BACKGROUND: Atrial natriuretic peptide (ANP) has vasodilating and diuretic/natriuretic properties, both of which contribute to lower blood pressure. These effects are mediated by binding of ANP to a cell-surface receptor [type A guanylyl cyclase (GC-A)]. It has been demonstrated by studies in monogenetic mouse models that the ANP/GC-A system participates in the maintenance of blood pressure homeostasis. METHODS: In male patients with essential hypertension (EH; n = 36) as the only cardiovascular risk factor and normotensive controls (n = 12), blood flow was measured in the forearm circulation in response to i.a. infusion of synthetic human ANP, acetylcholine, orciprenaline, and sodium nitroprusside by strain-gauge venous plethysmography. In blood samples, cyclic guanosine'5-monophosphate (cGMP) and ANP concentrations were measured at resting conditions and during exogenous ANP infusion. In 200 patients with EH, genomic DNA was screened for an inhibitory deletion mutation of the GC-A gene, which has been recently linked to EH in a Japanese cohort. RESULTS: The vasodilatations in response to ANP and acetylcholine were impaired in the forearm circulation of patients with EH, whereas the responses to orciprenaline and nitroprusside were preserved. Plasma ANP and cGMP concentrations were increased in the patients with EH both at resting conditions and during ANP infusion; the resting plasma cGMP levels correlated significantly with the plasma ANP levels (r = 0.68). A specific deletion mutation of the GC-A gene did not account for the diminished relaxant effects of ANP in our study population. CONCLUSIONS: The vascular ANP/GC-A pathway is altered in patients with EH, in addition to the known defects on the nitric oxide/cGMP pathway. Attenuation of the vasodilative responses to ANP suggests impaired receptor or postreceptor responsiveness of GC-A. It is possible that this dysfunction participates in the pathomechanism of EH.
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