DOCSLIB.ORG

Phentolamine Mesylate Relaxes Penile Corpus Cavernosum Tissue by Adrenergic and Non-Adrenergic Mechanisms

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phentolamine Mesylate Relaxes Penile Corpus Cavernosum Tissue by Adrenergic and Non-Adrenergic Mechanisms International Journal of Impotence Research (1998) 10, 215±223 ß 1998 Stockton Press All rights reserved 0955-9930/98 $12.00 http://www.stockton-press.co.uk/ijir Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms A Traish, S Gupta, C Gallant, Y-H Huang and I Goldstein Department of Urology, Boston University School of Medicine, Boston, MA 02118 Aim of the study: We investigated the biochemical and physiological mechanisms of action of phentolamine mesylate (VasomaxTM) in regulating erectile tissue smooth muscle contractility in human and rabbit corpus cavernosum. Methods: The binding activity of phentolamine was investigated in a cell-free system by displacement of speci®c and selective radiolabelled ligands to alpha 1 and 2 adrenergic receptors. The physiologic activity of phentolamine-mediated relaxation of adrenergic and non-adrenergic pre-contracted erectile tissue strips of human and rabbit corpus cavernosum were studied in organ bath chambers. Results: In corpus cavernosum membranes, phentolamine displaced binding of the selective alpha 1 receptor antagonists [125I]HEAT and [3H]prazosin and the alpha 2 receptor antagonists [3H]rauwolscine and [3H]RX 821002 with relatively high af®nity. Phentolamine caused concentration dependent relaxation in erectile tissue strips pre-contracted with adrenergic agonists phenylephrine, norepinephrine, oxymetazoline and UK 14 304, as well as with non- adrenergic contractile agents endothelin and KCl. Biochemical and physiologic studies reveal that the concentration of phentolamine required to displace half maximal binding or to produce half- maximal relaxation was similar to that found in human plasma 30 min after ingestion of 40 mg of VasomaxTM. Reversible inhibition of nitric oxide synthase by L-nitroarginine or mechanical disruption of endothelium diminished non-adrenergic phentolamine-mediated erectile tissue relaxation. Conclusions: Phentolamine mesylate induced relaxation of corpus cavernosum erectile tissue by direct antagonism of alpha 1 and 2 adrenergic receptors and by indirect functional antagonism via a non-adrenergic, endothelium-mediated mechanism suggesting nitric oxide synthase activation. Keywords: phentolamine mesylate; a-adrenergic receptors; erectile dysfunction; corpus caverno- sum smooth muscle; penile erection Introduction therapy as treatment for male erectile dysfunction, Zorgniotti,2 Gwinup3 and Wagner et al4 have utilized oral and buccal formulations of phentola- Phentolamine mesylate, an adrenergic antagonist, mine mesylate in pilot studies. has been marketed as an injectable substance A new formulation of oral phentolamine mesylate (Regitine, Ciba-Geigy) for over 40 y in the United (VasomaxTM) is currently being investigated for its States. It is approved for the treatment of pheochro- safety and ef®cacy in the treatment of male erectile mocytoma-related hypertension, for the diagnosis of dysfunction.5±8 Pharmacokinetic studies in normal pheochromocytoma and for norepinephrine-related volunteers have revealed that the mean phentola- dermal necrosis. Since 1984, phentolamine mesylate mine plasma concentration, 30 min after oral inges- has also been successfully utilized, in combination tion of 40 mg VasomaxTM tablets, was 16 ng/ml (42± with other vasoactive agents, for the intracavernosal 50 nM).9 Recent double-blind, placebo controlled, pharmacological treatment of male erectile dysfunc- multi-institutional clinical trials with VasomaxTM 1 tion. Due to inherent problems with self-injection have documented signi®cant improvement in erec- tile function compared to placebo in patients with minimal erectile dysfunction.5±8 Correspondence: Dr I Goldstein, Department of Urology, The molecular mechanisms of action underlying Doctors Of®ce Building, 720 Harrison Ave, Suite 606, Boston, MA 02118, USA. phentolamine mesylate-induced improvement of Received 29 December 1997; accepted in revised form erectile function are thought to be exclusively 16 March 1998 related to local inhibition of post-synaptic alpha- Phentolamine mesylate in penile erection A Traish et al 216 adrenergic receptors, however, local