Adrenergic Effects Research Articles

Dr. Bilder and Colleagues Reply

Back to table of contents Previous article Next article Letter to the EditorFull AccessDr. Bilder and Colleagues ReplyROBERT M. BILDER, Ph.D., JAN VOLAVKA, M.D., Ph.D., LESLIE CITROME, M.D., M.P.H., PÀL CZOBOR, Ph.D., MATTHEW HOPTMAN, Ph.D., MIRANDA CHAKOS, M.D., JOSEPH P. McEVOY, M.D., THOMAS B. COOPER, M.A., and JEFFREY A. LIEBERMAN, M.D., ROBERT M. BILDERSearch for more papers by this author, Ph.D., JAN VOLAVKASearch for more papers by this author, M.D., Ph.D., LESLIE CITROMESearch for more papers by this author, M.D., M.P.H., PÀL CZOBORSearch for more papers by this author, Ph.D., MATTHEW HOPTMANSearch for more papers by this author, Ph.D., MIRANDA CHAKOSSearch for more papers by this author, M.D., JOSEPH P. McEVOYSearch for more papers by this author, M.D., THOMAS B. COOPERSearch for more papers by this author, M.A., and JEFFREY A. LIEBERMANSearch for more papers by this author, M.D., Orangeburg, N.Y.Published Online:1 Dec 2002https://doi.org/10.1176/appi.ajp.159.12.2118-aAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We appreciate the comments of Drs. de Haan and van Amelsvoort regarding our recent article and are happy to expand on speculation regarding putative mechanisms underlying the observed treatment effects. First, we should highlight that our comments regarding the doses used in our study referred to clinical practice in the management of patients with suboptimal treatment response—not to putative levels of receptor occupancy—and readers should recognize the unique challenges inherent in treating this patient population.Second, we believe that the contention of Drs. de Haan and van Amelsvoort that higher D2 receptor occupancy limited cognitive improvement is not supported by our data. Several facts argue against this interpretation. The mean dose levels (milligrams per day) achieved in the second period of the study (last observation carried forward) were 526.6 (SD=140.3) for clozapine, 30.4 (SD=6.6) for olanzapine, 11.6 (SD=3.2) for risperidone, and 25.7 (SD=5.7) for haloperidol, as described elsewhere (1). We thus believe that at follow-up all patients in the olanzapine, risperidone, and haloperidol groups likely had levels of D2 receptor occupancy well in excess of 80% and within the range at which D2 occupancy asymptotes (2). Therefore, the possible discrepancies between groups in D2 occupancy were probably subtler than suggested by Drs. de Haan and van Amelsvoort.It is still conceivable that even subtle differences in overall D2 occupancy or other differences, such as rates of D2 receptor dissociation (2, 3), may help explain the differences in neurocognitive function observed in our study. If the differences between treatments were mediated primarily by differences in D2 receptor occupancy, changes in motor function (the strongest correlates of D2 receptor availability in the striatum [Volkow et al., 1998]) should have differed between groups, but this was not the case. Moreover, if neurocognitive improvement had been limited by high D2 occupancy, the clozapine-treated patients might have been predicted to show the greatest improvement, but they did not (despite good clinical efficacy).We examined the effects of all antipsychotic doses and anticholinergic treatment effects (using benztropine doses and extrapyramidal symptom ratings) and found that these variables did not substantially influence our findings. In summary, we believe that our data do not support a simple explanation of neurocognitive improvement in terms of lower D2 receptor occupancy, and thus we highlighted in our Discussion not only the possible D2 receptor effects but also a broad range of other possible mechanisms that might be responsible, including serotonergic, adrenergic, cholinergic, histaminergic, and non-D2 dopaminergic receptor effects, that may have differed among treatments.We believe further that our findings agree well with a larger literature, suggesting that attempts to explain complex clinical effects in terms of receptor binding profiles have been challenging at best (4). We agree that it would be valuable to conduct research comparing the neurocognitive effects of antipsychotic treatments, specifically targeting levels of D2 receptor occupancy, as an experimental manipulation. It is important to recognize, however, that any strategy of reducing D2 receptor occupancy for cognitive augmentation might best target patients with a history of treatment response more favorable than our patients showed to minimize the possible clinical risks of relapse.Reprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.

Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men

Stimulation of energy expenditure (EE) with selective thermogenic beta-adrenergic agonists may be a promising approach for treating obesity. We analyzed the effects of the highly selective human beta(3)-adrenergic agonist L-796568 on 24-h EE, substrate oxidation, and body composition in obese, weight-stable men. In this 2-center, double-blind, randomized, parallel-group study, we measured 24-h EE before and after 28 d of treatment with L-796568 (375 mg/d) or placebo during weight maintenance (ie, without dietary intervention) in nondiabetic, nonsmoking men aged 25-49 y with body mass index (in kg/m(2)) of 28-35 (n = 10 subjects per treatment group). The mean change in 24-h EE from before to after treatment did not differ significantly between groups (92 +/- 586 and 86 +/- 512 kJ/24 h for the L-796568 and placebo groups, respectively). The change in 24-h nonprotein respiratory quotient from before to after treatment did not differ significantly between groups (0.009 +/- 0.021 and 0.009 +/- 0.029, respectively). No changes in glucose tolerance were observed, but triacylglycerol concentrations decreased significantly with L-796568 treatment compared with placebo (-0.76 +/- 0.76 and 0.42 +/- 0.31 mmol/L, respectively; P < 0.002). Overall, treatment-related changes in body composition were not observed, but higher plasma L-796568 concentrations in the L-796568 group were associated with greater decreases in fat mass (r = -0.69, P < 0.03). Treatment with L-796568 for 28 d had no major lipolytic or thermogenic effect but it lowered triacylglycerol concentrations. This lack of chronic effect on energy balance is likely explained by insufficient recruitment of beta(3)-responsive tissues in humans, down-regulation of the beta(3)-adrenergic receptor-mediated effects with chronic dosing, or both.

Effect of a long-duration physical exercise on fat cell lipolytic responsiveness to adrenergic agents and insulin in obese men.

The aim of the study was to investigate whether a long-lasting bout of exercise modifies the lipolytic beta- and antilipolytic-alpha(2)-adrenergic effect and the antilipolytic effect of insulin in obese subjects. Biopsies of abdominal subcutaneous adipose tissue were performed before and immediately after 2 h exercise (at 50% of VO(2max)) on an ergometric bicycle. Nine healthy obese male subjects (mean age 38.0+/-3.5 y; mean body mass index (BMI) 35.6+/-3.9 kg/m(2)) were included in the experiment. :The lipolytic responsiveness to adrenaline, isoprenaline (beta-adrenergic agonist), UK-14304 (alpha(2)-adrenergic agonist) and insulin was studied in the isolated fat cell obtained by biopsies of subcutaneous adipose tissue from the peri-umbilical region before and after exercise. After exercise, an increase was observed in spontaneous lipolytic rate, and in the lipolytic effect of isoprenaline, but no modification in the lipolytic action of adrenaline. Antilipolytic effects of UK-14304 and insulin were not changed by the single bout of exercise. A single bout of long-term exercise increased the responsiveness of adipose tissue to beta-adrenergic stimulation of lipolysis in obese subjects.

Cardiovascular regulation during hypoxia in embryos of the domestic chicken Gallus gallus.

Renewed interest in the use of the embryonic chicken as a model of perinatal cardiovascular regulation has inspired new questions about the control mechanisms that respond to acute perturbations, such as hypoxia. The objectives of this study were to determine the cardiovascular responses, the regulatory mechanisms involved in those cardiovascular responses, and whether those mechanisms involved the central nervous system (CNS) of embryonic chickens. Heart rate (f(H)) and blood pressure were measured in chicken embryos of different incubation ages during exposure to different levels of hypoxia (15, 10, and 5% O(2)). At all levels of hypoxia and at all developmental ages, a depression of f(H) and arterial pressure was observed, with the exception of day 20 embryos in 15 and 10% O(2). The intensity of the embryonic f(H) and blood pressure responses were directly related to the level of hypoxia used. Muscarinic and alpha-adrenergic receptor stimulation limited the hypoxic hypotension on days 15-19 and 15-21, respectively, as indicated after blockade with atropine and phentolamine. During the final 3 days of incubation, the intensity of the hypoxic hypotension was magnified due to alpha-vasodilation caused by beta-adrenergic and muscarinic receptor stimulation. In 19- to 21-day-old embryos, the f(H) response to hypoxia was limited by alpha-adrenergic receptor stimulation as indicated by the accentuated bradycardia after blockade with phentolamine. Furthermore, on day 21, atropine limited the hypoxic bradycardia, indicating that muscarinic receptors also play a role in the f(H) response at this age. In addition, the muscarinic actions on the heart and the adrenergic effects on the vasculature appeared to occur through a hypoxic-induced direct release from chromaffin tissue and autonomic nerve terminals. Thus, in embryonic chickens, the only cardiovascular response to hypoxia that involves the CNS was the cholinergic regulation of arterial pressure after day 15 of incubation. Therefore, although embryonic chickens and fetal sheep, the standard models of perinatal cardiovascular physiology, respond to hypoxia with a similar redistribution of cardiac output, the underlying mechanisms differ between these species.

