Edited for the Society by Eva King Killam

VOLUME 256. NUMBER 2. FEBRUARY 1991

JPETAB 256 (2) 421-819 (1991)

The Journal of

PHAR IACOLOCYAND EXPERIMENTAL THERAPEUTICS

A Publication of The American Society

for Pharmacology and Experimental TherapeuticsFounded by John J. Abel -1909

From S

�rne�t �

_______ L�� Use our VldepPat�h 1l’�cklng Systern�f

spatial and tof any other

Precisely meture, tremors, ‘C

startle, with-. MonitOr an

single I

ilus re Bd kinetIcpometic �latforms �F1

�ze data from 32 c�:�our Home Cage Acti

�b�m

�1

Cellular Pharmacology

Toshio NarahashiRonald P. RubinGeorge B. Weiss

The Journalof

PHARMACOLOGYAND EXPERIMENTAL THERAPEUTICS

A Publication of The American Society

for Pharmacology and Experimental Therapeutics

Founded by John J. Abel 1909EDITOR

Eva King Killam

ASSISTANT EDITOR

Mannfred A. Hollinger

EDITORS FOR SPECIFIC FIELDS

Analgesia and Drug Abuse

william L. DeweyBilly Martin

Autonomic Pharmacology

Robert R. Ruffolo, Jr.Robert E. Stitzel

Behavioral Pharmacology

John A. Harvey

Cardiovascular Pharmacology

Leslie E. BaileyHenry R. Besch, Jr.Theodore M. BrodySue Piper Duckles

Endocrine Pharmacology

Paula H. Stem

Gastrointestinal Pharmacology

Timothy S. GaginellaChemotherapy Frank Porreca

H. George Mandel Immunopharmacology

Developmental Pharmacology Sydney SpectorBemard L Mirkin Neuropharmacology

Drug Metabolism and Disposition Edmund G. AndersonEdward BresnickJordan L Holtzman

David B. BylundS. J. EnnaCharles 0. Rutledge

Prostaglandins and Leukotrienes

Guy C. Le BretonK. U. Malik

Pulmonary Pharmacology

Mannfred A. Hoilinger

Renal Pharmacology

William 0. Bemdt

Toxicology

Curtis D. Klaassen

EDITORIAL ADVISORY BOARD

Margaret AcaraMartin W. AdlerEdson X. AlbuquerqueJulius C. AllenJames B. AppelLewis AronowWilliam D. AtchisonAlbert J. AzzaroRobert L. BalsterPaul BassMichael A. BeavenDonald M. BersJohn A. BevanC. Paul BianchiDavid A. BlakeAlan S. BloomFloyd E. BloomPeter G. BradfordCarl K. BucknerTheodore J. CiceroMarlene L. CohenCharles R. CraigLuigi X. CubedduE. E. DanielWilliam C. de GroatLouis DiamondGerald F. DiBonaRobert J. DinersteinWalter R. DixonJ. W. Downie

Linda DykstraHugh L. EvansJerry M. FarleyHarold FeinbergGregory 0. FinkStephen K. FisherGarret A. FitzGeraldRay W. FullerGerard L. GebberJames W. GibbC. Norman GillisShn N. GinThomas P. GreenGarrett J. GrossR. Adron HamsRichard J. HeadJ. Paul HiebleStephen G. HoltzmanJerry B. HookE. H. JefferyRobert M. JoyGeorge J. KaloyanidesAlexander G. KarczmarTerry KenakinConan KometskyEdwin A. KroegerDavid D. KuSuzanne G. LaychockTonyJ.-F. Lee

Roberto LeviGeorge E. LindenmayerHorace H. LohBenedict R. LucchesiThomas A. McCaldenRobert B. McCallDonald E. McMillanW. H. MorseHasan MukhtarKevin MullaneL. Charles MumnJose M. MusacchioAllen H. NeimsJon A. NormanRobert F. O’DeaAchilles J. PappanoLeslie V. PariseGavril W. PastemakWilliam A. PettingerLarissa A. PohoreckyGarth PowisDonald V. PnolaRussell A. ProughDavid RaebumArthur RainesArnold SchwartzLewis S. SeidenPaul J. SilverDavid J. Smith

