Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats.

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (prehypertensive phase) to SHR's 28-30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28-30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.

Unrecognised pheochromocytoma in pregnancy discovered through metoclopramide-triggered hypertensive emergency.

PURPOSE: Pheochromocytoma, a catecholamine-secreting tumour leading to neurological and cardiovascular life-threatening conditions through hypertension crisis, occurs in 0.1-0.5% of hypertensive patients, but it is extremely rare in pregnancy (0.0018-0.006%). Some classes of drugs, even commonly used in pregnancy, can trigger catecholamine secretion, precipitating the clinical situation. MATERIALS AND METHODS AND RESULTS: We report a 33-year-old woman, gravida 2 para 1, with previous mild hypertension, was admitted to the emergency room, at 28 2/7 weeks of gestation due to headache, tachycardia and severe arterial hypertension (220/120 mm Hg) triggered by the antiemetic metoclopramide used for a week because of nausea. In the emergency room, a paradoxical rise in blood pressure followed intravenous labetalol infusion was observed. Both metoclopramide and labetalol-triggered hypertensive crisis raised the suspicion of an undiagnosed pheochromocytoma. Diagnostic work-up showed elevated normetanephrine urinary excretion ​​and a right adrenal pheochromocytoma by abdominal magnetic resonance imaging. Oral alpha-1 and beta-1-adrenergic antagonist and calcium-channel blocker were started. At 33-weeks of gestation, she underwent a caesarean section giving birth to a female child. Seven weeks later she underwent a video-laparoscopic right adrenalectomy which normalised her blood pressure. CONCLUSIONS: Both metoclopramide, a selective dopamine type-2 receptor antagonist and partial agonist of 5-hydroxytryptamine 4 receptor, and labetalol, a non-selective ß-adrenoreceptor-blocker with weak α1-adrenergic antagonism, exacerbated an acute hypertensive crisis revealing an unrecognised pheochromocytoma in a pregnant patient. Careful attention to potential drug-triggered catecholamine crises and especially early recognition of pheochromocytomas, are mandatory in hypertensive pregnant women. A missed or delayed diagnosis could result in catastrophic results affecting foetal and maternal outcomes.

Case Report: Irreversible Watery Diarrhea, Severe Metabolic Acidosis, Hypokalemia and Achloridria Syndrome Related to Vasoactive Intestinal Peptide Secreting Malignant Pheochromocytoma.

Background: Pheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP). Clinical Case: A 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on 68GaDOTA-octreotate positron emission tomography. Metastasis in lumbar region and lung were present. Both chromogranin A and VIP levels were high (more than10 times the normal value) with slightly elevated urine normetanephrine and metanephrine excretion. Right adrenalectomy was performed and a somatostatin analogue therapy with lanreotide started. Immunostaining showed chromogranin A and VIP co-expression, with weak somatostatin-receptor-2A positivity. In two months, patient clinical conditions deteriorated with severe WDHA and multiple liver and lung metastasis. Metabolic acidosis and hypokalemia worsened, leading to hemodynamic shock and exitus. Conclusions: A rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells.