E. coli 06 on alpha-adrenergic receptor functions have been investigated in muscle strips from the outlet region of the feline bladder. The endotoxin from this strain, known to cause urinary tract infections, inhibited the alpha-adrenergic contractions induced by phenylephrine and noradrenaline. This inhibition was dose-dependent, correlated to time of exposure, and reversible. Alpha-adrenergic receptor function in muscle strips from cat aorta was also inhibited, but not cholinergic stimulation of muscle segments from the bladder.

Adrenergic receptor functions in the urinary bladder and its outlet region

Autonomic nerve impulses are conveyed to the smooth musculature of the lower urinary tract by transmittor substances acting on muscle receptors. These impulses have partly or completely ceased in children with congenital neurogenic bladder disturbances. In order to evaluate the significance of a defect sympathetic innervation for collection of urine and micturition the adrenergic receptor functions have been investigated. Alpha-adrenergic receptor function was found in the outlet region of the bladder, i.e. bladder base, bladder neck and proximal urethra, of man and cat. Stimulation of this type of receptor leads to a contraction of the internal sphincter of the bladder. Beta-adrenergic receptor function could be identified in both the corpus-fundus region and in the outlet region. Low concentrations of beta-adrenergic agonists relaxed the internal sphincter as did adrenaline and noradrenaline in low concentrations. Higher concentrations of these cathecolamines contracted the same region. In children with myelomeningocele the adrenergic receptor functions could be activated by local application of drugs in the bladder.