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Acute effect of nitric oxide on Raynaud's phenomenon in scleroderma
Research letters
Acute effect of nitric oxide on Raynaud’s phenomenon in scleroderma Robert R Freedman, Reda Girgis, Maureen D Mayes Intra-arterial infusions of L-arginine and sodium nitroprusside significantly decreased the occurrence of laboratory-induced Raynaud’s phenomenon in scleroderma patients. Raising the concentration of nitric oxide may be of therapeutic value in this population.
Although most patients with scleroderma have Raynaud’s phenomenon, optimum treatments for the disorder have not been developed.1 We have shown2 that patients with Raynaud’s phenomenon and scleroderma have normal amounts of finger vasodilation in response to intra-arterial sodium nitroprusside (SNP), but none to methacholine; these findings suggest an impairment of vascular endothelial function. Other work3 has shown that patients with Raynaud’s phenomenon but not scleroderma have enhanced finger vasodilation in response to methacholine. We investigated whether intra-arterial L-arginine, the endothelial substrate for nitric oxide (NO) formation,4 or SNP, a direct donor of NO, would block Raynaud’s phenomenon induced by cooling in the laboratory. We studied 12 women and three men with Raynaud’s phenomenon and scleroderma, of mean age 47·2 years (SD 11·7). Eight had diffuse scleroderma, and seven had limited scleroderma. None had hypercholesterolaemia. Medication was withheld for 1 week before the study, and patients gave written informed consent according to procedures approved by our institutional review board. The patients, wearing scrub suits, sat in a room controlled for temperature (25ºC) and humidity, while a 20-gauge catheter was inserted percutaneously in a brachial artery, with lidocaine as a local anaesthetic. Eight patients were randomly assigned to receive an infusion of L-arginine (Clinalfa, Laeufelfingen, Switzerland; 8·5 mg/min) and seven were assigned SNP (5 g/min). After 10 min, the room temperature was decreased to 4ºC, and the patient held a 1 L beaker of iced water for 2 min. The beaker was then placed on a table for 2 min and the hands were photographed. This procedure was repeated for up to 40 min until an apparent attack of Raynaud’s phenomenon, defined as two of three colour changes (blanching, cyanosis, or rubor), occurred. The slides were scored by two independent raters, who were unaware of which drug (if any) the hands had received. The numbers of fingers showing Raynaud’s phenomenon were compared for the two hands, drugs, and raters by analysis of variance.5 The minimum level of statistical significance was p<0·05. All patients had attacks during the procedure. The number of fingers Hand
Drug L-arginine
SNP
Infused hand Control hand
1·1 (1·4)* 3·2 (1·4)
2·3 (1·7)* 3·5 (1·5)
*Significantly (p<0·002) lower than control hand values.
Mean (SD) number of fingers per hand that showed Raynaud’s phenomenon during laboratory cooling
THE LANCET • Vol 354 • August 28, 1999
showing attacks was significantly (p=0·002) lower in infused hands than in the control hands (table). There were no significant differences between the two drugs or raters. We suggest that NO released from the vascular endothelium by the addition of L-arginine, or given directly as SNP, blocks some attacks of Raynaud’s phenomenon induced in scleroderma patients under controlled conditions. These findings are consistent with, but do not prove, the hypothesis that the NO pathway is involved in the vasospastic attacks. Nevertheless, our observations may suggest therapeutic options for patients with Raynaud’s phenomenon and scleroderma. This study was supported by research grants HL-30604 and AR5-2217 from the US National Institutes of Health. 1
Herrick AL. Advanced in treatment of systemic sclerosis. Lancet 1998; 352: 1875–75. 2 Freedman RR, Girgis R, Mayes MD. Adrenergic and endothelial dysfunction in Raynaud’s phenomenon and scleroderma. J Rheumatol (in press). 3 Kahn R, Coffman JD. Enhanced cholingeric cutaneous vasodilation in Raynaud’s Phenomenon. Circulation 1994; 89: 1183–88. 4 Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; ii: 997–1000. 5 Freedman RR, Baer RP, Mayes MD. Blockade of vasospastic attacks by ␣2 -adrenergic but not ␣1-adrenergic antagonists in idiopathic Raynaud’s disease. Circulation 1995; 92: 1448–51.
Departments of Psychiatry and Behavioural Neurosciences, and Obstetrics and Gynaecology (Prof R R Freedman PhD), and Department of Internal Medicine (R Girgis MB , Prof M D Mayes MD), Wayne State University School of Medicine, Detroit, MI 48201, USA Correspondence to: Prof Robert R Freedman, C S Mott Center, 275 E Hancock Avenue, Detroit, MI 48201, USA (e-mail: [email protected])
Acne fulminans in late-onset congenital adrenal hyperplasia Marianne Placzek, Klaus Degitz, Heinrich Schmidt, Gerd Plewig, Acne may be the only clinical sign of androgen excess in men. We report a boy with acne fulminans and androgen excess due to late-onset congenital adrenal hyperplasia.
