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HYPOTENSIVE EFFECT OF ANGIOTENSIN-CONVERTING-ENZYME INHIBITOR SQ 20,881
353 may be still more diminished, and closing volume may be capable of intruding into tidal volume, with consequent hypoxxmia, even more easily. In obese adultsclosing volume, although not greatly increased, falls within the normal range of breathing both in the sitting posture and more noticeably when the patient lies down. In a small newborn infant the volume of the feed is proportionately large in comparison with the volume of the abdominal contents. We would therefore suggest that, after feeding, expiratory reserve volume is diminished and that the already proportionately large closing volume intrudes significantly into the child’s tidal volume with resultant hypoxsemia. Perhaps in future it may be possible to make the appropriate measurements to see whether such mechanisms as we suggest are indeed operating. Department of Respiratory Diseases, University of Edinburgh,
City Hospital, Greenbank Drive,
G. J. R. MCHARDY.
Edinburgh EH10 5SB. Department of Child Life and Health University of Edinburgh, Royal Hospital for Sick Children, Sciennes Road, Edinburgh.
H. SIMPSON.
BODY-TEMPERATURE AND MYASTHENIA
SIR,—The keen observation of Dr Borenstein and Professor Desmedt (July 13, p. 63) seems to shatter another adage of neuromythology-that " myasthenic symptoms typically appear in the evening when the patient is tired and
disappear after a night’s
rest
"8
(italics mine).
The authors noted that changes of only 2°C influenced significantly neuromuscular transmission in the myasthenic muscle. Since the myasthenic muscle recovers from post-activation exhaustion within a relatively short period, the textbook postulation of a cumulative myasthenic effect as the day goes on is divorced from the experimental evidence. Surely the circadian variation in body-temperature, being in the range of 2°C with a maximum commonly found in the evening, is a more likely explanation of observed facts. Department of Neurology, St. Laurence’s Hospital, Dublin.
be administered cautiously because they can cause serious hypotensive episodes. We have administered the nonapeptide SQ 20,881 to 23 hypertensive patients in doses ranging from 0-5 to 5-4 mg. per kg. and have not encountered any excessive tension.1O In 6 of these patients who exhibited only a partial drop of the blood-pressure in response to convertingenzyme blockade, subsequent sodium depletion greatly enhanced the blood-pressure response to administration of the nonapeptide. These results fully support our animal studies 11 and those of others, all of which indicate that angiotensin blockade with this or other such peptide blockers 12given in excess has little or no effect on the bloodpressure of either normal or hypertensive animals unless it is given after rather drastic sodium depletion. Altogether the experience indicates that under circumstances of adequate sodium intake the renin system plays a minor role in supporting these normotensive or hypertensive states. The findings provide additional evidence for our hypothesis that the blood-pressure setting is largely determined by a dynamic interaction between a sodium-volume factor and the renin-angiotensin factor.13 The hypotensive reaction reported by Duhme et al. should come as no surprise, since under conditions of extreme volume depletion blood-pressure may become almost exclusively renin-angiotensin dependent, and blockade of this component therefore could result in severe hypotension. Additional sympathetic blockade by guanethidine aggravated the situation by defeating another emergency mechanism needed to support blood-pressure. It is our impression that the administration of SQ 20,881 by itself is perfectly safe and devoid of hypotensive reactions, provided that it does not coincide with severe volume depletion and/or blockade of the sympathetic system, in which case any drug interfering with the reninangiotensin system (e.g., propranolol or methyldopa) or indeed any vasodilator could cause severe hypotension and even shock. to
Columbia Presbyterian Medical Center, 630 West 168th Street, New York, N.Y. 10032, U.S.A.
HARALAMBOS GAVRAS HANS R. BRUNNER IRENE GAVRAS JOHN H. LARAGH.
PETR SKRABANEK. WHAT ARE WE PLAYING AT ?
