Arg389Gly beta 1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo.

There are marked interethnic differences in beta 1-adrenoceptor-mediated responsiveness, with sensitivity decreased in African-Americans and increased in Chinese compared with Caucasians. Therefore, the frequency of a common naturally occurring polymorphism of the human beta 1-adrenoceptor gene (Arg389Gly), which has functional importance in vitro, was determined in 194 African-Americans, 316 Caucasian-Americans, 221 Hispanic-Americans and 142 Chinese. African-Americans were found to have a significantly lower frequency of the Arg389 allele than the other three ethnic groups (all P < 0.01). In the populations studied, the order of the distribution of the Arg389 allele was: Chinese (74%) > Caucasians (72%) > Hispanics (67%) > African-Americans (58%). To determine the functional significance of the Arg389Gly beta 1-adrenoceptor polymorphism, in-vivo heart rate responses to exercise were compared in healthy subjects homozygous for the Arg (n = 9) and Gly (n = 8) alleles. Heart rate response to exercise was not affected by genotype (P = 0.4). Although ethnic differences in the frequency of the beta 1-adrenoceptor Arg389Gly polymorphism exist, the polymorphism does not appear to have functional significance in healthy subjects and therefore may not contribute to ethnic differences in response to drugs acting through the beta 1-adrenoceptor.

Distribution of beta 3-adrenoceptor mRNA in human tissues.

The beta 3-adrenoceptor is a G protein-coupled receptor which mediates metabolic functions of the endogenous catecholamines epinephrine and norepinephrine. Questions exist regarding distribution of the beta 3-adrenoceptor in human tissue. In order to examine the distribution of beta 3-adrenoceptor mRNA in human tissues, we used sensitive and specific RNase protection assays without previous PCR amplification in an extensive list of human tissues. We confirm the presence of beta 3-adrenoceptor mRNA in human white fat from several locations, gall bladder, and small intestine, as well as extend the distribution of beta 3-adrenoceptor mRNA to previously uncharacterized human tissues such as stomach and prostate. The presence of beta 3-adrenoceptor mRNA in human white adipose tissue has important implications regarding possible use of beta 3-adrenoceptor selective agonists as anti-obesity agents, and the demonstration of beta 3-adrenoceptor mRNA in a number of gastrointestinal tissues and prostate raises the question of the role of the beta 3-adrenoceptor in motility and secretory processes.

Protein phosphorylation in isolated human adipocytes-adrenergic control of the phosphorylation of hormone-sensitive lipase.

The effect of adrenergic agents on protein phosphorylation in human adipocytes was examined. Freshly isolated human fat cells were incubated with 32PO4 in order to label intracellular ATP, then treated with a variety of adrenergic and other pharmacologic agents. Treatment with the beta-adrenergic agonist isoproterenol led to a significant increase in phosphate content of at least five protein bands (Mr 52, 53, 63, 67, 84 kDa). The increase in phosphorylation was partially inhibited by the alpha-2 agonist clonidine. Epinephrine, a combined alpha and beta agonist, was less effective at increasing phosphate content of the proteins than was isoproterenol. Neither insulin nor the alpha-1 agonist phenylephrine had any discernible effect on the pattern of protein phosphorylation. The 84 kDa phosphorylated peptide band appears to contain hormone-sensitive lipase, a key enzyme in the lipolytic pathway which is activated by phosphorylation. These results are somewhat different than previously reported results for rat adipocytes, and represent the first report of overall pattern and adrenergic modulation of protein phosphorylation in human adipocytes.

Transcranial Doppler blood flow measurement during cesarean section in two patients with cerebral vascular disease.

We present two cases of neurovascular disease in pregnancy in which transcranial Doppler was used to assess the status of the cerebral circulation during cesarean section under regional anesthesia. One woman had been found to have moyamoya disease, following a series of transient ischemic attacks during her first pregnancy, which ended in spontaneous abortion. On this occasion she was delivered by cesarean section under slowly-induced epidural anesthesia, using ephedrine to maintain the blood pressure, and transcranial Doppler revealed no change in signal in her left middle cerebral artery. Both mother and baby had an uneventful post natal course. The second case involved a primiparous woman with a large arteriovenous malformation that had been detected following generalized seizures, which were treated with valproic acid. Her cesarean section was conducted under spinal anesthesia, and her blood pressure maintained with ephedrine. Again transcranial Doppler revealed no change in signal in her middle cerebral artery during the procedure. We believe this is a potentially useful technique to monitor the cerebral circulation intraoperatively in the presence of cerebrovascular disease.

