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.

Borate transporters are membrane transport proteins that regulate intracellular borate levels. In plants, borate is a micronutrient essential for growth but is toxic in excess, while in yeast, borate is unnecessary for growth and borate export confers tolerance. Borate transporters share structural homology with human bicarbonate transporters in the SLC4 family despite low sequence identity and differences in transported solutes. Here, we characterize the S. cerevisiae borate transporter Bor1p and examine whether key biochemical features of SLC4 transporters extend to borate transporters. We show that borate transporters and SLC4 transporters share multiple properties, including lipid-promoted dimerization, sensitivity to stilbene disulfonate-derived inhibitors, and a requirement for an acidic residue at the solute binding site. We also identify several amino acids critical for Bor1p function and show that disease-causing mutations in human SLC4A1 will eliminate in vivo function when their homologous mutations are introduced in Bor1p. Our data help elucidate mechanistic features of Bor1p and reveal significant functional properties shared between borate transporters and SLC4 transporters.

The SLC4 family of transporters includes the archetypal transporter Band 3, or Anion Exchanger 1 (AE1), a bicarbonate and chloride ion exchanger essential for human respiration and the most abundant membrane protein in red blood cells. Mutations in SLC4 transporters such as AE1 can lead to diseases such as hereditary spherocytosis or renal tubular acidosis. The SLC4 family shares sequence and structural homology with borate transporters, which are found in plants and fungi and regulate cellular borate levels to protect against borate toxicity. Here we generated mutations in the S. cerevisiae borate transporter Bor1 homologous with known disease‐causing mutations of human AE1, and then tested for borate transport activity in a genetic complementation assay. Our results identify mutants with impaired function but wild‐type expression levels, as well as mutants with impaired function and depleted expression levels. These results are consistent with varying modes of deleterious impact of protein expression, sorting, and function that have been attributed to mutations in human AE1. These data show that mutations equivalent to disease‐causing mutations in human AE1 have major effects in ScBor1, strengthening the functional connection between SLC4 proteins and borate transporters. Additionally, we demonstrate that the ScBor1 D347 residue, which is homologous to the essential E681 of human AE1, can be complemented by the D347E but not D347N substitution, underscoring the necessity of having an acidic residue at this highly conserved functional location. Lastly, we identify several new amino acids critical for function through mutagenesis and complementation studies. These data collectively highlight similarities in the biochemical features of ScBor1 and HsAE1 and help shed light on the mechanisms of borate transporters and their SLC4 homologs.