Is Endotracheal Adrenaline Deleterious Because of the Beta Adrenergic Effect?

Is Endotracheal Adrenaline Deleterious Because of the Beta Adrenergic Effect?

Hypocaloric diet reduces exercise-induced alpha 2-adrenergic antilipolytic effect and alpha 2-adrenergic receptor mRNA levels in adipose tissue of obese women.

Previous investigations have shown that alpha 2-adrenoceptor (alpha 2-AR) stimulation blunts lipid mobilization during physiological activation of the sympathetic nervous system promoted by exercise in sc abdominal adipose tissue (SCAAT) in obese men. To investigate the effect of a low calorie diet (LCD) on the alpha 2-adrenergic responsiveness and on the expression of alpha 2-AR and beta 2-adrenoceptor (beta 2-AR) in SCAAT, 11 obese women (weight: 99.1 +/- 4.6 kg; body mass index: 34.3 +/- 1.1 kg/m(2)) received a 12-wk diet providing 500 kcal/d less than their usual diet. The exercise-induced alpha 2-adrenergic antilipolytic effect was investigated in SCAAT before and at the end of LCD. Changes in extracellular glycerol concentration and local blood flow were measured in SCAAT during a 45-min exercise bout (50% of heart rate reserve) using a control microdialysis probe and a probe supplemented with the alpha2-AR antagonist phentolamine. SCAAT biopsies were performed for determination of mRNA levels using RT-competitive PCR. Plasma catecholamine responses to exercise bout were not different before and at the end of LCD. Before LCD, the exercise-induced increase in extracellular glycerol concentration was potentiated by phentolamine supplementation, while this potentiating effect of the alpha-antagonist was not observed at the end of LCD. No changes were observed for beta 2-AR and hormone-sensitive lipase mRNA levels, while alpha 2-AR mRNA level was significantly decreased in adipose tissue during LCD. These findings show that alpha 2-AR-mediated antilipolytic action is reduced by a moderate hypocaloric diet and that down-regulation of alpha 2-AR mRNA levels may participate in the decrease of the alpha 2-adrenergic effect revealed by microdialysis.

Hypocaloric Diet Reduces Exercise-Induced 2-Adrenergic Antilipolytic Effect and 2-Adrenergic Receptor mRNA Levels in Adipose Tissue of Obese Women

Hypocaloric Diet Reduces Exercise-Induced 2-Adrenergic Antilipolytic Effect and 2-Adrenergic Receptor mRNA Levels in Adipose Tissue of Obese Women

Vasodilating properties of extracts from the leaves of Musanga cecropioides (R. Brown).

The mechanisms of action involved in the hypotensive properties of the aqueous extract of the leaves of Musanga cecropioides were investigated. The effect of the aqueous leaf extract of M. cecropioides, found to contain mostly saponins, flavonoids and procyanidins, was investigated on vascular smooth muscle and also in an in vivo direct invasive blood pressure study in both normotensive and hypertensive rats. The hypotensive or antihypertensive properties of the extracts appear to be due partly to a direct or indirect vasodilator effect and also to some alpha(1)- and beta(2)-adrenergic blocking effects. The extract also exhibited significant endothelium-dependent vascular smooth muscle relaxation, accounted for by the release of nitric oxide (NO), and induced significant angiotensin converting enzyme (ACE) inhibitory effects thereby supporting its vasodilator mechanism of action.

