TOLBUTAMIDE: AN INOTROPIC EFFECT ON RABBIT ATRIA
1
604 TOLBUTAMIDE: AN INOTROPIC EFFECT ON RABBIT ATRIA ROGER F. PALMER KENNETH C. LASSETER JEANE MCCARTHY. Department of Pharmacology, University of Miami Medical School, Miami, Florida. Sm,ŇSince the report of the University Group Diabetes Program study suggesting that the administration of tolbutamide is associated with an increase in cardiovascular deaths, we have examined the effects of this drug on isolated rabbit atria. We were unable to find any previous report of the effects of this drug on myocardial contractility. Atria removed from freshly stunned rabbits and preloaded with 3 g. tension in a Krebs-Ringer solution at 3?°C were stimulated at a constant rate of 120 per minute by a Grass stimulator. Contractions were recorded using a Grass transducer and poly- graph. The sodium salt of tolbutamide, as supplied by the manufacturer (Upjohn Inc.), was twice recrystallised in ethanol to remove traces of calcium before use. The drug was added when contractions reached a constant amplitude. Six consecutive atria responded with an increase in amplitude of contraction to 121±5% of the control at a drug concentration of 10 mg. per 100 ml. (3-7 x 10-4M). The implications of this positive inotropism, if it can be reproduced in human beings, may be of interest in the interpretation of the increase in cardiovascular deaths during tolbutamide therapy. One interpretation centres about the increased work and oxygen demand that an inotropic agent would impose on the myocardium. Indeed, inotropic agents have been shown to extend the area of experimental myocardial infarction. 2 The cardiovascular effects of this drug are being further examined in this laboratory, but this initial observation seemed worthy of early dissemination. 1. Diabetes, 1970, 19, suppl. 2. 2. Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanabe, T., Covell, J. W., Ross, J., Braunwald, E. Circulation, 1971, 43, 67. Diarv of the Week MARCH 21 To 27 Monday, 22nd ROYAL POSTGRADUATE MEDICAL SCHOOL, Hammersmith Hospital, London W.12 4 P.M. Dr. D. G. Julian: Some Unresolved Problems in Acute Coronary Disease. INSTITUTE OF DERMATOLOGY, St. John’s Hospital for Diseases of the Skin, Lisle Street, London W.C.2 4.30 P.M. Dr. Imrich Sarkany: The Sweat Glands. MANCHESTER MEDICAL SOCIETY 8.30 P.M. (Medical School.) General Practice. Dr. R. C. Cunningham: Mental Subnormality. Wednesday, 24th ROYAL POSTGRADUATE MEDICAL SCHOOL 11.45 A.M. Dr. D. K. Peters: Goodpasture’s Syndrome. 2 P.M. Prof. P. L. Mollison: Experiments on the Suppression of Primary Rh-immunisation. INSTITUTE OF DERMATOLOGY 4.30 P.M. Mr. J. W. Hadgraft: The Pharmacy of Dermatologic Preparations. INSTITUTE OF ORTHOPEDICS, 234 Great Portland Street, London WlN 6AD 6 P.M. Dr. D. A. H. Yates: Rheumatological Aspects of Soft Tissue Lesions. INSTITUTE OF UROLOGY, 10 Henrietta Street, London W.C.2 5 P.M. Mr. D. M. Wallace: Techniques of Urinary Diversion. ROYAL FREE HOSPITAL, Gray’s Inn Road, London W.C.1 5.15 P.M. Dr. Geoffrey Slaney: The Results of Treatment of Cancer of the Colon and Rectum. MANCHESTER MEDICAL SOCIETY 5 P.M. (Roscoe Building, Brunswick Street.) Sir Solly Zuckerman: Two Manchester Anatomists. (Telford lecture.) Thursday, 25th ROYAL COLLEGE OF SURGEONS OF ENGLAND, Lincoln’s Inn Fields, London WC2A 3PN 5 P.M. Mr. J. G. Gow: Genito-urinary Tuberculosis-A Study of the Disease in One Unit Over a Period of 24 Years. (Hunter- ian lecture.) Obituary DAVID GAVIN MILLAR M.B.Durh., F.R.C.S., M.R.C.O.G. Prof. David Millar, foundation professor of human reproduction and obstetrics at Southampton Univer- sity Medical School, died on March 4 at the age of 41. He was born in Durham, the son of a local general practitioner, and, after his early education at Durham School, he studied medicine in the University of Durham (at Newcastle upon Tyne), and graduated with honours in 1952. He was elected F.R.C.S. in 1959 and M.R.C.O.G. in 1962. As an undergraduate he won the University Gibson prize in obstetrics and the B.M.A. competition for medical students for an essay on " the training of the student in the personal relationship between doctor and patient". After house-jobs and National Service in the R.A.M.C., he returned to the University in 1956 as a demonstrator in anatomy. In 1960, after registrar appointments in the department of surgery, he began his close association with obstetrics and gynxcology, first as a Luccock research fellow, then progressing as first assistant, lecturer, and senior lecturer in Prof. J. K. Russell’s department of obstetrics and gynaecology