1387 sion of menstruation following the use of steroid contraceptives clearly some will have underlying causes not related to hormone treatment. 10, 11 However, in view of the previous reports of polycystic ovarian disease associated with synthetic sex-hormone therapy it is tempting to speculate whether oral contraception might have had a significant influence. The provocation of an underlying predisposition to polycystic ovarian disease after the manner suggested by Rhodes and Saunders2 is a consideration. St. Catherine’s
Hospital, Birkenhead, Merseyside, L42 0LQ.
R. CORCORAN G. D. ENTWISTLE.
HYPOTENSION DURING ANGIOTENSIN BLOCKADE WITH SARALASIN
SIR,-It has been reported 12 that treatment of nonmedicated high-renin hypertensive patients with the selective angiotensin antagonist, saralasin (1-sar-8-alaangiotensin ll)j failed to cause hypotension even at infusionrates as high as 100 fJ.g. per kg. per min. We should like to report a case of hypotension with premature ventricular contractions (r.v.c.s) during saralasin infusion in a patient under treatment with other potent antihypertensive drugs. A 64-year-old man with refractory hypertension for 7 years and under treatment withMinoxidil’ (Upjohn),13 spironolactone, methyldopa, propranolol, hydr-ochlorothiazide, frusemide, and digoxin had consistently exhibited high serum-renin values (> 40 ng. per ml. per hr.). The blood-supply to his left kidney had been compromised during repair of an abdominal aortic
Fig. 2-Correlation between plasma-saralasin concentration determined by radioimmunoassay" and fall in blood-pressure during several infusions. and
was begun. The patient was sleeping the control and infusion periods and when awakened was lucid and had no discomfort or symptoms of angina pectoris or shock. After the saralasin infusion was stopped, systolic blood-pressure continued to drop for 10 minutes (from 90 to 78 mm. Hg) and diastolic pressure became more or less stable at 63. A rapid reversal of the hypotension began at this point, and 20 and 30 minutes after stopping the saralasin infusion the blood-pressure had climbed to 108/76 and 147/100, respectively. One hour after the infusion, blood-pressure had returned to the pre-saralasin hypertensive level of 170/115. Shortly after discontinuing the saralasin infusion, unifocal P.v.c.s occurred at a peak rate of 1 every five seconds. This arrhythmia spontaneously dissipated as the blood-pressure returned toward preinfusion levels. a
rapid saline infusion
lightly throughout
The
pharmacological
nature
of the
blood-pressure
response to saralasin in this patient is confirmed by the correlation between these haemodynamic effects and plasma concentrations of saralasin measured by radio-
Fig. I-Effect of saralasin infusion on supine systolic and diastolic blood-pressure and heart-rate. aneurysm and the kidney showed no excretory function. Since the patient had chronic high renin values and since he had remained hypertensive (diastolic above 100 mm. Hg) during the aggressive anti-hypertensive regimen, saralasin acetate (Norwich Pharmacal) was infused in an attempt to restore normal bloodpressure and to determine the magnitude of renin dependency .of the hypertension. He remained supine for thirty minutes before saralasin infusion (1 !J.g. per kg. per min.), and arterial blood-pressure began to fall within 4 minutes of beginning treatment (fig. 1). Within 30 minutes blood-pressure had dropped from a preinfusion level of 166/120 to 114/70 mm. Hg, with only a slight increase in heart-rate from 66 to 70 per min. Increasing the infusion-rate to 3 jj.g. per kg. per min. caused a further fall in blood-pressure to 90/63 mm. Hg within several minutes, with no increase in heart-rate. The infusion was stopped at this point