Cholinergic and Adrenergic Systems Influence Mnestic Effects of Arginine-Vasopressin

Cholinergic and Adrenergic Systems Influence Mnestic Effects of Arginine-Vasopressin

Biochemical and pharmacological characterization of the venom of the black scorpion Heterometrus spinifer

The sting of the black scorpion Heterometrus spinifer, which can cause intense localized pain, has not been reported to produce lethal cardiovascular complications, which are well known to result from scorpion envenomation as a consequence of a massive release of catecholamines. Therefore, we have undertaken a biochemical and pharmacological characterization of the venom of H. spinifer. Pharmacologically, the venom (0.125 μL/mL) produced a marked, reversible contracture in the chick biventer cervicis muscle that was blocked by d-tubocurarine (2 μM) but not by tetrodotoxin (5 μM) and ω-conotoxin GVIA (3 μM). The anticholinesterase neostigmine (1 μM) potentiated the contracture by 5.3-fold. An ultra-filtrate fraction of MW < 3000 (F3K) of the venom produced a similar contracture in the biventer muscle, whereas the retentate of MW > 3000 did not. In the rat anococcygeus muscle, the venom produced a contractile response that was partially (37.4 ± 1.6%) blocked by atropine (5 μM); phentolamine (5 μM) blocked the remaining response. Tetrodotoxin (5 μM) did not block the contractile response of the venom on the anococcygeus muscle. Electrospray ionization-mass spectrometry/mass spectrometry confirmed the presence of high concentrations of acetylcholine (79.8 ± 1.7 μM) and norepinephrine (146.7 ± 19.8 μM) in H. spinifer venom, which can fully account for the observed cholinergic and adrenergic effects. In contrast to scorpion venoms that selectively target neuronal ion channels in mediating transmitter release, our data show that H. spinifer venom does not possess such activity, which likely explains the apparent lack of lethality of black scorpion envenomation.

The role of substance P release in the lung with esophageal acid

To investigate whether tachykinins are released in the airways by stimulating the esophagus, airway plasma extravasation induced by intraesophageal hydrochloric acid (HCl) in the presence or absence of the neutral endopeptidase (NEP) inhibitor phosphoramidon and the neurokinin-1-receptor antagonist FK888 was studied in anesthetized guinea pigs. Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy. Propranolol and atropine were used in all animals to block adrenergic and cholinergic nerve effects. Airway plasma leakage was evaluated by measuring extravasated Evans blue dye. One normal HCl infusion into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation induced by HCl infusion into the esophagus in the trachea and main bronchi, and FK888 significantly inhibited extravasation in a dose-related manner. In capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilaterally vagotomized animals. These results suggest that locally acting substances are released by intraesophageal HCl stimulation that cause airway plasma extravasation. These substances are generated through activation of neural pathways, including some that traffic through the vagus nerves that link the esophagus or airways.

Antihypertensive and vasorelaxing activities of synthetic xanthone derivatives

A series of xanthones and xanthonoxypropanolamines have been synthesized. The activity of compounds on cardiovascular system was evaluated. All the compounds tested exhibited effective hypotensive activity in anesthetized rats. An oxypropanolamine side chain substituted at the C-3 position of the xanthone nucleus significantly enhanced the hypotensive activity. In rat thoracic aorta, all the compounds tested significantly depressed the contractions induced by Ca 2+ (1.9 mM) in high K + (80 mM) medium and the phasic and tonic contractions caused by norepinephrine (3 μM). In the rat thoracic aorta, the phenylephrine- and high K +-induced 45Ca 2+ influx were both inhibited by a selective xanthone derivative, 13. In addition to the previously reported result of 13, evaluated as beta adrenoceptor blocker, the depressor and bradycardia effects of 9 are independent of the parasympathetic passway. These results suggest that 13 showed inhibitory effects on the contractile response caused by high K + and norepinephrine in rat thoracic aorta are mainly due to inhibition of Ca 2+ influx through both voltage-dependent and receptor-operated Ca 2+ channels. The vasodilating properties of 13 is due to its calcium channel and beta adrenergic blocking effects.