Complications with 25-gauge and 27-gauge Whitacre needles during combined spinal-epidural analgesia in labor.

Needle size and shape may influence the incidence of paresthesias, post-dural puncture headache and other complications during combined spinal-epidural (CSE) procedures. We have noted a relatively high incidence of transient paresthesias during placement of the spinal needle during CSE for labor analgesia. The purpose of this study was to compare the occurrence of paresthesia and post-dural puncture headache in parturients who received CSE analgesia with either a 25-gauge or 27-gauge Whitacre needle. In a prospective observational study, data were gathered from 478 consecutive women receiving labor analgesia. Incidence, duration, and character of any paresthesias upon spinal needle placement and the incidence and treatment of headache were recorded. The incidence of paresthesia with the two needles was similar (16% with 25-gauge vs 15.4% with 27 gauge) but the incidence of post-dural puncture headache was higher with the 25-gauge needle (4% vs 0.7% with 27 gauge, P < 0.05). Our data suggest that with Whitacre needles, 27-gauge might be preferable to 25-gauge needles to reduce the rate of post-dural puncture headache in parturients but that they do not alter the incidence of transient paresthesias.

An overview of induction and emergence characteristics of desflurane in pediatric, adult, and geriatric patients.

A major advantage of desflurane over currently available agents is that the blood-gas partition coefficient of desflurane is 0.42, lower than all available volatile anesthetics, and slightly lower than nitrous oxide. This property predicts rapid induction of and recovery from general anesthesia with desflurane. This review will summarize and compare results of studies that have examined various clinical characteristics of induction and emergence with desflurane in a variety of patient populations. Studies in pediatric patients, and in adults, have confirmed that inhalation induction with desflurane is rapid. However, there has been a high incidence of airway irritation and/or reactivity, including breath holding, coughing, excessive secretions, and laryngospasm. This incidence is significantly higher than that seen with halothane, making it unlikely that desflurane will supplant halothane for inhalation inductions. The hemodynamic effects of desflurane induction and maintenance with or without intravenous adjuvants appear similar to those seen with isoflurane. Several studies have compared emergence from anesthesia with desflurane with that from isoflurane-based anesthetics, and have demonstrated that initial emergence from a given depth of anesthesia, e.g., time to eye opening or response to verbal commands, is about twice as fast with desflurane. Similar results have been obtained in pediatric patients where emergence from desflurane is faster than that seen from halothane. Emergence from desflurane anesthesia appears similar in time-course to that from propofol-based anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac surgery causes desensitization of the beta-adrenergic receptor system of human lymphocytes.

Thirteen patients undergoing cardiac surgery were studied to examine whether beta-adrenergic desensitization occurs in the perioperative period surrounding cardiac surgery, using peripheral blood lymphocytes as a model. Lymphocytes were isolated before induction of anesthesia (PRE) and on the morning of the first postoperative day (POST). Cyclic adenosine monophosphate (cAMP) production from the lymphocytes was assayed in the untreated (BASAL) state, and after treatment with 5 microM isoproterenol, 10 microM prostaglandin E1, or 20 mM sodium fluoride with 10 microM AlCl3 (NaF). All cAMP values are reported as picomoles per 10(6) cells, mean +/- SEM. BASAL cAMP production did not change significantly between the PRE and POST samples (PRE, 1.2 +/- 0.1; POST, 1.0 +/- 0.1). Isoproterenol-stimulated cAMP was significantly lower postoperatively (PRE, 8.36 +/- 0.9; POST, 5.1 +/- 0.5; P less than 0.005). Prostaglandin E1-stimulated cAMP did not change (PRE, 21.7 +/- 2.4; POST, 25.3 +/- 2.5), and NaF-stimulated cAMP was increased postoperatively (PRE, 8.8 +/- 1.6; POST, 14.3 +/- 2.0; P less than 0.05). These findings suggest that cardiac surgery and/or cardiopulmonary bypass results in significant desensitization of the beta-adrenergic receptor/adenylate cyclase system of lymphocytes, which may parallel changes in the adrenergic response of other organ systems.

Longitudinal study of beta- and alpha-adrenergic receptor properties during human pregnancy.

