Modulation of Heme Oxygenase 1 by Nizatidine and Lisinopril in Healthy Subjects

Current therapeutic options for gastroparesis are limited to dietary modifications and
pharmacological (i.e., prokinetic and symptomatic) agents. Exciting and novel preliminary
data from our programs demonstrate that (i) reduced expression of heme oxygenase 1 (HO-1) is
responsible for loss of interstitial cells of Cajal and delayed gastric emptying in
non-obese diabetic (NOD) mice, (ii) upregulation of (HO-1) reverses delayed gastric emptying
in this model, perhaps by generating carbon monoxide (CO), which has anti-apoptotic and
cytoprotective actions, and may relax smooth muscle, and (iii) hemin upregulates HO-1 in
humans. However, hemin is exorbitant and can only be administered intravenously. A large
throughput screening assay uncovered that the histamine H2 receptor antagonist nizatidine
and the ACE inhibitor lisinopril upregulate HO-1 in Human Embryonic Kidney (HEK) cells.
Hence, this double-blind placebo-controlled study will randomly assign 24 healthy subjects
to one of 4 arms, and HO-1 protein activity and concentration will be assessed.

Inclusion criteria:

- Healthy subjects without clinical evidence of significant cardiovascular,
gastrointestinal, hematological, neurological, psychiatric or other disease that may
interfere with the objectives of the study and/or pose safety concerns

- Normal serum potassium and estimated glomerular filtration rate (eGFR) > 60 ml/minute

- Baseline systolic BP ≥ 110 mmHg

- No known hypersensitivity to lisinopril or nizatidine

- Able to provide written informed consent before participating in the study

- Able to communicate adequately with the investigator and to comply with the
requirements for the entire study.

Exclusion criteria:

- Pregnant

- Breast feeding

- Current smoker

- Symptoms of functional GI disorder as assessed by a validated questionnaire

- Previous history of peptic ulcer disease.