actions of chemicals were reagent grade and obtained from phentolamine in vascular smooth muscle may also commercial sources. include non-adrenergic pathways.10 The aim of this study was to detail, for the ®rst time, the biochem- ical and physiological mechanisms of action of phentolamine mesylate-mediated relaxation of cor- Biochemical binding studies pus cavernosum by adrenergic and non-adrenergic mechanisms. Membrane preparation and phentolamine mesylate binding to alpha 1 and 2 adrenergic receptors in corpus cavernosum smooth muscle were carried out Materials and methods as described previously.12±14 The data represents the cumulative observations from two or more indepen- dent experiments. Tissue procurement To examine the biochemical and physiological mechanisms of action of phentolamine mesylate- Physiological studies in organ bath chambers mediated relaxation, both human and rabbit corpus cavernosum erectile tissues were utilized, as indi- Human and rabbit corpus cavernosum strips were cated in the legend to the speci®c experiments. In mounted to force transducers (Grass Instruments general, initial experiments were performed with FT03, Quincy, MA) in 25 ml organ baths (37C) erectile tissue from the New Zealand White male containing Krebs solution and aerated with 5% CO2/ rabbit. The methodology of tissue harvest was 95% air to maintain a pH of 7.4. Optimal isometric approved by the Institutional Animal Care Commit- 11,12 tension for contraction was attained as described tee and has been previously reported. Data previously.11,13,14 The maximum contraction in- concerning phentolamine mesylate-mediated activ- duced by 80 mM KCl was determined for each strip ity in rabbit erectile tissue were then con®rmed before starting the experimental protocols. Dose using human erectile tissue. Human corpus caver- responses to various adrenergic agonists were nosum erectile tissues were procured during penile obtained by cumulative additions of drugs to the prosthesis implantation as approved by the Institu- chambers in half log increments starting at 1 nM and tional Review Board for Human Studies. In the continuing until the maximal contraction was operating room, erectile tissue biopsies were placed achieved with each treatment. For relaxation stu- in chilled physiological salt solution and immedi- dies, tissues were precontracted with a submaximal ately transported to the laboratory for experimenta- 11,12 concentration of phenylephrine (1 mM), KCl (20± tion as previously reported. 40 mM) or endothelin (30 nM). Once stable contrac- tion was reached, phentolamine dose responses were initiated by the addition of drug in half log Radioisotopes and chemicals increments (0.1 nM±0.1 mM). At the end of the experiment, 100 mM papaverine was added to deter- mine maximal relaxation. In experiments in which Zonagen Inc. (Houston, TX) provided phentolamine 3 the strips were pre-contracted with KCl, bretylium mesylate. [ H(N)]prazosin (34±45 Ci/mmol) and 2-{b- (10 mM), guanethidine (10 mM) and propranolol (4-hydroxy-3-[125I]iodophenyl)-ethylaminomethyl}- 125 (1 mM) were added to inhibit KCl-induced norepi- tetralone ([ I]HEAT) ( 2000 Ci/mmol) were ob- nephrine release.11,13 Relaxation data were normal- tained from New England Nuclear, Boston, MA. [3H] 3 ized as a percent of 80 mM KCl contraction for each RX821002 (54 Ci/mmol) and [ H] rauwolscine concentration. (74 Ci/mmol) were obtained from Amersham, (Ar- lington Heights, IL). Unlabeled prazosin and 5- methylurapidil (5-methyl-6[[3-[4-(2-methoxyphe- nyl)-1-piprazinyl]propyl]amino]-1,3-dimethyluracil) Statistical analysis were obtained from Research Biochemicals Inc., (Natick, MA). Phenylmethylsulfonyl ¯uoride, apro- tinin, L-nitroarginine and pepstatin A were obtained Relaxation of corpus cavernosum tissue to various from Sigma Chemical Company (St. Louis, MO). drugs is expressed as the percent change in tone. Endothelin-1 was obtained from Peninsula Lab. Inc., Maximum tone of the tissue is de®ned as that tone bretylium tosylate was obtained from American between the contraction to phenylephrine (1 mM) Critical Care, guanethidine ismelin monosulfate and the relaxation induced by papaverine (100 mM). was obtained from CIBA-Geigy Corning, RS 15385- Analysis of variance (ANOVA) was used to compare 197 was obtained from Roche Biosciences. All other the responses between control and phentolamine. Phentolamine