OBJECTIVE: Our goal was to ascertain whether alterations in beta- and alpha-adrenergic receptor number and function (cyclic adenosine monophosphate production) occur during and after pregnancy. Because the actions of beta- and alpha2-adrenergic receptors tend to oppose each other, we hypothesized that there might be progressive, possibly reciprocal changes in these receptors during and after pregnancy. STUDY DESIGN: Blood was obtained from 21 women at 10, 20, 30, and 37 weeks of pregnancy and 3 to 4 months post partum. Lymphocyte beta- and platelet alpha2-adrenergic receptor number and affinity were quantified by radioligand binding studies, and receptor function was assessed by cyclic adenosine monophosphate generation assays. RESULTS: Although there were suggestions of progressive alterations in some of the variables studied, beta- and alpha2-adrenergic receptor number, affinity, and function did not manifest any statistically significant changes. CONCLUSION: Pregnancy did not produce marked alterations in beta-adrenergic receptor or alpha2-adrenergic receptor properties.

Do receptors get pregnant too? Adrenergic receptor alterations in human pregnancy.

In this review we discuss adrenergic receptor number and function during pregnancy, with emphasis on evidence that pregnancy results in specific receptor alterations from the nonpregnant state. Changes in adrenergic receptor function or distribution in vascular smooth muscle may be in part responsible for the decreased vascular responsiveness seen in human pregnancy, and the lack of the normal alterations may be a part of the syndromes of gestational hypertension, including preeclampsia-eclampsia. The onset of labor may be influenced by adrenergic modulation, and receptor or postreceptor level molecular alterations may trigger or facilitate normal or preterm labor. Human studies are emphasized when possible to assess the role of adrenergic signal transduction regulation in the physiology and pathophysiology of normal and complicated human pregnancy.

Effect of cesarean delivery on perioperative regulation of the beta-adrenergic receptor system of human lymphocytes.

We studied the perioperative regulation of the beta-adrenergic receptor (beta AR) system in lymphocytes obtained before and after surgery from 12 patients undergoing cesarean delivery with spinal anesthesia. Receptor number (Bmax) and binding affinity (KD) were determined by Scatchard analysis of [125I]iodopindolol saturation binding curves. Receptor function was assessed by measuring cyclic adenosine 3',5'-monophosphate (cAMP) production in the unstimulated state and in response to stimulation by isoproterenol, forskolin, and prostaglandin E1. Basal cAMP production increased 48% postoperatively (P < 0.05), while stimulated cAMP production and Bmax and KD were not significantly changed after surgery. The response to surgery of the beta AR system on these patients differed from that of patients undergoing cardiothoracic and abdominal surgery in whom we previously found postoperative down-regulation and desensitization of the beta AR system. It is possible that this difference in response is due to amelioration of the stress response to surgery by regional anesthesia, and/or alterations in beta AR status by pregnancy. We conclude that pregnancy and regional anesthesia, but not changes in lymphocyte subset distribution, contributed to the lack of effect of surgery on the beta AR system in the patients studied.

Metabolism of desflurane and isoflurane to fluoride ion in surgical patients.

The metabolism of isoflurane and the investigational volatile anaesthetic desflurane to fluoride ion was examined in 25 surgical patients. The patients were randomly assigned to four groups, to receive isoflurane or desflurane at either 0.65 MAC or 1.25 MAC. Anaesthesia was induced in all patients with thiopentone and midazolam and included nitrous oxide 60% in addition to the volatile agent. Blood was drawn before induction and at the end of the operation for determination of serum fluoride ion concentration. Plasma fluoride ion concentrations increased (+ 1.36 +/- 0.93 microM, P less than 0.01) in patients receiving isoflurane but were unchanged (-0.13 +/- 0.50 microM) in patients receiving desflurane. Metabolic release of fluoride ion is less with desflurane than with isoflurane during administration of the anaesthetics to surgical patients, and is unlikely to be of clinical significance.

Desflurane and isoflurane in surgical patients: comparison of emergence time.

In order to examine the clinical potential of desflurane (difluoromethyl-1-fluoro-2,2,2-trifluoroethyl ether) in humans, a randomized, controlled study was designed to compare time of emergence from anesthesia in patients undergoing elective surgery under desflurane anesthesia to that of patients under isoflurane anesthesia. Twenty-eight patients were randomly divided into four groups. Group 1 received isoflurane 0.65 MAC; group 2, desflurane 0.65 MAC; group 3, isoflurane 1.25 MAC; and group 4, desflurane 1.25 MAC. Anesthesia was induced with sodium thiopental, and N2O 60% was added to the volatile agent. Mean anesthetic exposure times (min [mean +/- SD]) were 108 +/- 49 in group 1, 132 +/- 46 in group 2, 147 +/- 74 in group 3, and 166 +/- 71 in group 4, with no significant differences between groups. The times from discontinuation of anesthetic gases until patients opened their eyes and squeezed the investigator's hand in response to a command were averaged and recorded as "emergence time." Emergence time was significantly less with desflurane than with isoflurane given at the same MAC. Patients receiving isoflurane 0.65 MAC responded to commands 15.6 +/- 4.3 min after discontinuation of the anesthetic; patients in the desflurane 0.65 MAC group responded in 8.8 +/- 2.7 min (P less than 0.01). Emergence time for isoflurane 1.25 MAC was 30.0 +/- 11.0 min; for desflurane 1.25 MAC it was 16.1 +/- 6.0 min (P less than 0.05). Our results confirm that emergence from desflurane anesthesia is more rapid than from isoflurane.