immunoassay 14 (fig. 2). Duhme et al. 16 reported a case of severe hypotension without tachycardia in a hypovolaemic, renal hypertensive patient during blockade of the renin-angiotensin system with the converting enzyme inhibitor, SQ 20881. Their patient had not had any antihypertensive drugs during the 24 hours before treatment, but the absence of tachycardia during the episode may have been due to the lingering sympathoplegic effects of guanethidine. In the case reported here, hypotension-induced tachycardia did not occur, probably as a result of propranolol (160 mg. per day) blockade of P-adrenergic receptors. Gavras et al.16 also reported hypotension in volume-depleted subjects with SQ 20881 and suggested the possibility of hypotension with vasodilating and adrenergic blocking drugs. The observation reported here with the angiotensin antagonist, saralasin, supports this speculation concerning vasodilating drugs. However, further studies are necessary to implicate sympathetic blocking agents in this hypotensive drug interaction. We have treated nine hypertensive patients with saralasin, and in the three patients who responded with a decrease in blood-pressure, normal blood-pressure was achieved at infusion-rates between 0-15 and 20 (Lg. per kg. per min. All three of these patients were receiving a peripheral vasodilator and propranolol. and careful control of the saralasin dose was required to prevent hypotension. Pettinger, W. A., Keeton, K., Tanaka, K. J. clin. Pharm. Ther. 1975, 17, 146. 15. Duhme, D. W., Sancho, J., Athanasoulis, C., Haber, E., KochWeser, J. Lancet, 1974, i, 408. 16. Gavras, H., Brunner, H. R., Gavras, I., Laragh, J. H. ibid. 1974, ii,
14. 10. See Br. med. J. 1972, iv, 59. 11. Steele, S. J., Mason, B., Brett, A. ibid. 1973, iv, 343. 12. Brunner, H. R., Gavras, H., Laragh, J. H., Keenan, R. Lancet, 1973, ii, 1045. 13. Pettinger, W. A., Mitchell, H. C. New Engl. J. Med. 1973, 167, 289.
353.
1388
Angiotensin vasoconstriction may be the major determinant of vascular tone and blood-pressure in high-renin patients under treatment with antihypertensive drugs, particularly directly acting vasodilating agents. Angiotensin antagonism can induce hypotension and tachyarrhythmias under such circumstances. Screening programmes
seeking renin-dependent hypertensive subjects
should carefully exclude at the time of the test.
patients taking vasodilating drugs
Division of Clinical Pharmacology, Department of Pharmacology and Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75235, U.S.A.
WILLIAM A. PETTINGER KENT KEETON.
MYASTHENIA GRAVIS: RELATIONSHIP BETWEEN SERUM FACTOR BLOCKING ACETYLCHOLINE RECEPTORS AND ANTI-STRIATED-MUSCLE ANTIBODY
SIR,-We have lately described in myasthenia gravis (M.G.) a serum factor, probably an IgG, which blocks a-bungarotoxin (OC-13.T.) binding to acetylcholine (ACh) receptors at the normal human neuromuscular junction.l It is assumed that this is the same serum factor which blocks the more sensitive extrajunctional diffuse sarcoSince lemmal ACh receptors of denervated fibres. 1,22 anti-striated-muscle autoantibody (A.s.M.ab) is known to be present in about 30% of patients with M.G.,3its relationship to the blocking-factor is of importance. A.s.M.ab binds ultrastructurally to the sarcoplasmic reticulum at the I-band level4 throughout the muscle fibre and also reacts with the rare myoid cells nomally present in the thymus.6 Extension of our study has now demonstrated the serum a-B.T.-blocking factor in 64 of 89 patients with CORRELATION OF
A.s.M.ab
AND ct-B.T.-BLOCKING FACTOR IN M.G. SERA
Since there is a striking correlation of ACh-receptorblocking factor with A.s.M.ab in patients’ sera (see table), it is possible that they are the same. If so, blocking of oc-B.T. binding appears to be a more sensitive assay than that of demonstrable A.s.M.ab activity. Alternatively, the single discordant serum raises the possibility that these are two separate but usually simultaneously produced antibodies, since M.G. patients have been shown capable of producing several different autoantibodies.6 If the two activities are due to one antibody, that would suggest similar antigenic determinants between receptor (or juxtareceptor) at the neuromuscular junction, i-band sarcoplasmic reticulum, and a component of thymic myoid cells. Perhaps the discordance found in only 1 of 133 tested has another but not readily evident explanation. Dr Z. Vogel and Dr M. P. Daniels provided the immunological reagents, and Mr G. Hubbard provided technical assistance. S. P. R. is supported by the Muscular Dystrophy Association of America. Medical Neurology Branch, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
STEVEN P. RINGEL ADAM N. BENDER W. KING ENGEL.