HYPOTENSIVE EFFECT OF ANGIOTENSINCONVERTING-ENZYME INHIBITOR SQ 20,881
SIR,-Duhme et al.9 describe tion in
a severe
hypotensive
reac-
hypertensive patient after administration of the nonapeptide SQ 20,881 which competitively inhibits conversion of angiotensin i to angiotensin n. At the time of the peptide injection, this patient was actually normotensive, having been treated until the day before with a combination of antihypertensive agents including guanethidine, an agent known to require much more than 24 hours to be eliminated. More important, the patient had been vigorously sodium depleted with 80 mg. of frusemide on the eve of the study, as evidenced by a loss of over 3 kg. of fluid and by complaints of " postural lightheadedness " even before the administration of SQ 20,881. In this setting it does not seem reasonable to conclude that blockers of the renin-angiotensin system (P 113, SQ 20,881) have a
7. Farebrother, M. J. B., McHardy, G. J. R., Munro, J. F. Br. med. J. (in the press). 8. Lord Brain and J. N. Walton. Diseases of the Nervous System;
p. 864. London, 1969. 9. Duhme, D. W., Sancho, J., Athanasoulis, C., Haber, E., KochWeser, J. Lancet, 1974, i, 408. 10. Gavras, H., Brunner, H. R., Laragh, J. H., Sealey, J. E., Gavras, I., Vukovich, R. A. New Engl. J. Med. (in the press).
SIR,-When a doctor acts according to his conscience it has become a cliche to say that he is " playing at God ". When a section of the profession is driven to defending itself, Mrs Castle accuses it of " playing at politics ". And now that someone wants to take medicine out of politics The Lancet (July 20, p. 140) adds to our confusion by interpreting this as a call to " carry medicine back into the market-place ". Whatever are doctors of good will to do ? It is hard for the laity-and injudicious of politicians-to recognise that the interests of good doctors are inextricably linked to those of their patients. The further one is from the clinical scene the harder it is-even for non-clinical doctors-to understand or remember this. Clinicians are probably better qualified to play at politics than at the new " management " game. Indeed, I have come to believe that it would be better for the N.H.S. if they left the administration to get on with its job, and gave their independent advice to, and through, the new community health councils. There they would, I think, be more at home, and certainly nearer their patients (see Guardian, July 30, p. 12). H., Brunner, H. R., Vaughan, E. D., Jr., Laragh, J. H. Science, 1973, 180, 1369. 12. Johnson, J. A., Davis, J. O. Circulation Res. 1973, 32, suppl. I, p. 159. 13. Laragh, J. H. Am. J. Med. 1973, 55, 261. 11. Gavras,
City Hospital, Greenbank Drive,
G. J. R. MCHARDY.
Edinburgh EH10 5SB. Department of Child Life and Health University of Edinburgh, Royal Hospital for Sick Children, Sciennes Road, Edinburgh.
H. SIMPSON.
BODY-TEMPERATURE AND MYASTHENIA
SIR,—The keen observation of Dr Borenstein and Professor Desmedt (July 13, p. 63) seems to shatter another adage of neuromythology-that " myasthenic symptoms typically appear in the evening when the patient is tired and
disappear after a night’s
rest
"8
(italics mine).
The authors noted that changes of only 2°C influenced significantly neuromuscular transmission in the myasthenic muscle. Since the myasthenic muscle recovers from post-activation exhaustion within a relatively short period, the textbook postulation of a cumulative myasthenic effect as the day goes on is divorced from the experimental evidence. Surely the circadian variation in body-temperature, being in the range of 2°C with a maximum commonly found in the evening, is a more likely explanation of observed facts. Department of Neurology, St. Laurence’s Hospital, Dublin.