in the University of Newcastle upon Tyne. In 1966 he studied for a year in the U.S.A. at the University of Western Reserve, Cleveland, working under Prof. Charles Hendricks. The following year he was invited as visiting professor to the department of obstetrics and gynaecology. New York State University, Brooklyn, with Prof. Lou Hellman. In 1969 Millar was the first clinical professor (by a few days) to be appointed to the new medical school at Southampton. D. V. I. F. writes: " The untimely death of such a talented man is indeed a tragedy. His interests and spheres of influence were wide. While a research fellow in Newcastle he explored the problems of handling large amounts of obstetric data, and this led him to the computer field, where he rapidly became an expert in computer techniques, including both machine operating and programme development. He was one of the few medical men who really could talk authoritatively on the place of computers in medicine. " He was an excellent teacher, and it is most unfortunate that he did not live to see even the first entry of South- ampton students, for whom he had prepared so enthusiasti- cally the forward-looking curriculum which embodied the ideas and ideals suggested by the fact that his chair was the first in Britain in which the titles human reproduction and obstetrics were linked to replace the conventional obstetrics and gynxcology. " He was a competent obstetrician and gynaecologist and an equally able research-worker, absolutely dedicated in everything to which he turned his attention. In 1968 he was elected to the council of the Royal College of Obstetricians and Gynaecologists as a members’ repre- sentative, and here too his talents were soon recognised when he became a member and then chairman of the standard maternity-hospital report committee, a member of the examination committee, and chairman of the multiple-choice-question subcommittee. " David was a lucid thinker and a forceful speaker, equally capable presenting a formal lecture or giving an after-dinner speech. It was his particular wish that the nature of his fatal illness should be kept from most of his colleagues and friends, so that few witnessed the courage and example which he showed in the last few months. His death at this early age in a career which, although
Transcript of TOLBUTAMIDE: AN INOTROPIC EFFECT ON RABBIT ATRIA
604
TOLBUTAMIDE: AN INOTROPIC EFFECTON RABBIT ATRIA
ROGER F. PALMERKENNETH C. LASSETER
JEANE MCCARTHY.
Department of Pharmacology,University of Miami Medical School,
Miami, Florida.
Sm,ŇSince the report of the University Group DiabetesProgram study suggesting that the administration oftolbutamide is associated with an increase in cardiovasculardeaths, we have examined the effects of this drug on isolatedrabbit atria. We were unable to find any previous reportof the effects of this drug on myocardial contractility.
Atria removed from freshly stunned rabbits and preloaded with3 g. tension in a Krebs-Ringer solution at 3?°C were stimulatedat a constant rate of 120 per minute by a Grass stimulator.Contractions were recorded using a Grass transducer and poly-graph. The sodium salt of tolbutamide, as supplied by themanufacturer (Upjohn Inc.), was twice recrystallised in ethanolto remove traces of calcium before use. The drug was addedwhen contractions reached a constant amplitude.
Six consecutive atria responded with an increase inamplitude of contraction to 121±5% of the control at adrug concentration of 10 mg. per 100 ml. (3-7 x 10-4M).The implications of this positive inotropism, if it can bereproduced in human beings, may be of interest in theinterpretation of the increase in cardiovascular deathsduring tolbutamide therapy. One interpretation centresabout the increased work and oxygen demand that an
inotropic agent would impose on the myocardium. Indeed,inotropic agents have been shown to extend the area ofexperimental myocardial infarction. 2 The cardiovasculareffects of this drug are being further examined in thislaboratory, but this initial observation seemed worthy ofearly dissemination.
1. Diabetes, 1970, 19, suppl. 2.2. Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanabe, T., Covell,
J. W., Ross, J., Braunwald, E. Circulation, 1971, 43, 67.
Diarv of the Week
MARCH 21 To 27
Monday, 22ndROYAL POSTGRADUATE MEDICAL SCHOOL, Hammersmith Hospital,
London W.124 P.M. Dr. D. G. Julian: Some Unresolved Problems in Acute
Coronary Disease.INSTITUTE OF DERMATOLOGY, St. John’s Hospital for Diseases of the
Skin, Lisle Street, London W.C.24.30 P.M. Dr. Imrich Sarkany: The Sweat Glands.