mesylate in penile erection A Traish et al 217 Figure 1 Phentolamine mesylate displaces the alpha 1 adrenergic receptor antagonists [125I]HEAT and [3H]prazosin in rabbit corpus cavernosum. Membranes of corpus cavernosum smooth muscle were isolated and aliquots (200 ml, in triplicates) of the membranes were incubated at 25C for 1 h with 0.2 ml of buffer containing [3H] ligand (1 nM) in the absence (total binding) or presence of increasing concentrations (10711±1075 M) of unlabeled ligands. Binding was measured as described in the methods section. Speci®c binding was then determined by subtraction of nonspeci®c binding from total binding. The speci®c binding of each data point was plotted as percent of binding (compared to control) vs log molar concentrations of unlabeled ligands. (a) represents displacement of [125I]HEAT with phentolamine (j), 5 methylurapidil, (s) and prazosin (u). (b) represents displacement of [3H]prazosin with phentolamine (j), 5 methylurapidil, (s)
Load more

Recommended publications
  • Selective Labeling of Serotonin Receptors Byd-[3H]Lysergic Acid
    Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 5783-5787, December 1978 Biochemistry Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate (ergots/hallucinogens/tryptamines/norepinephrine/dopamine) PATRICIA M. WHITAKER AND PHILIP SEEMAN* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8 Communicated by Philip Siekevltz, August 18,1978 ABSTRACT Since it was known that d-lysergic acid di- The objective in this present study was to improve the se- ethylamide (LSD) affected catecholaminergic as well as sero- lectivity of [3H]LSD for serotonin receptors, concomitantly toninergic neurons, the objective in this study was to enhance using other drugs to block a-adrenergic and dopamine receptors the selectivity of [3HJISD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of (cf. refs. 36-38). We then compared the potencies of various a combination of 50 nM each of phentolamine (adde to pre- drugs on this selective [3H]LSD binding and compared these clude the binding of [3HJLSD to a-adrenoceptors), apmo ie, data to those for the high-affinity binding of [3H]serotonin and spiperone (added to preclude the binding of [3H[LSD to (39). dopamine receptors), it was found by Scatchard analysis that the total number of 3H sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catechol- METHODS amine-blocking drugs. The IC50 values (concentrations to inhibit Preparation of Membranes. Calf brains were obtained fresh binding by 50%) for various drugs were tested on the binding of [3HLSD in the presence of 50 nM each of apomorphine (A), from the Canada Packers Hunisett plant (Toronto).
    [Show full text]
  • United States Patent (19) (11) 4,310,524 Wiech Et Al
    United States Patent (19) (11) 4,310,524 Wiech et al. 45 Jan. 12, 1982 (54) TCA COMPOSITION AND METHOD FOR McMillen et al., Fed. Proc., 38,592 (1979). RAPD ONSET ANTDEPRESSANT Sellinger et al., Fed. Proc., 38,592 (1979). THERAPY Pandey et al., Fed. Proc., 38,592 (1979). 75) Inventors: Norbert L. Wiech; Richard C. Ursillo, Primary Examiner-Stanley J. Friedman both of Cincinnati, Ohio Attorney, Agent, or Firm-Millen & White 73) Assignee: Richardson-Merrell, Inc., Wilton, Conn. (57 ABSTRACT A method is provided for treating depression in a pa (21) Appl. No.: 139,498 tient therefrom and requiring rapid symptomatic relief, (22 Filed: Apr. 11, 1980 which comprises administering to said patient concur 51) Int. Cl. .................... A61K 31/33; A61K 31/135 rently (a) an effective antidepressant amount of a tricy clic antidepressant or a pharmaceutically effective acid (52) ...... 424/244; 424/330 addition salt thereof, and (b) an amount of an a-adrener 58) Field of Search ................................ 424/244, 330 gic receptor blocking agent effective to achieve rapid (56) References Cited onset of the antidepressant action of (a), whereby the PUBLICATIONS onset of said antidepressant action is achieved within Chemical Abst., vol. 66-72828m, (1967), Kellett. from 1 to 7 days. Chemical Abst, vol. 68-94371a, (1968), Martelli et al. A pharmaceutical composition is also provided which is Chemical Abst., vol. 74-86.048j, (1971), Dixit et al. especially adapted for use with the foregoing method. Holmberg et al., Psychopharm., 2,93 (1961). Svensson, Symp. Med. Hoechst., 13, 245 (1978). 17 Claims, No Drawings 4,310,524 1.