Roger P. SmithRoger 0. SpealmanJanice L. StickneyJohn L. SutkoBoris TabakoffA. E. TakemoriDavid A. TaylorRobert E. Ten EickThomas R. TephlyRichard E. TesselMartin J. M. C. ThoolenPieter B. M. W. M. TimmermansMyron L. ToewsTheodore J. TorphyU. TrendelenburgNorman J. UretskyPaul M. VanhoutteRalph VinegarLarry A. WalkerMartin A. WassermanR. Clinton WebbI. M. WeinerRichard M. WelchGrant R. WilkinsonMichael WilliamsMartin M. WinburyRaymond J. WinquistBarry B. WolfeHenry I. Yamamura

BOARD OF PUBLICATIONS TRUSTEES

Joel G. Hardman, Chairman: Arthur J. Atkinson, Jr., Marlene L. Cohen, T. Kendall Harden, Eva King Killam,Horace Loh, Kenneth E. Moore, Marcus M. Reidenberg, Robert E. Stitzel, Vincent G. Zannoni

EXECUTIVE OFFICER OF ThE SOCIETY

Kay A. Croker

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS (ISSN 0022-3565) is an official publication of The AmericanSociety for Pharmacology and Experimental Therapeutics and is published monthly by Williams & Wilkins, 428 E. Preston Street, Baltimore, MD 21202.3993. Second class postage paid at Baltimore, MD and at additional mailing offices. POSTMASTER: Send address changes to THE JOURNAL OFPHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 428 E. Preston St., Baltimore, MD 21202.3993. Indexed by Current Contents,Index Medicus and BioSciences Information Service. Subscription rates $170.00 ($235.00 foreign), institutions $285.00 ($350 foreign), single copy $18.00($22.00 foreign). Prices are subject to change. Copyright © 1991 by The American Society for Pharmacology and Experimental Therapeutics.

This advertisement expires within 60 days

Interdisciplinary ScientistU.S. Government

Food and Drug Administration

Position Description: The Food and Drug Administrationis seeking an interdisciplinary research scientist with spe-cialty training and experience in cardiovascular and pul-monary pathology. Responsibility include: assistance inthe design of cardiovascular and pulmonary investigationswhich lead to new and scientifically important findings, thedevelopment and application of appropriate techniques instudies requiring cardiovascular and pulmonary evalua-tion; the evaluation of cardiovascular and pulmonary tis-

sues from experimental animals for pathologic alterationof various types but with emphasis on changes producedas a result of administration of drugs; and use of his/herpathological expertise to extrapolate from the histologic

findings (cardiovascular-pulmonary) in tissues to mecha-nisms of drug toxicity in animals and humans.

Highly Desirable: Well trained scientist with a medicaldegree with pathology training or Ph.D. degree in patholo-gy with minor in pharmacology of toxicology and specialtytraining in pathology of cardiovascular and pulmonary tis-

sues. Must be able to carry out the evaluation of cardio-vascular and pulmonary tissues using techniques of his-topathology, histochemistry, immunochemistry (includingmonoclonal antibodies studies). Must have training inelectron microscopy. Such training should have demon-strated the ability to independently operate transmissionand scanning electron microscopes, take photos with bothof these instruments and interpret the resulting images.Must also have training in morphometry.

Salary: Ranges from $35,825.00 to $55,381 dependingon qualifications.

Positions Available: The positions available may befilled under one of the following: the Civil Service System

which requires U.S. citizenship; under the Service Fellow-ship Program that requires U.S. permanent residency andeligibility for U.S. citizenship within 4 years of appointmentor under the Visiting Associate Program which does notrequire U.S. permanent residency. Commission in the

U.S. Public Health Service, and oommensurate pay scalemay also be possible.

