The sulfaphenazole-sensitive pathway acts as a compensatory mechanism for impaired nitric oxide availability in patients with primary hyperparathyroidism. Effect of surgical treatment.
OBJECTIVE
The aim of this study was to assess whether patients with primary hyperparathyroidism (PHPT) show reduced endothelial function and to determine the mechanisms involved. The impact of parathyroidectomy (PTx) on endothelial function was also assessed.


BACKGROUND
Endothelial dysfunction is reported in patients with PHPT, but the mechanisms involved are unknown.


METHODS
We evaluated forearm blood flow changes (strain gauge plethysmography) induced by intraarterial acetylcholine or sodium nitroprusside in 17 PHPT women and 17 age-matched controls. Nitric oxide (NO) availability and oxidative stress were studied by repeating acetylcholine during intraarterial infusion of L-N(G)-monomethyl arginine (L-NMMA, a NO synthase inhibitor) and ascorbic acid (an oxidative stress scavenger). The role of cytochrome P450 epoxygenase (CYP 2C9)-derived endothelium-derived hyperpolarizing factor (EDHF) was assessed by repeating acetylcholine under intraarterial sulfaphenazole. In six PHPT patients, the study was repeated 12 months after successful PTx.


RESULTS
Responses to sodium nitroprusside and acetylcholine were similar in PHPT patients and controls. L-NMMA inhibited the response to acetylcholine in controls (P < 0.001), whereas it had no effect in PHPT patients. In both groups, ascorbic acid failed to affect acetylcholine. Sulfaphenazole administration, although not affecting vasodilation to acetylcholine in controls, blunted the response to acetylcholine in PHPT patients (P < 0.005). After PTx, the inhibitory effect of L-NMMA on acetylcholine was restored (P < 0.001), and the inhibitory effect of sulfaphenazole on acetylcholine was abrogated.


CONCLUSIONS
PHPT patients show compromised NO availability, whereas oxidative stress generation is not involved. A compensatory CYP 2C9-derived EDHF pathway is activated to sustain endothelium-dependent vasodilation. This PHPT-related endothelial dysfunction is reversed after PTx.
Virdis
Agostino
A
Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. a.virdis@med.unipi.it
Cetani
Filomena
F
Giannarelli
Chiara
C
Banti
Chiara
C
Ghiadoni
Lorenzo
L
Ambrogini
Elena
E
Carrara
Davide
D
Pinchera
Aldo
A
Taddei
Stefano
S
Bernini
Giampaolo
G
Marcocci
Claudio
C
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology; D065729:Cytochrome P-450 CYP2C9; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000378:metabolism* / Q000601:surgery; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D016105:Parathyroidectomy; D013426:Sulfaphenazole / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D013426:Sulfaphenazole; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D001205:Ascorbic Acid