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TOLBUTAMIDE: AN INOTROPIC EFFECT ON RABBIT ATRIA
604
TOLBUTAMIDE: AN INOTROPIC EFFECT
Obituary
ON RABBIT ATRIA
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 polygraph. 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. ROGER F. PALMER University of Miami Medical School, KENNETH C. LASSETER JEANE MCCARTHY. Miami, Florida. Department of Pharmacology,
1. 2.
Diabetes, 1970, 19, suppl. 2. Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanabe, T., Covell, J. W., Ross, J., Braunwald, E. Circulation, 1971, 43, 67.
DAVID GAVIN MILLAR
M.B.Durh., F.R.C.S., M.R.C.O.G. David Prof. Millar, foundation professor of human and obstetrics at Southampton Univerreproduction Medical School, died on March 4 at the age of 41. sity born in Durham, the son of a local general 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. He
was
practitioner, and,
D. V. I. F. writes: "
Diarv of the Week MARCH
21 To 27
Monday, 22nd 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.
ROYAL
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. (Hunterian lecture.)
untimely death of such a talented man is indeed 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. The
a
"
He was an excellent teacher, and it is most unfortunate that he did not live to see even the first entry of Southampton students, for whom he had prepared so enthusiastically 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’ representative, 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
TOLBUTAMIDE: AN INOTROPIC EFFECT
Obituary
ON RABBIT ATRIA
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 polygraph. 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. ROGER F. PALMER University of Miami Medical School, KENNETH C. LASSETER JEANE MCCARTHY. Miami, Florida. Department of Pharmacology,
1. 2.
Diabetes, 1970, 19, suppl. 2. Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanabe, T., Covell, J. W., Ross, J., Braunwald, E. Circulation, 1971, 43, 67.
DAVID GAVIN MILLAR
M.B.Durh., F.R.C.S., M.R.C.O.G. David Prof. Millar, foundation professor of human and obstetrics at Southampton Univerreproduction Medical School, died on March 4 at the age of 41. sity born in Durham, the son of a local general 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. He
was
practitioner, and,
D. V. I. F. writes: "
Diarv of the Week MARCH
21 To 27
Monday, 22nd 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.
ROYAL
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. (Hunterian lecture.)
untimely death of such a talented man is indeed 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. The
a
"
He was an excellent teacher, and it is most unfortunate that he did not live to see even the first entry of Southampton students, for whom he had prepared so enthusiastically 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’ representative, 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