Bioscience Corporation, Van Nuys, California 91405, U.S.A.
HENRY J. SMITH.
ATMOSPHERIC OZONE AND FEMORAL FRACTURES
SIR,— Dr Burton and his colleagues (April 5, p. 795) quote the Report on Hospital Inpatient Enquiries as evidence for a reported increase of about 12% per annum in the incidence of fractured femoral neck in people over 65 years. Is this enormous increase, which would soon cripple nearly all our senior citizens, a misinterpretation of the statistics ? The published discharge-rates for men and women aged 65 years and over do not show such rapid increases. 2-yearly 1961-2 1963-4 1965-6 1967-8 1969-70
(72%). In 32 of these 64 patients (50%) A.s.M.ab was demonstrable by fluorescence microscopy. The 25 M.G. patients who did not have the oc-B.T.-blocking factor did not have evidence of A.s.M.ab. In all, 32 of 89 patients (36%) showed evidence of A.s.M.ab, a figure in keeping with previous results.33 All 9 patients with M.G. and thymoma had both the oc-B.T.-blocking factor and A.s.M.ab. None of the 36 non-thymoma non-M.G. disease controls, including patients with various immune disorders, or of 8 normal controls showed either the blocking-factor or A.s.M.ab. 1 non-M.G. patient, who had a thymoma and polymyositis, had A.s.M.ab but no oc-B.T.-blocking factor. A.s.M.ab is known to be present in thymoma patients who do not have M.G.3
M.G.
1. 2. 3.
4. 5.
Bender, A. N., Ringel, S. P., Engel, W. K., Daniels, M. P., Vogel, Z. Lancet, 1975, i, 607. Almon, R. R., Andres, C. G., Appel, S. H. Science, 1974, 186, 55. Strauss, A. J. L., Seegel, B. C., Hsu, K. C., Burkolder, P. M., Nastuk, W. L., Osserman, K. E. Proc. Soc. exp. Biol. Med. 1960, 105, 184. Mendell, J. R., Whitaker, J. N., Engel, W. K. J. Immun. 1973, 111, 847. Van der Geld, H., Feltkamp, T. E. W., Van Loghem, J. J., Oosterhuis, H. J. G. H. Proc. Soc. exp. Biol. Med. 1964, 115, 782.
annual hospital discharge-rates per 10,000 population Men Women Years mean
....
....
....
....
....
12-9 14-2 14-0 14-7 15-9
34-2 37-4 36-6 41-9 48-5
The rate of rise for men is about 1—2% per annum and for women 4-5%. In earlier years the Report on Hospital Inpatient Enquiries gave rates for the elderly in only one group (65+ years); since 1968 they have been presented in two age-groups, 65-74 and 75 +. The single age-group 65 + has been calculated in the table from the populations at risk. Increases of 12% per annum following the published rates for men and women aged 65+ in 1961 would reach the mortalities recorded for 75+ in 1970. The rates are not true rates of incidence but of hospital admissions and discharges; two or more admissions of one patient will inflate the rate. Treatment of this condition never leads to degenerative complete recovery in old people but depends on the surgical provision of a prosthesis. Successful treatment of a condition which formerly was inevitably fatal must increase the chance of subsequent hospital admissions for care and maintenance of the prosthesis. Or sometimes a patient will survive to break the other femur or may eventually be admitted with a final breakdown of the prosthesis. Moreover, the exponential rise in the true incidence of fractures with age is so precipitous in later years that a relatively small increase in expectation of life will increase the apparent rate in such residual age-groups as 65+ or 6.
