A First Report of HCTZ and Dicyclomine Induced Uncharacteristic Contraction Alkalosis.

Background: Contraction alkalosis is characterized by low serum sodium and chloride and high serum carbon dioxide and bicarbonate levels. Case Report: A 28-year-old Caucasian active-duty male with a history of autosomal dominant polycystic kidney disease and diarrhea-predominant Irritable Bowel Syndrome (D-IBS) presented to his primary care provider (PCP) with elevated blood pressure (136/96 mmHg), was diagnosed with stage-2 hypertension, and started oral HCTZ (25 mg/day). His medications included dicyclomine (10 mg oral three times daily). Subsequently, (Visit 1), his blood pressure was 130/91 mmHg and he was started on telmisartan (20 mg/day). At Visit 2, 4 weeks later, his blood pressure improved (121/73 mmHg); however, blood chemistry revealed elevated serum CO2 (32 mEq/L) and chloride (94 mmol/L). Four days later, the patient presented to the Emergency Department with dyspnea and swallowing difficulty. The patient returned to his PCP 3 days later complaining of cough, congestion, vomiting, and mild dyspnea, blood pressure of 124/84 mmHg. Two months later, sudden onset of projectile vomiting and abdominal pain while running was reported, resolved by rehydration and a single oral dose of prochlorperazine 25 mg. Three months later, (Visit 3), he complained of lightheadedness and cloudy judgment, suggesting contraction alkalosis. HCTZ was discontinued and telmisartan was increased to 20 mg twice daily. A follow-up blood chemistry panel 2 weeks later revealed serum chloride and CO2 levels within normal limits and blood pressure under 130/80 mmHg. Conclusion: This is the first known report of contraction alkalosis driven by drug-drug interaction between dicyclomine and HCTZ.

Stop the flow: a paradigm for cell signaling mediated by reactive oxygen species in the pulmonary endothelium.

The lung endothelium is exposed to mechanical stimuli through shear stress arising from blood flow and responds to altered shear by activation of NADPH (NOX2) to generate reactive oxygen species (ROS). This review describes the pathway for NOX2 activation and the downstream ROS-mediated signaling events on the basis of studies of isolated lungs and flow-adapted endothelial cells in vitro that are subjected to acute flow cessation (ischemia). Altered mechanical stress is detected by a cell-associated complex involving caveolae and other membrane proteins that results in endothelial cell membrane depolarization and then the activation of specific kinases that lead to the assembly of NOX2 components. ROS generated by this enzyme amplify the mechanosignal within the endothelial cell to regulate activation and/or synthesis of proteins that participate in cell growth, proliferation, differentiation, apoptosis, and vascular remodeling. These responses indicate an important role for NOX2-derived ROS associated with mechanotransduction in promoting vascular homeostasis.

Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS.

Loss of fluid shear stress (ischemia) to the lung endothelium causes endothelial plasma membrane depolarization via ATP-sensitive K(+) (K(ATP)) channel closure, initiating a signaling cascade that leads to NADPH oxidase (NOX2) activation and ROS production. Since wortmannin treatment significantly reduces ROS production with ischemia, we investigated the role of phosphoinositide 3-kinase (PI3K) in shear-associated signaling. Pulmonary microvascular endothelial cells in perfused lungs subjected to abrupt stop of flow showed membrane depolarization and ROS generation. Stop of flow in flow-adapted mouse pulmonary microvascular endothelial cells in vitro resulted in the activation of PI3K and Akt as well as ROS generation. ROS generation in the lungs in situ was almost abolished by the PI3K inhibitor wortmannin and the PKC inhibitor H7. The combination of the two (wortmannin and H7) did not have a greater effect. Activation of NOX2 was greatly diminished by wortmannin, knockout of Akt1, or dominant negative PI3K, whereas membrane depolarization was unaffected. Ischemia-induced Akt activation (phosphorylation) was not observed with K(ATP) channel-null cells, which showed minimal changes in membrane potential with ischemia. Activation of Akt was similar to wild-type cells in NOX2-null cells, which do not generate ROS with ischemia. Cromakalim, a K(ATP) channel agonist, prevented both membrane depolarization and Akt phosphorylation with ischemia. Thus, Akt1 phosphorylation follows cell membrane depolarization and precedes the activation of NOX2. These results indicate that PI3K/Akt and PKC serve as mediators between endothelial cell membrane depolarization and NOX2 assembly.