    [Show full text]
  • Alpha- and Beta-Adrenergic Receptor Blockade in the Treatment of Hypertension
    Br Heart J: first published as 10.1136/hrt.36.6.588 on 1 June 1974. Downloaded from British Heart Journal, 1974, 36, 588-596. Alpha- and beta-adrenergic receptor blockade in the treatment of hypertension P. A. Majid, M. K. Meeran, M. E. Benaim,' B. Sharma and S. H. Taylor From the Cardiovascular Unit, University Department ofMedicine, The General Infirmary, Leeds The effects of single and combined selective blockade of the sympathetic alpha- and beta-receptors were examined in patients with severe hypertension (diastolic pressure > I20 mmHg) uncomplicated by cardiac or renal failure. Given intravenously to 12 patients the alpha-receptor antagonist phentolamine and the beta-receptor antagonist oxprenolol together produced a reduction in systemic arterialpressure to normal levels and a reduction in left ventricular end-diastolic pressure without change in the cardiac output; these effects were maintained. Separately, neither drug resulted in such a satisfactory circulatory reponse. In 6 patients continued oral treatment for 6 months with progressively increased doses of oxprenolol alone up to 480 mg daily, in divided doses, produced a moderate reduction in blood pressure. The addition of oral phentolamine 20 mg t.d.s. resulted in an immediate reduction of blood pressure to normal levels, both at rest and during walking, without postural or other side effects, and without habituation to treatment over a period of 6 months. Arguments are presented that such treatment may have significant advantages over other current medicinal treatments of severe hypertensive vascular disease. http://heart.bmj.com/ In uncomplicated essential hypertension the raised et al., I965a; Majid et al., 197I).
    [Show full text]
  • To Five-Year-Old Dental Patients Elliot V
    PEDIATRIC DENTISTRY V 39 / NO 1 JAN / FEB 17 O RANDOMIZED CONTROL TRIAL Phase Four, Randomized, Double-Blinded, Controlled Trial of Phentolamine Mesylate in Two- to Five-year-old Dental Patients Elliot V. Hersh, DMD, MS, PhD1 • Rochelle Lindemeyer, DMD2 • Joel H. Berg, DDS, MS3 • Paul S. Casamassimo, DDS, MS4 • Judith Chin, DDS, MS5 • Adam Marberger, DDS6 • Brent P. Lin, DMD7 • Matthew C. Hutcheson, MS8 • Paul A. Moore, DMD, PhD, MPH9 • Pediatric Soft Tissue Anesthesia Recovery Group10 Abstract: Purpose: The purpose of this study was to evaluate, using a randomized, double-blind methodology: (1) the safety of phentolamine mesylate (Oraverse) in accelerating the recovery of soft tissue anesthesia following the injection of two percent lidocaine plus 1:100,000 epine- phrine in two- to five-year-olds; and (2) efficacy in four- to five-year-olds only. Methods: One hundred fifty pediatric dental patients underwent routine dental restorative procedures with two percent lidocaine plus 1:100,000 epinephrine with doses based on body weight. Phentolamine mesylate or a sham injection (two to one ratio) was then administered. Subjects were monitored for safety and, in four- to five-year-olds, for efficacy during the two-hour evaluation period. Results: There were no significant differences in adverse events between the phentolamine and sham injections. Compared to sham, phentolamine was not associated with nerve injury, increased analgesic use, or abnormalities of the oral cavity. Phentolamine was associated with transient decreased blood pressure in some children. In four- and five-year-olds, phentolamine induced more rapid recovery of lip anesthesia by 48 minutes (P<0.0001).
    [Show full text]
  • Oral Phentolamine: an Alpha-1, Alpha-2 Adrenergic Antagonist for the Treatment of Erectile Dysfunction
    International Journal of Impotence Research (2000) 12, Suppl 1, S75±S80 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction I Goldstein1 1Department of Urology, Boston University School of Medicine, Boston, MA, USA Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high af®nity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30±40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are suf®cient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1±5 and 15) from screening to the end of treatment was signi®cantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satis®ed or very satis®ed compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts.
