622
EFFECT OF MAGNESIUM
(Mg) ON HYPERVENTILATION
IN RETT’S
SYNDROME
Detection of CNP RT-PCR.
+ =relapse and remission induced during three repeated attempts of withdrawal and reintroduction of magnesium ND = not done (parents unwilling to stop magnesium)
cyanosis decreased from 15 (range 12-25) before the start of 5 (1-8) afterwards (table). In the seventh case, apnoeic episodes were short but hyperventilation was associated with agitated behaviour and an increase in hand stereotypies. These episodes were recorded over 30 min per day for 5 days at the same time by the same examiner, before and 1 month after magnesium was introduced. Fewer episodes of hyperventilation occurred during treatment (21 vs 5). Convulsions in four children, which had often been observed during prolonged apnoea, decreased to less
treatment to
than 50%.
During follow-up of 1-4 years, magnesium was stopped three times in five patients. Each time overbreathing recurred within 6 weeks and decreased within 3 weeks after magnesium was reintroduced (table). Serum magnesium was normal in all patients before treatment (mean 0-9 mmol/1), which suggests that magnesium is acting pharmacologically rather than by correcting a deficit, and increased on treatment (1 .05 mmol/1), but this was not significant. All patients had respiratory alkalosis before magnesium was given. On treatment, blood gases were normal. The parents of all seven girls commented that on magnesium hand stereotypies were fewer and behaviour was less agitated. Despite remission of hyperventilation, however, the patients continued to be severely mentally
handicapped. Magnesium counteracts intracellular lactic acidosis and acts as an N-methyl-D-aspartate (NMDA) channel blocker.6 As with other such blockers, magnesium can reduce excitotoxic neuronal damage.7 Magnesium orotate or citrate were equally effective. Therefore it seems unlikely that orotate, a nootropic substance, was the active component. Children’s Clinic, Universty of Munich, and Children’s Centre, 8000 Munich 2, FRG
JOSEPH EGGER NIKOLAUS HOFACKER WITTICH SCHIEL HANS HOLTHAUSEN
DG, Frost JD, Zoghbi HJ, Percy AK. Rett’s syndrome characterization of respiratory patterns and sleep. Ann Neurol 1987; 21: 377-82. 2. Southall DP, Kerr AM, Tirosh E, Amos P, Lang MH, Stephenson JP. Hyperventilation in the awake state: potentially treatable component of Rett syndrome. Arch Dis Child 1988; 63: 1039-48. 3. Pelligra R, Norton RD, Wilkinson R, Leon HA, Matson WR. Rett syndrome: stimulation of endogenous biogenic amines. Neuropediatrics 1992; 23: 131-37. 4. Nielsen JB, Friberg L, Lou H. Immature pattern of brain activity m Rett syndrome. 1. Glaze
Arch Neurol 1990; 47: 982-86. 5. Hagberg B. Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet 1986; 1 (suppl):
(top)
and ANP-B receptor
transcripts by
PCR primers (CNP-sense 5’ACCATGCACCTCTCCCAGCT-3’, antisense 5’-CTAACATCCCAGGCCGCTCA-3’; ANP-B receptorantisense 5’-CTACsense 5’-TGACCAGCTGAGGCTACGCA-3’, AACTTCCATATAAGGT-3’) were prepared After RT of 1 wg total RNA, resulting cDNA was subjected to PCR. PCR products were separated on 1 % agarose gels, and Southern blotting was done with 32P-labelled synthetic oligomer (CNP-5’-CAACAAGAAGGGCTTGTCCAA-3’; ANP-B receptor-5’GGTGGTCGAGGAGACAT-
GGAT-3’)
as
probe.
BNP are the atrium and ventricle, respectively, CNP is distributed mainly in the central nervous system.2,3 The natriuretic peptide family is considered to act as cardiac hormone and as neuropeptide.’ Cultured endothelial cells produce CNP, a production that is augmented by transforming growth factor &bgr;,2 which is one of the key growth factors involved in vascular remodelling. The natriuretic peptide family can inhibit not only vasoconstriction but also vascular growth.’ We therefore wondered whether a vascular natriuretic peptide system is present, in which CNP serves a local regulator of vascular tone and growth. We report gene expression of CNP and its specific receptor, ANP-B receptor, which is one of the three subtypes of natriuretic receptors3,4 in the human vascular wall. Our reverse transcription and polymerase chain reaction (RT-PCR) with two sets of primers2,5 detected CNP and ANP-B receptor gene transcripts with the predicted sizes in human brain, which contains considerable amounts of CNP and ANP-B receptor, while no transcripts were detectable in liver. Our results demonstrate that the thoracic aortic tissues obtained from necropsy samples with different diseases (F/65, multiple myeloma; F/88,
generalised burn; M/84, oesophageal cancer, M/56, malignant phaeochromocytoma) contained substantial levels of transcripts of CNP and the ANP-B receptor in the same samples (figure). Detection of CNP transcript with its receptor in the human vascular wall strongly indicates the presence of the vascular natriuretic peptide system. The system may control vascular tone and growth locally, alone, or in concert with the endocrine natriuretic peptide system (ANP and BNP). Since the pathophysiological significance of a local renin-angiotensin system as a paracrine regulator has been demonstrated in the vascular wall6 and the natriuretic peptide system can antagonise reninangiotensin, the in-vivo demonstration of a vascular natriuretic peptide system in man should be of clinical relevance.