Acne does not usually warrant laboratory investigations.1 Increased sebum production is recognised as a possible cause. Sebum production is androgen regulated, and androgen excess can provoke severe acne in susceptible individuals. In women, acne due to excessive androgen production is frequently accompanied by hirsutism or menstrual irregularities; in men, however, severe acne may be the only clinical sign of androgen excess. We report a boy with biochemical features of late-onset congenital adrenal hyperplasia (adrenogenital syndrome)
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Acute effect of nitric oxide on Raynaud’s phenomenon in scleroderma Robert R Freedman, Reda Girgis, Maureen D Mayes Intra-arterial infusions of L-arginine and sodium nitroprusside significantly decreased the occurrence of laboratory-induced Raynaud’s phenomenon in scleroderma patients. Raising the concentration of nitric oxide may be of therapeutic value in this population.
Although most patients with scleroderma have Raynaud’s phenomenon, optimum treatments for the disorder have not been developed.1 We have shown2 that patients with Raynaud’s phenomenon and scleroderma have normal amounts of finger vasodilation in response to intra-arterial sodium nitroprusside (SNP), but none to methacholine; these findings suggest an impairment of vascular endothelial function. Other work3 has shown that patients with Raynaud’s phenomenon but not scleroderma have enhanced finger vasodilation in response to methacholine. We investigated whether intra-arterial L-arginine, the endothelial substrate for nitric oxide (NO) formation,4 or SNP, a direct donor of NO, would block Raynaud’s phenomenon induced by cooling in the laboratory. We studied 12 women and three men with Raynaud’s phenomenon and scleroderma, of mean age 47·2 years (SD 11·7). Eight had diffuse scleroderma, and seven had limited scleroderma. None had hypercholesterolaemia. Medication was withheld for 1 week before the study, and patients gave written informed consent according to procedures approved by our institutional review board. The patients, wearing scrub suits, sat in a room controlled for temperature (25ºC) and humidity, while a 20-gauge catheter was inserted percutaneously in a brachial artery, with lidocaine as a local anaesthetic. Eight patients were randomly assigned to receive an infusion of L-arginine (Clinalfa, Laeufelfingen, Switzerland; 8·5 mg/min) and seven were assigned SNP (5 g/min). After 10 min, the room temperature was decreased to 4ºC, and the patient held a 1 L beaker of iced water for 2 min. The beaker was then placed on a table for 2 min and the hands were photographed. This procedure was repeated for up to 40 min until an apparent attack of Raynaud’s phenomenon, defined as two of three colour changes (blanching, cyanosis, or rubor), occurred. The slides were scored by two independent raters, who were unaware of which drug (if any) the hands had received. The numbers of fingers showing Raynaud’s phenomenon were compared for the two hands, drugs, and raters by analysis of variance.5 The minimum level of statistical significance was p<0·05. All patients had attacks during the procedure. The number of fingers Hand
Drug L-arginine
SNP
Infused hand Control hand
1·1 (1·4)* 3·2 (1·4)
2·3 (1·7)* 3·5 (1·5)
*Significantly (p<0·002) lower than control hand values.
Mean (SD) number of fingers per hand that showed Raynaud’s phenomenon during laboratory cooling
THE LANCET • Vol 354 • August 28, 1999
showing attacks was significantly (p=0·002) lower in infused hands than in the control hands (table). There were no significant differences between the two drugs or raters. We suggest that NO released from the vascular endothelium by the addition of L-arginine, or given directly as SNP, blocks some attacks of Raynaud’s phenomenon induced in scleroderma patients under controlled conditions. These findings are consistent with, but do not prove, the hypothesis that the NO pathway is involved in the vasospastic attacks. Nevertheless, our observations may suggest therapeutic options for patients with Raynaud’s phenomenon and scleroderma. This study was supported by research grants HL-30604 and AR5-2217 from the US National Institutes of Health. 1
Herrick AL. Advanced in treatment of systemic sclerosis. Lancet 1998; 352: 1875–75. 2 Freedman RR, Girgis R, Mayes MD. Adrenergic and endothelial dysfunction in Raynaud’s phenomenon and scleroderma. J Rheumatol (in press). 3 Kahn R, Coffman JD. Enhanced cholingeric cutaneous vasodilation in Raynaud’s Phenomenon. Circulation 1994; 89: 1183–88. 4 Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; ii: 997–1000. 5 Freedman RR, Baer RP, Mayes MD. Blockade of vasospastic attacks by ␣2 -adrenergic but not ␣1-adrenergic antagonists in idiopathic Raynaud’s disease. Circulation 1995; 92: 1448–51.
Departments of Psychiatry and Behavioural Neurosciences, and Obstetrics and Gynaecology (Prof R R Freedman PhD), and Department of Internal Medicine (R Girgis MB , Prof M D Mayes MD), Wayne State University School of Medicine, Detroit, MI 48201, USA Correspondence to: Prof Robert R Freedman, C S Mott Center, 275 E Hancock Avenue, Detroit, MI 48201, USA (e-mail: [email protected])
Acne fulminans in late-onset congenital adrenal hyperplasia Marianne Placzek, Klaus Degitz, Heinrich Schmidt, Gerd Plewig, Acne may be the only clinical sign of androgen excess in men. We report a boy with acne fulminans and androgen excess due to late-onset congenital adrenal hyperplasia.
Acne does not usually warrant laboratory investigations.1 Increased sebum production is recognised as a possible cause. Sebum production is androgen regulated, and androgen excess can provoke severe acne in susceptible individuals. In women, acne due to excessive androgen production is frequently accompanied by hirsutism or menstrual irregularities; in men, however, severe acne may be the only clinical sign of androgen excess. We report a boy with biochemical features of late-onset congenital adrenal hyperplasia (adrenogenital syndrome)
739