    [Show full text]
  • Avocado, Banana, Patient Should Avoid Food High in Indoles: Avocado, Banana, Tomato, Plum, Walnut, Pineapple, and Eggplant
    Special Dietary Consideration for 24 Hour Urine Special Dietary Consideration for 24 Hour Urine Collection for 5-HIAA Collection for 5-HIAA Patient should avoid food high in indoles: avocado, banana, Patient should avoid food high in indoles: avocado, banana, tomato, plum, walnut, pineapple, and eggplant. tomato, plum, walnut, pineapple, and eggplant. Drugs which can interfere with testing due to physiologic Drugs which can interfere with testing due to physiologic response: Acetaminophen, Alpha and Beta Blockers, response: Acetaminophen, Alpha and Beta Blockers, Atenolol, Bromocriptine, Bronchodilators, Clonidine, Digoxin, Atenolol, Bromocriptine, Bronchodilators, Clonidine, Digoxin, Isoniazid, L-Dopa, Labetelol, Methyldopa, Monoamine Isoniazid, L-Dopa, Labetelol, Methyldopa, Monoamine Oxidase Inhibitors, Nitroglycerin, Sympathomimetic Amines, Oxidase Inhibitors, Nitroglycerin, Sympathomimetic Amines, Phenobarbital, Phenothiazines, Phentolamine, Reserprine, Phenobarbital, Phenothiazines, Phentolamine, Reserprine, Salicylates, Tricyclic Antidepressants. Salicylates, Tricyclic Antidepressants. Special Dietary Consideration for 24 Hour Urine Special Dietary Consideration for 24 Hour Urine Collection for 5-HIAA Collection for 5-HIAA Patient should avoid food high in indoles: avocado, banana, Patient should avoid food high in indoles: avocado, banana, tomato, plum, walnut, pineapple, and eggplant. tomato, plum, walnut, pineapple, and eggplant. Drugs which can interfere with testing due to physiologic Drugs which can interfere with testing
    [Show full text]
  • Intracavernosal Injection Therapy in the Management of ED
    Intracavernosal Injection Therapy in the Management of ED ISSM SAO PAULO 2014 Hossein Sadeghi-Nejad, MD, FACS Professor of Surgery in Urology Rutgers– New Jersey Medical School Hackensack University Medical Center Chief of Urology, VA NJ Health Care System Paraty, Brazil HSN 2014 Disclosures Auxilium: Principal Investigator American Urol Assoc.: Guidelines Panel Journal of Sexual Medicine: Ed Board NY Section AUA: Board of Directors SMSNA: Board of Directors (Secretary) ISSM (Communications Committee Chair) Outline Introduction to ICI ICI and Color Penile Doppler Ultrasound in Diagnosis of ED ICI Therapy in the Treatment ED ICI for Penile Rehabilitation After Radical Prostatectomy (RP) ICI and Erectile Dysfunction Prior to ICI, psychosexual Rx, surgery, VED for ED patients Opened door for pharmacological Rx ICI first described by Virag in 19822 – 80mg papaverine injection improved blood flow to cavernous tissue Advent of PDE-5 inhibitors supplanted ICI as first-line therapy 1. Lewis et al. J Sex Med, 2010, vol 7, pp.1598-1607. 2. Virag, J Urol, 2002, vol 167, pp. 1196. “I had been wondering why he was wearing sweatpants. Suddenly I knew. It was a big penis, and he just walked around the stage, showing it off.” A. Melman Brindley GS. Cavernosal alpha-blockade: a new technique for investigating and treating erectile impotence. Br J Psychiatry 1983;143:332-337. Vasculogenic ED and ICI Vasculogenic ED: arterial insufficiency and / or corporeal venous occlusive dysfunction (CVOD) Color penile Doppler ultrasound (CPDU) in conjunction with ICI – Correlated with abnormalities on pelvic arteriography and cavernosometry1 – Help detect vascular abnormalities and differentiate between vasculogenic ED1 1.