Simpson, J. A. Ann. N.Y. Acad. Sci. 1966, 135,
506.
Hospital, Birkenhead, Merseyside, L42 0LQ.
R. CORCORAN G. D. ENTWISTLE.
HYPOTENSION DURING ANGIOTENSIN BLOCKADE WITH SARALASIN
SIR,-It has been reported 12 that treatment of nonmedicated high-renin hypertensive patients with the selective angiotensin antagonist, saralasin (1-sar-8-alaangiotensin ll)j failed to cause hypotension even at infusionrates as high as 100 fJ.g. per kg. per min. We should like to report a case of hypotension with premature ventricular contractions (r.v.c.s) during saralasin infusion in a patient under treatment with other potent antihypertensive drugs. A 64-year-old man with refractory hypertension for 7 years and under treatment withMinoxidil’ (Upjohn),13 spironolactone, methyldopa, propranolol, hydr-ochlorothiazide, frusemide, and digoxin had consistently exhibited high serum-renin values (> 40 ng. per ml. per hr.). The blood-supply to his left kidney had been compromised during repair of an abdominal aortic
Fig. 2-Correlation between plasma-saralasin concentration determined by radioimmunoassay" and fall in blood-pressure during several infusions. and
was begun. The patient was sleeping the control and infusion periods and when awakened was lucid and had no discomfort or symptoms of angina pectoris or shock. After the saralasin infusion was stopped, systolic blood-pressure continued to drop for 10 minutes (from 90 to 78 mm. Hg) and diastolic pressure became more or less stable at 63. A rapid reversal of the hypotension began at this point, and 20 and 30 minutes after stopping the saralasin infusion the blood-pressure had climbed to 108/76 and 147/100, respectively. One hour after the infusion, blood-pressure had returned to the pre-saralasin hypertensive level of 170/115. Shortly after discontinuing the saralasin infusion, unifocal P.v.c.s occurred at a peak rate of 1 every five seconds. This arrhythmia spontaneously dissipated as the blood-pressure returned toward preinfusion levels. a
rapid saline infusion
lightly throughout
The
pharmacological
nature
of the
blood-pressure
response to saralasin in this patient is confirmed by the correlation between these haemodynamic effects and plasma concentrations of saralasin measured by radio-
Fig. I-Effect of saralasin infusion on supine systolic and diastolic blood-pressure and heart-rate. aneurysm and the kidney showed no excretory function. Since the patient had chronic high renin values and since he had remained hypertensive (diastolic above 100 mm. Hg) during the aggressive anti-hypertensive regimen, saralasin acetate (Norwich Pharmacal) was infused in an attempt to restore normal bloodpressure and to determine the magnitude of renin dependency .of the hypertension. He remained supine for thirty minutes before saralasin infusion (1 !J.g. per kg. per min.), and arterial blood-pressure began to fall within 4 minutes of beginning treatment (fig. 1). Within 30 minutes blood-pressure had dropped from a preinfusion level of 166/120 to 114/70 mm. Hg, with only a slight increase in heart-rate from 66 to 70 per min. Increasing the infusion-rate to 3 jj.g. per kg. per min. caused a further fall in blood-pressure to 90/63 mm. Hg within several minutes, with no increase in heart-rate. The infusion was stopped at this point
immunoassay 14 (fig. 2). Duhme et al. 16 reported a case of severe hypotension without tachycardia in a hypovolaemic, renal hypertensive patient during blockade of the renin-angiotensin system with the converting enzyme inhibitor, SQ 20881. Their patient had not had any antihypertensive drugs during the 24 hours before treatment, but the absence of tachycardia during the episode may have been due to the lingering sympathoplegic effects of guanethidine. In the case reported here, hypotension-induced tachycardia did not occur, probably as a result of propranolol (160 mg. per day) blockade of P-adrenergic receptors. Gavras et al.16 also reported hypotension in volume-depleted subjects with SQ 20881 and suggested the