be administered cautiously because they can cause serious hypotensive episodes. We have administered the nonapeptide SQ 20,881 to 23 hypertensive patients in doses ranging from 0-5 to 5-4 mg. per kg. and have not encountered any excessive tension.1O In 6 of these patients who exhibited only a partial drop of the blood-pressure in response to convertingenzyme blockade, subsequent sodium depletion greatly enhanced the blood-pressure response to administration of the nonapeptide. These results fully support our animal studies 11 and those of others, all of which indicate that angiotensin blockade with this or other such peptide blockers 12given in excess has little or no effect on the bloodpressure of either normal or hypertensive animals unless it is given after rather drastic sodium depletion. Altogether the experience indicates that under circumstances of adequate sodium intake the renin system plays a minor role in supporting these normotensive or hypertensive states. The findings provide additional evidence for our hypothesis that the blood-pressure setting is largely determined by a dynamic interaction between a sodium-volume factor and the renin-angiotensin factor.13 The hypotensive reaction reported by Duhme et al. should come as no surprise, since under conditions of extreme volume depletion blood-pressure may become almost exclusively renin-angiotensin dependent, and blockade of this component therefore could result in severe hypotension. Additional sympathetic blockade by guanethidine aggravated the situation by defeating another emergency mechanism needed to support blood-pressure. It is our impression that the administration of SQ 20,881 by itself is perfectly safe and devoid of hypotensive reactions, provided that it does not coincide with severe volume depletion and/or blockade of the sympathetic system, in which case any drug interfering with the reninangiotensin system (e.g., propranolol or methyldopa) or indeed any vasodilator could cause severe hypotension and even shock. to
Columbia Presbyterian Medical Center, 630 West 168th Street, New York, N.Y. 10032, U.S.A.
HARALAMBOS GAVRAS HANS R. BRUNNER IRENE GAVRAS JOHN H. LARAGH.
PETR SKRABANEK. WHAT ARE WE PLAYING AT ?
HYPOTENSIVE EFFECT OF ANGIOTENSINCONVERTING-ENZYME INHIBITOR SQ 20,881
SIR,-Duhme et al.9 describe tion in
a severe
hypotensive
reac-
hypertensive patient after administration of the nonapeptide SQ 20,881 which competitively inhibits conversion of angiotensin i to angiotensin n. At the time of the peptide injection, this patient was actually normotensive, having been treated until the day before with a combination of antihypertensive agents including guanethidine, an agent known to require much more than 24 hours to be eliminated. More important, the patient had been vigorously sodium depleted with 80 mg. of frusemide on the eve of the study, as evidenced by a loss of over 3 kg. of fluid and by complaints of " postural lightheadedness " even before the administration of SQ 20,881. In this setting it does not seem reasonable to conclude that blockers of the renin-angiotensin system (P 113, SQ 20,881) have a
7. Farebrother, M. J. B., McHardy, G. J. R., Munro, J. F. Br. med. J. (in the press). 8. Lord Brain and J. N. Walton. Diseases of the Nervous System;
p. 864. London, 1969. 9. Duhme, D. W., Sancho, J., Athanasoulis, C., Haber, E., KochWeser, J. Lancet, 1974, i, 408. 10. Gavras, H., Brunner, H. R., Laragh, J. H., Sealey, J. E., Gavras, I., Vukovich, R. A. New Engl. J. Med. (in the press).
SIR,-When a doctor acts according to his conscience it has become a cliche to say that he is " playing at God ". When a section of the profession is driven to defending itself, Mrs Castle accuses it of " playing at politics ". And now that someone wants to take medicine out of politics The Lancet (July 20, p. 140) adds to our confusion by interpreting this as a call to " carry medicine back into the market-place ". Whatever are doctors of good will to do ? It is hard for the laity-and injudicious of politicians-to recognise that the interests of good doctors are inextricably linked to those of their patients. The further one is from the clinical scene the harder it is-even for non-clinical doctors-to understand or remember this. Clinicians are probably better qualified to play at politics than at the new " management " game. Indeed, I have come to believe that it would be better for the N.H.S. if they left the administration to get on with its job, and gave their independent advice to, and through, the new community health councils. There they would, I think, be more at home, and certainly nearer their patients (see Guardian, July 30, p. 12). H., Brunner, H. R., Vaughan, E. D., Jr., Laragh, J. H. Science, 1973, 180, 1369. 12. Johnson, J. A., Davis, J. O. Circulation Res. 1973, 32, suppl. I, p. 159. 13. Laragh, J. H. Am. J. Med. 1973, 55, 261. 11. Gavras,