Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a rare variant of idiopathic central diabetes insipidus. Several different mutations in the human vasopressin-neurophysin II (AVP-NP II) gene have been described. We studied nine family members from three generations of an ADNDI pedigree at the clinical, morphological, and molecular levels. AVP concentrations were measured during diagnostic fluid restriction tests. Coronal and sagittal high resolution T1-weighted images of the pituitary were obtained from affected and healthy family members. PCR was used to amplify the AVP-NP II precursor gene, and PCR products were directly sequenced. Under maximal osmotic stimulation, AVP serum levels were close to or below the detection limit in affected individuals. Magnetic resonance imaging studies revealed the characteristic hyperintense ("bright spot") appearance of the posterior pituitary in two healthy family members. This signal was absent in all four ADNDI patients examined. The coding sequences of AVP and its carrier protein, neurophysin II, were normal in all family members examined. Affected individuals showed a novel single base deletion (G 227) in the translation initiation codon of the AVP-NP II signal peptide on one allele. The mutation in the AVP-NP II leader sequence appears to be responsible for the disease in this kindred, possibly by interfering with protein translocation. The absence of the hyperintense posterior pituitary signal in affected individuals could reflect deficient posterior pituitary function.
As a result of our recently published studies we have thought that altitude diuresis resulting from hypoxic stimulation of the arterial chemoreceptors reduces the cardiac volume overload. To test this hypothesis, cardiovascular, endocrine and renal responses to stepwise acute exposure to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers a mean of 24 days, SD 11, after descending from Himalayan altitudes of at least 4,000 m, with those found in ten non-acclimatized recumbent volunteers. The results showed that natriuresis and diuresis typified the renal responses to altitude exposure of both the acclimatized as well as non-acclimatized subjects, as long as altitude was well tolerated. It was concluded that the renal effects were mediated by atrial natriuretic peptide release and slight suppression of arginine-vasopressin (AVP) secretion, that the increased urine flow at altitude offset the cardiac (volume) overload resulting from hypoxic stimulation of the arterial chemoreceptors, and that enhanced AVP secretion, as found in the non-acclimatized subjects at and above 4,000 m, coincided with subjective and objective distress, i.e. with inadequate altitude adjustment owing to insufficient chemoreflex effects and central hypoxia.
The mechanism of endothelin-1 (ET-1)-induced atrial natriuretic peptide (ANP) release was studied in neonatal rat ventricular cardiomyocytes. These cells expressed a single high-affinity class of ETAreceptor (dissociation constant = 54 ± 18 pM, n = 3), but no ETB receptors. Incubation of cardiomyocytes with ET-1 led to concentration-dependent ANP release and prostacyclin production. ET-1-induced ANP release was affected by neither protein kinase C (PKC) inhibition or downregulation nor by cyclooxygenase inhibition, indicating that ET-1-stimulated ANP secretion is not a PKC-mediated, prostaglandin-dependent process. Furthermore, ET-1 significantly stimulated adenosine 3′,5′-cyclic monophosphate (cAMP) production and increased cytosolic calcium concentration in these preparations. Both ET-1-induced calcium influx and ANP release were decreased by the cAMP antagonist Rp-cAMPS, the Rp diastereoisomer of cAMP. Moreover, ET-1-induced ANP secretion was strongly inhibited in the presence of nifedipine as well as in the absence of extracellular calcium. Thus our results suggest that ET-1 stimulates ANP release in ventricular cardiomyocytes via an ETAreceptor-mediated pathway involving cAMP formation and activation of a nifedipine-sensitive calcium channel.
The role of the Ca2+-sensitive phospholipid-dependent protein kinase C (PKC) was studied in cultured rat aortic smooth-muscle cells, known to respond to angiotensin II (Ang II) by producing prostacyclin, determined by the release of 6-oxo-prostaglandin F1 alpha. PKC activity was measured in the cytosol and the solubilized membrane fraction after DEAE-cellulose chromatography using a linear NaCl gradient. Ang II stimulated the activity of PKC in the cytosolic and in the membrane fractions of aortic smooth-muscle cells. These increases in PKC activity were concentration-dependent and occurred rapidly, reaching a plateau within 10 min. In contrast, phorbol 12-myristate 13-acetate (PMA) rapidly decreased cytosolic PKC activity and at the same time increased membrane PKC activity to reach a plateau after 20 min. Cytosolic PKC activity from control and Ang II-stimulated cells was found to be less dependent on [Ca2+] than was the highly [Ca2+]-dependent membrane PKC activity from the same cells. In contrast, membrane PKC activity from PMA-treated cells was largely [Ca2+]-independent. In the presence of 10 nM-PMA, the sensitivity of cultured smooth-muscle cells towards Ang II was increased, and maximal values of Ang II-induced prostacyclin production were enhanced by about 60%. In cells incubated with both Ang II and PMA, an additive effect on membrane PKC activity was observed, whereas cytosolic PKC activity was suppressed as in cells treated with PMA alone. These results suggest that an increase of the membrane, but not the cytosolic, PKC activity represents a positive signal in the prostacyclin production induced by Ang II stimulation of aortic smooth-muscle cells. PMA seems to induce a state of activation of membrane PKC which does not need increased intracellular [Ca2+] to be fully expressed, whereas Ang II-stimulated membrane PKC activity requires higher Ca2+ concentrations. The possibility exists that the addition of both signals leads to the augmentation of Ang II-stimulated prostacyclin production.
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