Is endotracheal adrenaline deleterious because of the beta adrenergic effect?

IV adrenaline increases coronary and cerebral perfusion pressures during cardiopulmonary resuscitation. We recently showed that endotracheal adrenaline can decrease blood pressure (BP), a detrimental effect presumably mediated by the beta 2-adrenergic receptor unopposed by alpha-adrenergic vasoconstriction. This prospective, randomized, laboratory comparison of endotracheal adrenaline (0.05 mg/kg diluted with normal saline to 10 mL total volume) with or without nonselective beta-blocker (propranolol) pretreatment was conducted in an attempt to clarify the mechanism of this BP decrease. Five mongrel dogs were given 0.05 mg/kg endotracheal adrenaline (diluted) or 0.05 mg/kg endotracheal adrenaline followed by an IV propranolol (0.1 mg/kg) pretreatment. Each dog served as its own control (10 mL of normal saline administered endotracheally) and received each regimen at least one week apart. Endotracheal adrenaline given after the propranolol pretreatment produced an increase in systolic, diastolic, and mean arterial BPs, from 165/110 mm Hg (mean 128 mm Hg) to 177.5/125 mm Hg (mean 142.5 mm Hg), respectively, as opposed to the hypotensive effect of isolated endotracheal adrenaline (P < 0.03). Thus, endotracheal adrenaline was associated with predominantly beta-adrenergic-mediated effects, causing hypotension via peripheral vasodilatation unopposed by alpha-adrenergic vasoconstriction. The search for the optimal dose of endotracheal adrenaline should be aimed at achieving the higher alpha-adrenergic vasoconstrictive threshold.

Cremaster muscle is not sexually dimorphic, but that from boys with undescended testis reflects alterations related to autonomic innervation

Background/Purpose: The genitofemoral nerve and its motor neuron are known to be sexually dimorphic. An association has been suggested to exist between antiandrogen-induced undescended testis and the genitofemoral nerve. Therefore, the cremaster muscles (CM) from boys and girls with inguinal hernia and boys with undescended testis were compared to evaluate the failed descent through sexual dimorphism. Methods: Samples of CM were obtained from 10 boys and 10 girls with inguinal hernia and 10 boys with undescended testis. Sections were stained for ATPase reactions after acid and alkaline preincubations, and for the expression of myosine heavy chains. The percentages of type 1 and type 2 fibers, and mean diameters of fibers according to the types were determined for each group. Values were compared through Mann-Whitney U test, and P values less than.05 were considered to be significant. Results: CM have mainly been composed of type 1 fibers. Distributions of type 1 and 2 fibers have not shown a difference among groups. Mean diameters of both type 1 and type 2 fibers from girls (P <.05), and mean diameter of type 2 fibers from boys with undescended testis have been significantly smaller than those encountered in boys with inguinal hernia (P <.05). Conclusions: Although the mean diameter of type 1 fibers from boys with undescended testis has been as large as those encountered in boys with inguinal hernia, mean diameter of type 2 fibers has been as small as those encountered in girls. Among various reasons to selectively diminish the size of type 2 fibers, lack of beta adrenergic effect appears to be the most satisfactory explanation. J Pediatr Surg 36:877-880. Copyright © 2001 by W.B. Saunders Company.

Human Breast Adipocytes Express Interleukin-6 (IL-6) and Its Receptor System: Increased IL-6 Production by -Adrenergic Activation and Effects of IL-6 on Adipocyte Function

Human Breast Adipocytes Express Interleukin-6 (IL-6) and Its Receptor System: Increased IL-6 Production by -Adrenergic Activation and Effects of IL-6 on Adipocyte Function

β-Adrenergic receptors in the failing heart: the good, the bad, and the unknown

β-Adrenergic receptors in the failing heart: the good, the bad, and the unknown

In vivo regulation of Na/Ca exchanger expression by adrenergic effectors.