Applications: Submit current curriculum vitae or U.S.Government application form (SF-I 71) to:

DEPARTMENT OF HEALTHAND HUMAN SERVICES

Public Health ServiceFood and Drug Administration

Division of Human Resources ManagementRoom 4B18

5600 Fishers LaneRockvilie, MD 20857

Attention: Mr. Henry Zecher

AUTHOR INDEX

Apparsundaram, S., 486

Areso, P., 656Baldi, E., 581Beckmann, M. L., 542

Behrens, N. D., 462Beniston, D., 650Bennett, E. L., 650

Boarder, M. R., 628Boeckxstaens, G. E., 441Bogers, J. J., 441

Bousquet, P., 606Braff, D. L., 530

Brann, M. R., 727

Brown, T. J., 480Bult, H., 441

Burks, T. F., 547Bushnell, P. J., 741Cannon, J. G., 751

Chang, A. S.�S., 734

Chen, C.-J., 486

Christ, G. J., 553Cipkus.Dubray, L. A., 492

Cohen, M. L., 695Cohen, R. B., 639Colatsky, T. J., 639

Conway, P. G., 621

Cooke, J. P., 704

Daniel, E. E., 670

De Man, J. G., 441Done, F., 727

Duckles, S. P., 513, 519

Dunn, M. J., 581El.Fakahany, E. E., 468Farmer, S. C., 547

Feldman, J., 606

Flynn, J. R., 751

F#{246}rstermann, U., 677

Frazer, A., 656

Fr#{246}lich,J. C., 677

Frnka, J. V., 734

Fujimoto, J. M., 448

Fujiwara, M., 683

Gambarana, C., 656Gerber, J. G., 542

Gessner, G., 614Geyer, M. A., 530

Gonon, F., 606Granneman, J. G., 421

Hamahashi, T., 634

Han, B.-J., 704Hartman, H. B., 621

Hasegawa, H., 773

Hauser, J., 592Havens, C. N., 639Heikkila, R. E., 506

Heim, K. F., 537Hensler, J. G., 656Herman, A. G., 441

Hieble, J. P., 599Hofman, G. A., 665

Horn, D. S., 710

H#{246}nack,D., 432

Homer, E., 614Hubbard, J. W., 621

Hupe, D. J., 462Ichiyama, A., 773

Ishikawa, K., 650Itoh, T., 634

Janssen, L. J., 670Jean-Jacques, M., 553Johnston, P. A., 587Kachur, J. F., 562Kamatchi, G. L., 426

Kamisaki, Y., 634Kaneko, E., 773Kau, S. T., 587

Keith, V. A., 530

Khan, S. A., 492Kimura, T., 525

Knight, D. L., 787, 795

Kobayashi, T., 773

Kosley, R. W., Jr., 621Koster, A. Sj., 665Kuhn, M., 677Kurahashi, K., 683

Lai,J.,689Lam, D. M.-K., 734

Lambrecht, G., 727Lappi, S. E., 757

Law, P. Y., 710

Lebedinsky, Y., 621

Lee, F., 704

Lee, N. H., 468

Legrand, C., 767Leonard, P. A., 751

Lichtenstein, L. M., 717Lin, M., 645Lodge, N. J., 639Loh, H. H., 710Lokhandwala, M. F., 486Long, J. P., 751Lookingland, K. J., 500

Loscaizo, J., 704L#{246}scher,W., 432

Lucaites, V. L., 695Lutfy, K., 575

Ma, S., 751Major, T. C., 568Maltier, J..P., 767Manzanares, J., 500

Martinez, J. L., Jr., 650

Mason, N. R., 695Massamiri, T., 519

McGonigle, P., 811Mei, L., 689

Meijer, D. K. F., 458Meisheri, K. D., 492

Mendelsohn, L. G., 695Mermet, C., 606Mita, C., 634Moore, K. E., 500Mukaiyama, 0., 525

Mulder, G. J., 458Mutschler, E., 727

Nelson, T. E., 645

Nemeroff, C. B., 787, 795

Nies, A. S., 542Noordhoek, J., 665

Nordstrom, L. C., 621Noronha-Blob, L., 562

Nudelman, K. A., 650

Oleynek, J. J., 492

Olszyk, V. B., 741

O’Malley, G. J., 621

Oosterbosch, L., 441

Ordway, G. A., 656

Otten, A., 677

Owens, M. J., 787, 795

Padilla, S. S., 741

Panek, R. L., 568

Peachell, P. T., 717

Pelckmans, P. A., 441

Pendleton, R. G., 614

Peters, K., 462

Pfefferkorn, E. R., 462

Polhuijs, M., 458

Pope, C. N., 741

Porreca, F., 547Pracyk, J. B., 757Purohit, S. 5., 492

Rady,J.J.,448Raeburn, D., 480

Ramwell, P. W., 537

Rapundalo, S. T., 568Redegeld, F. A. M., 665

Rigolot, C., 767

Riordan, D. E., 506Ritchie, J. C., 787, 795Rivi#{232}re,P. J. M., 547

Roerig, S. C., 448Roeske, W. R., 689

Rosenzweig, M. R., 650Satoh, S., 525

Sauermelch, C. F., 599Schelm, J. A., 780Schleimer, R. P., 717Schulteis, G., 650Shaffer, J. E., 704Shibanoki, S., 650