MANCHESTER MEDICAL SOCIETY8.30 P.M. (Medical School.) General Practice. Dr. R. C. Cunningham:
Mental Subnormality.
Wednesday, 24thROYAL POSTGRADUATE MEDICAL SCHOOL
11.45 A.M. Dr. D. K. Peters: Goodpasture’s Syndrome.2 P.M. Prof. P. L. Mollison: Experiments on the Suppression of
Primary Rh-immunisation.INSTITUTE OF DERMATOLOGY
4.30 P.M. Mr. J. W. Hadgraft: The Pharmacy of DermatologicPreparations.
INSTITUTE OF ORTHOPEDICS, 234 Great Portland Street, LondonWlN 6AD
6 P.M. Dr. D. A. H. Yates: Rheumatological Aspects of Soft TissueLesions.
INSTITUTE OF UROLOGY, 10 Henrietta Street, London W.C.25 P.M. Mr. D. M. Wallace: Techniques of Urinary Diversion.
ROYAL FREE HOSPITAL, Gray’s Inn Road, London W.C.15.15 P.M. Dr. Geoffrey Slaney: The Results of Treatment of Cancer
of the Colon and Rectum.MANCHESTER MEDICAL SOCIETY
5 P.M. (Roscoe Building, Brunswick Street.) Sir Solly Zuckerman:Two Manchester Anatomists. (Telford lecture.)
Thursday, 25thROYAL COLLEGE OF SURGEONS OF ENGLAND, Lincoln’s Inn Fields,
London WC2A 3PN5 P.M. Mr. J. G. Gow: Genito-urinary Tuberculosis-A Study of
the Disease in One Unit Over a Period of 24 Years. (Hunter-ian lecture.)
Obituary
DAVID GAVIN MILLAR
M.B.Durh., F.R.C.S., M.R.C.O.G.
Prof. David Millar, foundation professor of humanreproduction and obstetrics at Southampton Univer-sity Medical School, died on March 4 at the age of 41.He was born in Durham, the son of a local general
practitioner, and, after his early education at Durham
School, he studied medicine in the University of Durham(at Newcastle upon Tyne), and graduated with honoursin 1952. He was elected F.R.C.S. in 1959 and M.R.C.O.G.in 1962.As an undergraduate he won the University Gibson
prize in obstetrics and the B.M.A. competition for medicalstudents for an essay on " the training of the student inthe personal relationship between doctor and patient".After house-jobs and National Service in the R.A.M.C.,he returned to the University in 1956 as a demonstratorin anatomy. In 1960, after registrar appointments in thedepartment of surgery, he began his close association withobstetrics and gynxcology, first as a Luccock researchfellow, then progressing as first assistant, lecturer, andsenior lecturer in Prof. J. K. Russell’s department ofobstetrics and gynaecology in the University of Newcastleupon Tyne. In 1966 he studied for a year in the U.S.A.at the University of Western Reserve, Cleveland, workingunder Prof. Charles Hendricks. The following year hewas invited as visiting professor to the department ofobstetrics and gynaecology. New York State University,Brooklyn, with Prof. Lou Hellman. In 1969 Millar wasthe first clinical professor (by a few days) to be appointedto the new medical school at Southampton.D. V. I. F. writes:" The untimely death of such a talented man is indeed
a tragedy. His interests and spheres of influence werewide. While a research fellow in Newcastle he exploredthe problems of handling large amounts of obstetric data,and this led him to the computer field, where he rapidlybecame an expert in computer techniques, includingboth machine operating and programme development.He was one of the few medical men who really could talkauthoritatively on the place of computers in medicine.
" He was an excellent teacher, and it is most unfortunatethat he did not live to see even the first entry of South-ampton students, for whom he had prepared so enthusiasti-cally the forward-looking curriculum which embodied theideas and ideals suggested by the fact that his chair was thefirst in Britain in which the titles human reproduction andobstetrics were linked to replace the conventional obstetricsand gynxcology.
" He was a competent obstetrician and gynaecologistand an equally able research-worker, absolutely dedicatedin everything to which he turned his attention. In 1968he was elected to the council of the Royal College ofObstetricians and Gynaecologists as a members’ repre-sentative, and here too his talents were soon recognisedwhen he became a member and then chairman of thestandard maternity-hospital report committee, a memberof the examination committee, and chairman of the
multiple-choice-question subcommittee." David was a lucid thinker and a forceful speaker,
equally capable presenting a formal lecture or giving anafter-dinner speech. It was his particular wish that thenature of his fatal illness should be kept from most of hiscolleagues and friends, so that few witnessed the courageand example which he showed in the last few months.His death at this early age in a career which, although