The Na/Ca exchanger encoded by the NCX1 gene plays an important role in calcium homeostasis in cardiac muscle. We previously identified three in vitro signaling pathways that are of major importance in the regulation of Na/Ca exchanger gene expression in neonatal cardiac myocytes, the protein kinase A (PKA) and protein kinase C (PKC) pathways, and intracellular Ca(2+). To determine whether these pathways are important in vivo, we stimulated the PKA and PKC pathways and examined functional expression of the Na/Ca exchanger in adult rat heart. After a 3- and 7-day treatment, norepinephrine (200 microg x kg(-1) x h(-1)), isoproterenol (150 microg x kg(-1) x h(-1)), and phenylephrine (200 microg x kg(-1) x h(-1)) each stimulated a significant increase in NCX1 mRNA levels (35-85%, P < 0.05). Norepinephrine also stimulated a 35% increase in protein abundance (P < 0.05), a 20% decrease in relaxation duration (P < 0.05), and a 25% reduction in the fluorescence decay constant (P < 0.05) after a 7-day treatment. We conclude that a 7-day treatment of alpha- and beta-adrenergic agonists increases the expression of functional Na/Ca exchangers in adult rat heart.

Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo.

Overactivity of the sympathetic nervous system (SNS) has been related to increased cardiovascular morbidity. Historical reports suggest hastening of blood coagulation following intravenous administration of epinephrine. Given the important role of the hemostatic system in atherosclerosis and thrombosis, it is surprising that short-term adrenergic effects on blood coagulation, fibrinolysis and platelet activity have not been scrutinized closely. To elucidate such effects in vivo, this paper reviews human studies in which alpha- and beta-sympathomimetic agents had been infused. The literature suggests a dose-dependent stimulation of factor VIII clotting activity, von Willebrand factor antigen, tissue-type plasminogen activator, and platelets within a 15- to 40-min infusion of epinephrine. Precise mechanisms underlying hemostatic changes with sympathetic activation remain to some extent speculative. However, there is evidence from adrenoreceptor blockade studies that coagulation and fibrinolysis molecules are released into circulation by stimulation of vascular endothelial beta-adrenoreceptors (most likely beta2-receptors). Combined alpha2- and beta2-adrenoreceptor-related mechanism(s) are responsible for platelet activation. Short-term activation of the SNS effects regular hemostatic activity. While in healthy individuals the hemostatic balance between coagulation and fibrinolysis may be preserved, catecholamine surge may trigger a hypercoagulable state and enhance the odds of overt thrombosis in patients with atherosclerotic disease.

No Evidence for Association of Alpha 1a Adrenoceptor Gene Polymorphism and Clozapine-Induced Urinary Incontinence

Clozapine is an effective atypical antipsychotic that has high affinity for many neurotransmitter receptors. Among the adverse effects of clozapine, urinary incontinence is commonly found and is suggested to be caused by α-adrenergic blockade. We tested the hypothesis that clozapine-induced urinary incontinence is related to a genetic variant of the α_1a-adrenoceptor. We also tested whether the α_1a-receptor gene confers susceptibility to schizophrenic disorders. Our result indicated that the α_1a-adrenoceptor gene polymorphism investigated plays no major role in the pathogenesis of schizophrenia or in clozapine-induced urinary incontinence. Considering the superior effects of clozapine and its potent adrenergic antagonistic effects, it is of interest to investigate the association between this polymorphism and the treatment response.

Mechanisms of calcium buffering in adrenergic neurones and effects of ageing: testing the limits of homeostasis.

Journal of Autonomic PharmacologyVolume 20, Issue 2 p. 63-75 Mechanisms of calcium buffering in adrenergic neurones and effects of ageing: testing the limits of homeostasis W. J. Pottorf, W. J. Pottorf Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;Search for more papers by this authorS. P. Duckles, S. P. Duckles Department of Pharmacology, College of Medicine, University of California, Irvine, CA 92697, USASearch for more papers by this authorJ. N. Buchholz, J. N. Buchholz Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;Search for more papers by this author W. J. Pottorf, W. J. Pottorf Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;Search for more papers by this authorS. P. Duckles, S. P. Duckles Department of Pharmacology, College of Medicine, University of California, Irvine, CA 92697, USASearch for more papers by this authorJ. N. Buchholz, J. N. Buchholz Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA;Search for more papers by this author First published: 28 June 2008 https://doi.org/10.1046/j.1365-2680.2000.00165.xCitations: 11 J. N. Buchholz Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume20, Issue2April 2000Pages 63-75 RelatedInformation