    [Show full text]
  • Phentolamine Mesylate for Injection USP, 5Mg
    PHENTOLAMINE MESYLATE- phentolamine mesylate injection Precision Dose Inc. ---------- Phentolamine Mesylate for Injection USP, 5mg DESCRIPTION Phentolamine Mesylate for Injection, USP is an antihypertensive, available in vials for intravenous and intramuscular administration. Each vial contains phentolamine mesylate, USP, 5 mg, and mannitol USP, 25 mg, in sterile, lyophilized form. Phentolamine Mesylate, USP is 4,5-dihydro-2-[N-(m-hydroxyphenyl)-N-(p-methylphenyl) amino methyl]-1H- imidazole 1:1 methanesulfonate, and its structural formula is Phentolamine mesylate, USP is a white or off-white, odorless crystalline powder with a molecular weight of 377.46. Its solutions are acid to litmus. It is freely soluble in water and in alcohol, and slightly soluble in chloroform. It melts at about 178°C. CLINICAL PHARMACOLOGY Phentolamine Mesylate for Injection, USP produces an alpha-adrenergic block of relatively short duration. It also has direct, but less marked, positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle. Phentolamine Mesylate for Injection, USP has a half-life in the blood of 19 minutes following intravenous administration. Approximately 13% of a single intravenous dose appears in the urine as unchanged drug. INDICATIONS AND USAGE Phentolamine Mesylate for Injection, USP is indicated for the prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision. Phentolamine Mesylate for Injection, USP is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. Phentolamine Mesylate for Injection, USP is also indicated for the diagnosis of pheochromocytoma by the Phentolamine Mesylate for Injection, USP blocking test.
    [Show full text]
  • Lysergic Acid Biethylamide Binds to a Novel Serotonergic Site on Rat Choroid Plexus Epithelial Cells’
    0270.6474/85/0512-3178$02.00/O The Journal of Neuroscrence Copyrrght 0 Society for Neuroscrence Vol. 5, No. 12, pp. 3178-3183 Printed I” U S A December 1985 ‘*%Lysergic Acid Biethylamide Binds to a Novel Serotonergic Site on Rat Choroid Plexus Epithelial Cells’ KEITH A. YAGALOFF AND PAUL R. HARTIG’ Department of Biology, Johns Hopkins University, Baltimore, Maryland 2 1218 Abstract ‘251-Lysergic acid diethylamide (‘251-LSD) binds with high Materials and Methods affinity to serotonergic sites on rat choroid plexus. These Autoradrography. Coronal sections (6 to 8 pm) of frozen adult rat brains sites were localized to choroid plexus epithelial cells by use were thaw-mounted onto subbed mrcroscope slides, air-drred for 20 min, of a novel high resolution stripping film technique for light and stored at -20°C In dessrcated microscope boxes. The mounted trssue microscopic autoradiography. In membrane preparations sections were brought to room temperature and then labeled with ‘?LSD from rat choroid plexus, the serotonergic site density was bv a technique srmilar to the method of Nakada et al. (1984). Sections were 3100 fmol/mg of protein, which is lo-fold higher than the incubated for 60 min at room temperature In 50 mM Tris-HCI buffer (pH 7.6) density of any other serotonergic site in brain homogenates. containina either 1.5 nM ‘?LSD (2000 Ci/mmol) or 1.5 nM “51-LSD and 1 UM The choroid plexus site exhibits a novel pharmacology that ketansen;, to determine nonspecific binbrng. ‘?LSD was synthesized ‘by does not match the properties of 5hydroxytryptamine-la (5 the method of Morettr-Rojas et al.