Alterations of the beta-adrenergic receptor system after thoracic and abdominal surgery.

We studied perioperative regulation of the beta-adrenergic receptor (beta AR) in lymphocytes obtained from 12 patients undergoing noncardiac thoracic surgery and 12 patients undergoing abdominal surgery. beta AR number (Bmax) and dissociation constant (KD) were determined from [125I]iodopindolol saturation binding curves. Function of the beta AR/adenylyl cyclase system was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol (ISO) and prostaglandin E1 (PGE1). In thoracic surgery patients, basal and ISO-stimulated cAMP production were significantly decreased postoperatively, by 44% and 45%, respectively, with no change in PGE1-stimulated cAMP. Bmax decreased from 1369 +/- 138 (mean +/- SE) sites/cell to 891 +/- 82 sites/cell postoperatively, while the KD increased from 26.7 +/- 5.6 pM to 37.8 +/- 5.1 pM. In the abdominal surgery patients, there were no significant alterations in cAMP production, but Bmax decreased, from 1235 +/- 146 sites/cell preoperatively to 888 +/- 65 sites/cell postoperatively, while the KD increased from 18.8 +/- 3.6 pM to 58.1 +/- 12.5 pM. The beta AR and its associated effector system are altered during the perioperative period of abdominal and thoracic surgery.

Down-regulation and desensitization of the beta-adrenergic receptor system of human lymphocytes after cardiac surgery.

We used the beta-adrenergic receptor (beta AR) system of human lymphocytes as a model to examine perioperative adrenergic regulation in 12 patients undergoing coronary artery bypass grafting and 12 patients undergoing mitral or aortic valve replacement. beta AR function was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol and prostaglandin E1. Receptor number and dissociation constant (KD) were assessed with [125I]iodopindolol. In the valve surgery patients, basal, isoproterenol-stimulated, and prostaglandin E1-stimulated cAMP production were significantly decreased postoperatively, by 39%, 55%, and 24%, respectively. beta AR number decreased from a mean of 1333 +/- 143 sites/cell to 897 +/- 56 sites/cell postoperatively, whereas the KD increased from 12.9 +/- 1.1 pM to 37.0 +/- 7.3 pM. In the coronary artery bypass graft patients, there were no significant alterations in cAMP production or receptor number, but the KD increased from 19.8 +/- 2.9 pM to 57.5 +/- 11.8 pM. These findings suggest that cardiac surgery and/or cardiopulmonary bypass may result in significant down-regulation and desensitization of the beta AR system of lymphocytes, which may parallel alterations in other organ systems.

Fetal bradycardia and uterine hyperactivity following subarachnoid administration of fentanyl during labor.

BACKGROUND AND OBJECTIVES: Changes in uterine tone have been postulated as the cause of fetal bradycardia following subarachnoid administration of fentanyl for labor analgesia. Such a case occurred in a 20-year-old parturient with an intrauterine pressure catheter in place. METHODS: The patient was given intravenous terbutaline, after which contractions ceased for 20-30 minutes and then resumed. RESULTS: The patient underwent successful cesarean delivery. Retrospective analysis of the data revealed a significant increase in uterine tone and contractions following fentanyl administration. CONCLUSIONS: This case supports the view that changes in uterine tone, producing a hyperdynamic contractile state and a resulting decrease in uteroplacental perfusion, may explain the fetal bradycardia following subarachnoid opioid administration. Cases that do not resolve spontaneously may respond to intravenous terbutaline.

Persistent alterations of the autonomic nervous system after noncardiac surgery.

UNLABELLED: BACKGROUND. Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both beta-adrenergic receptor (betaAR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation. METHODS: The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine betaAR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals. RESULTS: After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol-stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol-stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery. CONCLUSIONS: Persistent downregulation and desensitization of the lymphocyte betaAR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at-risk period after major surgery appears to be about 1 week or more.