Shimaji, H., 683Shirahase, H., 683

Simmerman, J., 568

Simpson, P. J., 780

Slotkin, T. A., 757

Smith, G. F., 780

Sonsalla, P. K., 506

Subramaniam, S., 811

Swerdlow, N. R., 530

Swirtz, M. A., 492

Szabo, S., 592

Tacke, R., 727

Takeuchi, A., 525

Taylor, D. G., Jr., 568Thomas, G., 537

Thomson, S., 704

Tibiri#{231}a,E., 606

Ticku, M. K., 426

Usui, H., 683van de Leo, P. G. F., 665

Van Maercke, Y. M., 441Vivat, V., 767

Volpe, P., 645Ward, T., 741

Weinberger, S. B., 650Weishaar, R. E., 568

Wess, J., 727Whitty, C. J., 421

Wilkes, L. C., 628Willette, R. N., 599Wilson, S. K., 801Yamamura, H. I., 689Yoburn, B. C., 575

* For rats and mice --

4-lane exerciser.

Electronically controlled

speed.* Electric stimulation grids.

GRIP STRENGTH METER for rats and mice

* Objectively measures

animal deficiencyin strength.

INEXPENSIVE ANIMAL ACTIVITY METERS* “Mini” activity meter

uses standard plastic cages.* Can be used with rats or mice.

* 15 Infrared sensors.

* Separates ambulatory

from total activity.* Multi-cage system available

w/ IBM-PC interface.

CARDIAC OUTPUT FOR RATS

* Thermodilution method

using 1/3 mm temp.

microprobes.

* Can be interfaced to an

IBM-PC.

* Measures: CO, S.V. BP,

Mean Transit Time, Ejection

Fraction and much more.

VENTILATORS

* Mechanical (piston)

positive pressure ventilators

for rodents and larger

animals.

ECONOMICAL O2/CO2 METABOLIC SYSTEM- � � * 02 Consumption/C02 pro-

� duction computer (IBM-PC).I- � � * Open-circuit

I � indirect calorimeter.I � Completely computerized.

‘� � * Single channel.

-.� .... � * Also available-multi-channel

systems for rats, mice, bacteria, horses, and humans.

�RMOMETER

* Interface to IBM-PC for

1 to 256 thermocouples.

Variety of temp. probes

(rectal, skin, implantable).

Software provides graphics

and real-time plotting.

* Also special software for

t ,�A registeredfor human use Pyrogenic Activity studies.

MAZES -- “FIGURE 8” AND “RADIAL ARM”

: * Computerized system with�. universal maze software

� (for IBM-PC) monitors inter-

� ruption of 128 IR sensors.

I * Data LOTUS 1-2-3compatible.

VIDEO TRACKERS FOR WATER MAZES

�--�I� * Measures activity, distance

traveled, pattern of move-

‘ ment, & rotations of multi-

1 �L ple animals w/ I TV camera.I \ * Vertical activity (3-D)

� I measurements w/ 2 cameras.

� ..� � * Ideal for water maze, human

� � �_�_j and animal gait analysis.

PH: (614) 488-61 76 FAX: (614) 276-0529 TLX: 2465 14 Toll Free: 1-800-669-501 1

New Products New Products

LAB ANIMAL RESEARCH EQUIPMENTINEXPENSIVE EXERCISER

-,‘ ‘-j � - . used for Rats* Extremely small ai�sample�

flow :-�5ml/min. �* Analog output to mps�,

recorders. . � �

* Digital Thsplay N2O � �

measurements. � �#{149}#{149}.;1 �

‘�.J ;� �: �.�i�#{149} I- � �L1l

For our complete catalog please contact: Columbus Instruments International Corp.

P.O. Box 44049 Columbus, Ohio 43204 USA