Impaired vasodilator responses to atrial natriuretic peptide in essential hypertension.

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.

High salt intake increases uroguanylin expression in mouse kidney.

The intestinal peptides, guanylin and uroguanylin, may have an important role in the endocrine control of renal function. Both peptides and their receptor, guanylyl cyclase C (GC-C), are also expressed within the kidney, suggesting that they may act locally in an autocrine/paracrine fashion. However, their physiological regulation within the kidney has not been studied. To begin to address this issue, we evaluated the distribution of uroguanylin and guanylin messenger RNA (mRNA) in the mouse nephron and the regulation of renal expression by changes in dietary salt/water intake. Expression was determined in 1) wild-type mice, 2) two strains of receptor-guanylyl cyclase-deficient mice (ANP-receptor-deficient, GC-A-/-, and GC-C-deficient mice); and 3) cultured renal epithelial (M-1) cells, by RT-PCR, Northern blotting and immunocytochemistry. Renal uroguanylin messenger RNA expression was higher than guanylin and had a different distribution pattern, with highest levels in the proximal tubules, whereas guanylin was mainly expressed in the collecting ducts. Uroguanylin expression was significantly lower in GC-C-/- mice than in GC-A-/- and wild-types, suggesting that absence of a receptor was able to down-regulate ligand expression. Salt-loading (1% NaCl in drinking water) increased uroguanylin-mRNA expression by >1.8-fold but had no effect on guanylin expression. Uroguanylin but not guanylin transcripts were detected in M-1 cells and increased in response to hypertonic media (+NaCl or mannitol). Our results indicate that high-salt intake increases uroguanylin but not guanylin expression in the mouse kidney. The synthesis of these peptides by tubular epithelium may contribute to the local control of renal function and its adaptation to dietary salt.