    [Show full text]
  • Combination Therapy for Erectile Dysfunction
    International Journal of Impotence Research (2002) 14, 54–60 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir Combination therapy for erectile dysfunction: a randomized, double blind, unblinded active-controlled, cross-over study of the pharmacodynamics and safety of combined oral formulations of apomorphine hydrochloride, phentolamine mesylate and papaverine hydrochloride in men with moderate to severe erectile dysfunction PI Lammers1*, E Rubio-Aurioles2, R Castell3, J Castaneda3, R Ponce de Leon4, D Hurley4, M Lipezker4, LA Loehr1 and F Lowrey1 1Zonagen, Inc., USA; 2Asociacio´n Mexicana para la Salud Sexual Me´xico; 3Hospital General de Me´xico; and 4Estadisticos y Clinicos Asociados, Mexico Oral therapy has become first line treatment for patients with mild to moderate erectile dysfunction (ED). Studies have shown that sildenafil may not be effective in all patients, and has been associated with a variety of adverse effects and an adverse interaction with nitrates and inhibitors of cytochrome P450 enzymes. The objective was to compare the efficacy and safety of three different oral combinations with the highest dose of sildenafil in men with moderate to severe ED. Randomized, double blind, unblinded active-controlled, Phase II study was carried out at three sites in Mexico. After a 4-week placebo run-in period, patients received all four of the following treatments using a 4-way cross-over design: 40 mg phentolamine (PM) þ 6mg apomorphine (Apo); 40 mg PM þ 150 mg papaverine (Pap); 40 mg PM þ 6 mg Apo þ 150 mg Pap (Tricombo); 100 mg sildenafil (SC).
    [Show full text]
  • Inhibition of Noradrenaline Release by Lysergie Acid Diethylamide
    t Brit.J,Pharmacol. 49, 706-708 (1973). 706 Short cor_tmlotications 2 hours. The tissue was finally suspended in a 3 ml organ bath maintained at 36°C Inhibition of noradrenaline and gassed with 95 O,/oO,,,: 5%CO,.. The intramural nerves were excited by a field release by lysergie acid current (1 ms rectilinear pulses of supra- diethylamide maximal strength) applied between platinum electrodes set in the top and J. HUGHES bottom of ,the bath. Contractions were , monitored with an isometric transducer Department of Pharmacology, coupled to a Grass Polygraph. To study University o] Aberdeen, Scotland transmitter release the vas was stimulated at 0-2 Hz for 3"5 rain every 15 minutes. .... Lysergicacid diethylamide(LSD)inhibits the The bath fluid was removed 30 s after the release of'labelled noradrcnaline from the end of each stimulation period and the guinea-pig vas deferens during intramural labelled catecholamines were isolated by nerve stimulation and causes a corresponding alumina column chromatography (Boadle- reduction in the contractions of the smooth Biber, Hughes & Roth, 1970). The activity of the alumina eluate was determined in muscle. These effects of LSD are most pro- minent at low stimulus frequencies and they a Packard liquid scintillation counter ,_ are prevented by treatment with phentolamine. (Model 2425). Basal samples for the 4 rain _ It is concluded that LSD inhibits noradren- preceding the onset of each stimulation aline release by interacting with presynaptic period were taken and treated as described above, the basal radioactivity was deducted c_-adrenoceptors, from the stimulated efflux. Attention has focussed mainly on two aspects of the pharmacology of lysergic Results.--LSD tartrate caused a rapid acid diethylamide (LSD), firstly its ability and prolonged inhibition of the contrac- ...
    [Show full text]
  • ADHD - an Overview of Therapy, Overdose and Treatment
    2010, Volume 4, Issue 4 ADHD - An Overview of Therapy, Overdose and Treatment Case Scenario: What is the mechanism of toxicity and symptoms of Mom walked into the older sibling’s room to find her 23- overdose for ADHD medications? month-old son with open bottles of clonidine and Ritalin®. Methylphenidate, dextroamphetamine/ It is unknown how many pills have been ingested. The amphetamine, and lisdexamfetamine boost child is transported to the ED. dopamine and norepinephrine by blocking What is ADHD (Attention Deficit Hyperactivity reabsorption, though the exact mechanism of Disorder) and what medications are used to treat it? action in treating ADHD in children and adults is ADHD is a common diagnosis in both pediatric unknown. Overdose is characterized by CNS and and adult populations. Symptoms of ADHD in cardiovascular toxicity, and hyperthermia. Overall, children and teens include the effects are one of sympathomimetic inattention and/or hyperactivity excess with elevated levels of and impulsive behavior norepinephrine, dopamine, and serotonin. inappropriate to the child’s age. Neurological effects include restlessness, Symptoms in adults may vary irritability, insomnia, hyperactivity, from that of children, with hallucinations, convulsions, and coma. emphasis on restlessness, Cardiovascular effects include arrhythmias trouble concentrating and staying (atrial and ventricular), hypertension focused, disorganization and (systolic and diastolic), palpitations, forgetfulness, impulsivity, and tachycardia, and circulatory collapse. difficulties
    [Show full text]