possibility of hypotension with vasodilating and adrenergic blocking drugs. The observation reported here with the angiotensin antagonist, saralasin, supports this speculation concerning vasodilating drugs. However, further studies are necessary to implicate sympathetic blocking agents in this hypotensive drug interaction. We have treated nine hypertensive patients with saralasin, and in the three patients who responded with a decrease in blood-pressure, normal blood-pressure was achieved at infusion-rates between 0-15 and 20 (Lg. per kg. per min. All three of these patients were receiving a peripheral vasodilator and propranolol. and careful control of the saralasin dose was required to prevent hypotension. Pettinger, W. A., Keeton, K., Tanaka, K. J. clin. Pharm. Ther. 1975, 17, 146. 15. Duhme, D. W., Sancho, J., Athanasoulis, C., Haber, E., KochWeser, J. Lancet, 1974, i, 408. 16. Gavras, H., Brunner, H. R., Gavras, I., Laragh, J. H. ibid. 1974, ii,
14. 10. See Br. med. J. 1972, iv, 59. 11. Steele, S. J., Mason, B., Brett, A. ibid. 1973, iv, 343. 12. Brunner, H. R., Gavras, H., Laragh, J. H., Keenan, R. Lancet, 1973, ii, 1045. 13. Pettinger, W. A., Mitchell, H. C. New Engl. J. Med. 1973, 167, 289.
353.
1388
Angiotensin vasoconstriction may be the major determinant of vascular tone and blood-pressure in high-renin patients under treatment with antihypertensive drugs, particularly directly acting vasodilating agents. Angiotensin antagonism can induce hypotension and tachyarrhythmias under such circumstances. Screening programmes
seeking renin-dependent hypertensive subjects
should carefully exclude at the time of the test.
patients taking vasodilating drugs
Division of Clinical Pharmacology, Department of Pharmacology and Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75235, U.S.A.
WILLIAM A. PETTINGER KENT KEETON.
MYASTHENIA GRAVIS: RELATIONSHIP BETWEEN SERUM FACTOR BLOCKING ACETYLCHOLINE RECEPTORS AND ANTI-STRIATED-MUSCLE ANTIBODY
SIR,-We have lately described in myasthenia gravis (M.G.) a serum factor, probably an IgG, which blocks a-bungarotoxin (OC-13.T.) binding to acetylcholine (ACh) receptors at the normal human neuromuscular junction.l It is assumed that this is the same serum factor which blocks the more sensitive extrajunctional diffuse sarcoSince lemmal ACh receptors of denervated fibres. 1,22 anti-striated-muscle autoantibody (A.s.M.ab) is known to be present in about 30% of patients with M.G.,3its relationship to the blocking-factor is of importance. A.s.M.ab binds ultrastructurally to the sarcoplasmic reticulum at the I-band level4 throughout the muscle fibre and also reacts with the rare myoid cells nomally present in the thymus.6 Extension of our study has now demonstrated the serum a-B.T.-blocking factor in 64 of 89 patients with CORRELATION OF
A.s.M.ab
AND ct-B.T.-BLOCKING FACTOR IN M.G. SERA
Since there is a striking correlation of ACh-receptorblocking factor with A.s.M.ab in patients’ sera (see table), it is possible that they are the same. If so, blocking of oc-B.T. binding appears to be a more sensitive assay than that of demonstrable A.s.M.ab activity. Alternatively, the single discordant serum raises the possibility that these are two separate but usually simultaneously produced antibodies, since M.G. patients have been shown capable of producing several different autoantibodies.6 If the two activities are due to one antibody, that would suggest similar antigenic determinants between receptor (or juxtareceptor) at the neuromuscular junction, i-band sarcoplasmic reticulum, and a component of thymic myoid cells. Perhaps the discordance found in only 1 of 133 tested has another but not readily evident explanation. Dr Z. Vogel and Dr M. P. Daniels provided the immunological reagents, and Mr G. Hubbard provided technical assistance. S. P. R. is supported by the Muscular Dystrophy Association of America. Medical Neurology Branch, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
STEVEN P. RINGEL ADAM N. BENDER W. KING ENGEL.