Second Division, Department of Medicine, Kyoto University School of Medicine,
Kyoto 606, Japan
YASATO KOMATSU KAZUWA NAKAO HIROSHI ITOH SHIN-ICHI SUGA YOSHIHIRO OGAWA HIROO IMURA
47-59.
Bregestovski P, Asher P, Herber A, Prochiantz A Magnesium gates glutamate-activated channels in mouse central neurons. Nature 1984; 307: 462-65. 7. Rothman SM, Olney JW. Excitotoxicity and the NMDA receptor. Trends Neurol Sci 6. Novak L,
1987; 10: 299-302.
Vascular natriuretic peptide SIR,—The natriuretic peptide family consists of, at least,
1. Nakao
2.
3. 4.
three
distinct peptides:
atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) derived from three different genes. The peptides are implicated in body-fluid homoeostasis and bloodpressure contro1.1 While the major production sites for ANP and
5.
6.
K, Ogawa Y, Suga S, Imura H. Molecular biology and biochemistry of the natriuretic peptide system. J Hypertens (m press). Suga S, Nakao K, Itoh H, et al. Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-&bgr;—possible existence of "vascular natriuretic peptide system". J Clin Invest (in press). Koller KJ, Lowe DG, Bennett GL, et al. Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 1991; 252: 120-23 Suga S, Nakao K, Hosoda K, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide. Endocrinology 1992; 130: 229-39. Hosoda K, Nakao K, Suga S, et al Gene expression of three types of receptors for natriuretic peptides m human tissues (abstr). J Hypertens 1990; 8 (suppl 3): S32. Paul M, Bachmann J, Ganten D. The tissue renin-angiotensin systems in cardiovascular disease. Trends Cardiovasc Med 1992, 2: 94-99
EFFECT OF MAGNESIUM
(Mg) ON HYPERVENTILATION
IN RETT’S
SYNDROME
Detection of CNP RT-PCR.
+ =relapse and remission induced during three repeated attempts of withdrawal and reintroduction of magnesium ND = not done (parents unwilling to stop magnesium)
cyanosis decreased from 15 (range 12-25) before the start of 5 (1-8) afterwards (table). In the seventh case, apnoeic episodes were short but hyperventilation was associated with agitated behaviour and an increase in hand stereotypies. These episodes were recorded over 30 min per day for 5 days at the same time by the same examiner, before and 1 month after magnesium was introduced. Fewer episodes of hyperventilation occurred during treatment (21 vs 5). Convulsions in four children, which had often been observed during prolonged apnoea, decreased to less
treatment to
than 50%.
During follow-up of 1-4 years, magnesium was stopped three times in five patients. Each time overbreathing recurred within 6 weeks and decreased within 3 weeks after magnesium was reintroduced (table). Serum magnesium was normal in all patients before treatment (mean 0-9 mmol/1), which suggests that magnesium is acting pharmacologically rather than by correcting a deficit, and increased on treatment (1 .05 mmol/1), but this was not significant. All patients had respiratory alkalosis before magnesium was given. On treatment, blood gases were normal. The parents of all seven girls commented that on magnesium hand stereotypies were fewer and behaviour was less agitated. Despite remission of hyperventilation, however, the patients continued to be severely mentally
handicapped. Magnesium counteracts intracellular lactic acidosis and acts as an N-methyl-D-aspartate (NMDA) channel blocker.6 As with other such blockers, magnesium can reduce excitotoxic neuronal damage.7 Magnesium orotate or citrate were equally effective. Therefore it seems unlikely that orotate, a nootropic substance, was the active component. Children’s Clinic, Universty of Munich, and Children’s Centre, 8000 Munich 2, FRG
JOSEPH EGGER NIKOLAUS HOFACKER WITTICH SCHIEL HANS HOLTHAUSEN
DG, Frost JD, Zoghbi HJ, Percy AK. Rett’s syndrome characterization of respiratory patterns and sleep. Ann Neurol 1987; 21: 377-82. 2. Southall DP, Kerr AM, Tirosh E, Amos P, Lang MH, Stephenson JP. Hyperventilation in the awake state: potentially treatable component of Rett syndrome. Arch Dis Child 1988; 63: 1039-48. 3. Pelligra R, Norton RD, Wilkinson R, Leon HA, Matson WR. Rett syndrome: stimulation of endogenous biogenic amines. Neuropediatrics 1992; 23: 131-37. 4. Nielsen JB, Friberg L, Lou H. Immature pattern of brain activity m Rett syndrome. 1. Glaze
Arch Neurol 1990; 47: 982-86. 5. Hagberg B. Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet 1986; 1 (suppl):
(top)
and ANP-B receptor
transcripts by
PCR primers (CNP-sense 5’ACCATGCACCTCTCCCAGCT-3’, antisense 5’-CTAACATCCCAGGCCGCTCA-3’; ANP-B receptorantisense 5’-CTACsense 5’-TGACCAGCTGAGGCTACGCA-3’, AACTTCCATATAAGGT-3’) were prepared After RT of 1 wg total RNA, resulting cDNA was subjected to PCR. PCR products were separated on 1 % agarose gels, and Southern blotting was done with 32P-labelled synthetic oligomer (CNP-5’-CAACAAGAAGGGCTTGTCCAA-3’; ANP-B receptor-5’GGTGGTCGAGGAGACAT-
GGAT-3’)
as
probe.
BNP are the atrium and ventricle, respectively, CNP is distributed mainly in the central nervous system.2,3 The natriuretic peptide family is considered to act as cardiac hormone and as neuropeptide.’ Cultured endothelial cells produce CNP, a production that is augmented by transforming growth factor &bgr;,2 which is one of the key growth factors involved in vascular remodelling. The natriuretic peptide family can inhibit not only vasoconstriction but also vascular growth.’ We therefore wondered whether a vascular natriuretic peptide system is present, in which CNP serves a local regulator of vascular tone and growth. We report gene expression of CNP and its specific receptor, ANP-B receptor, which is one of the three subtypes of natriuretic receptors3,4 in the human vascular wall. Our reverse transcription and polymerase chain reaction (RT-PCR) with two sets of primers2,5 detected CNP and ANP-B receptor gene transcripts with the predicted sizes in human brain, which contains considerable amounts of CNP and ANP-B receptor, while no transcripts were detectable in liver. Our results demonstrate that the thoracic aortic tissues obtained from necropsy samples with different diseases (F/65, multiple myeloma; F/88,
generalised burn; M/84, oesophageal cancer, M/56, malignant phaeochromocytoma) contained substantial levels of transcripts of CNP and the ANP-B receptor in the same samples (figure). Detection of CNP transcript with its receptor in the human vascular wall strongly indicates the presence of the vascular natriuretic peptide system. The system may control vascular tone and growth locally, alone, or in concert with the endocrine natriuretic peptide system (ANP and BNP). Since the pathophysiological significance of a local renin-angiotensin system as a paracrine regulator has been demonstrated in the vascular wall6 and the natriuretic peptide system can antagonise reninangiotensin, the in-vivo demonstration of a vascular natriuretic peptide system in man should be of clinical relevance.
Second Division, Department of Medicine, Kyoto University School of Medicine,
Kyoto 606, Japan
YASATO KOMATSU KAZUWA NAKAO HIROSHI ITOH SHIN-ICHI SUGA YOSHIHIRO OGAWA HIROO IMURA
47-59.
Bregestovski P, Asher P, Herber A, Prochiantz A Magnesium gates glutamate-activated channels in mouse central neurons. Nature 1984; 307: 462-65. 7. Rothman SM, Olney JW. Excitotoxicity and the NMDA receptor. Trends Neurol Sci 6. Novak L,
1987; 10: 299-302.
Vascular natriuretic peptide SIR,—The natriuretic peptide family consists of, at least,
1. Nakao
2.
3. 4.
three
distinct peptides:
atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) derived from three different genes. The peptides are implicated in body-fluid homoeostasis and bloodpressure contro1.1 While the major production sites for ANP and
5.
6.
K, Ogawa Y, Suga S, Imura H. Molecular biology and biochemistry of the natriuretic peptide system. J Hypertens (m press). Suga S, Nakao K, Itoh H, et al. Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-&bgr;—possible existence of "vascular natriuretic peptide system". J Clin Invest (in press). Koller KJ, Lowe DG, Bennett GL, et al. Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 1991; 252: 120-23 Suga S, Nakao K, Hosoda K, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide. Endocrinology 1992; 130: 229-39. Hosoda K, Nakao K, Suga S, et al Gene expression of three types of receptors for natriuretic peptides m human tissues (abstr). J Hypertens 1990; 8 (suppl 3): S32. Paul M, Bachmann J, Ganten D. The tissue renin-angiotensin systems in cardiovascular disease. Trends Cardiovasc Med 1992, 2: 94-99