Bioscience Corporation, Van Nuys, California 91405, U.S.A.
HENRY J. SMITH.
ATMOSPHERIC OZONE AND FEMORAL FRACTURES
SIR,— Dr Burton and his colleagues (April 5, p. 795) quote the Report on Hospital Inpatient Enquiries as evidence for a reported increase of about 12% per annum in the incidence of fractured femoral neck in people over 65 years. Is this enormous increase, which would soon cripple nearly all our senior citizens, a misinterpretation of the statistics ? The published discharge-rates for men and women aged 65 years and over do not show such rapid increases. 2-yearly 1961-2 1963-4 1965-6 1967-8 1969-70
(72%). In 32 of these 64 patients (50%) A.s.M.ab was demonstrable by fluorescence microscopy. The 25 M.G. patients who did not have the oc-B.T.-blocking factor did not have evidence of A.s.M.ab. In all, 32 of 89 patients (36%) showed evidence of A.s.M.ab, a figure in keeping with previous results.33 All 9 patients with M.G. and thymoma had both the oc-B.T.-blocking factor and A.s.M.ab. None of the 36 non-thymoma non-M.G. disease controls, including patients with various immune disorders, or of 8 normal controls showed either the blocking-factor or A.s.M.ab. 1 non-M.G. patient, who had a thymoma and polymyositis, had A.s.M.ab but no oc-B.T.-blocking factor. A.s.M.ab is known to be present in thymoma patients who do not have M.G.3
M.G.
1. 2. 3.
4. 5.
Bender, A. N., Ringel, S. P., Engel, W. K., Daniels, M. P., Vogel, Z. Lancet, 1975, i, 607. Almon, R. R., Andres, C. G., Appel, S. H. Science, 1974, 186, 55. Strauss, A. J. L., Seegel, B. C., Hsu, K. C., Burkolder, P. M., Nastuk, W. L., Osserman, K. E. Proc. Soc. exp. Biol. Med. 1960, 105, 184. Mendell, J. R., Whitaker, J. N., Engel, W. K. J. Immun. 1973, 111, 847. Van der Geld, H., Feltkamp, T. E. W., Van Loghem, J. J., Oosterhuis, H. J. G. H. Proc. Soc. exp. Biol. Med. 1964, 115, 782.
annual hospital discharge-rates per 10,000 population Men Women Years mean
....
....
....
....
....
12-9 14-2 14-0 14-7 15-9
34-2 37-4 36-6 41-9 48-5
The rate of rise for men is about 1—2% per annum and for women 4-5%. In earlier years the Report on Hospital Inpatient Enquiries gave rates for the elderly in only one group (65+ years); since 1968 they have been presented in two age-groups, 65-74 and 75 +. The single age-group 65 + has been calculated in the table from the populations at risk. Increases of 12% per annum following the published rates for men and women aged 65+ in 1961 would reach the mortalities recorded for 75+ in 1970. The rates are not true rates of incidence but of hospital admissions and discharges; two or more admissions of one patient will inflate the rate. Treatment of this condition never leads to degenerative complete recovery in old people but depends on the surgical provision of a prosthesis. Successful treatment of a condition which formerly was inevitably fatal must increase the chance of subsequent hospital admissions for care and maintenance of the prosthesis. Or sometimes a patient will survive to break the other femur or may eventually be admitted with a final breakdown of the prosthesis. Moreover, the exponential rise in the true incidence of fractures with age is so precipitous in later years that a relatively small increase in expectation of life will increase the apparent rate in such residual age-groups as 65+ or 6.
Simpson, J. A. Ann. N.Y. Acad. Sci. 1966, 135,
506.
