Targeting Endoplasmic Reticulum Stress in Human Hypertension

Inclusion Criteria:

1. 18 to 80 years of age

2. No tobacco/nicotine use within preceding 6 months (e.g., cigarettes, chewingtobacco, nicotine gum or patches)

3. Systolic blood pressure <140 mmHg; diastolic blood pressure <90 mmHg (obtained atthe Screening and Familiarization Visit)

4. Normal 12-lead ECG (obtained at the Screening and Familiarization Visit and reviewedby a board-certified physician)

5. Normal clinical results from a medical exam reviewed by a board-certified physician (e.g., General Health Questionnaire obtained at the Screening and FamiliarizationVisit)

6. Body mass index (BMI) <35 unless athletic/muscular build; calculation = body weight (kg)/height (m2);

7. Females only: documentation of a negative pregnancy test prior to thefamiliarization and experimental sessions unless post-menopausal

Exclusion Criteria:

1. Not meeting the defined age criteria

2. Body mass index (BMI) >35 unless athletic/muscular build; calculation = body weight (kg)/height (m2)

3. Any tobacco/nicotine use within the last 6 months (e.g., cigarettes, chewingtobacco, nicotine gum or patches)

4. Positive pregnancy test

5. Females with an erratic/irregular menstrual cycle

6. Females who are breastfeeding

7. Women who are prescribed a continually releasing hormonal contraceptive (e.g.NuvaRingTM or other hormone releasing vaginal rings, Depo Provera shot, or birthcontrol implants such as Nexplanon)

8. Subjects who weigh less than 80 lbs.

9. Use of prescription drugs, non-prescription drugs, dietary supplements or herbalmedicines known to alter vascular function unless cleared prior to the study

10. Use of beta blockers

11. Daily use of bronchodilators

12. Use of anti-coagulant therapy

13. Implanted medical devices (e.g. cardiac pacemaker)

14. Current or past history of hyperthyroidism, or other thyroid hormone-related disease

15. Current use of hormone replacement therapy (e.g., estrogen, testosterone)

16. HbA1c >5.6

17. Resting systolic blood pressure of <100 mmHg; >140mmHg or diastolic blood pressure >90mmHg

18. Abnormal 12-lead ECG or uncontrolled heart rhythm issues causing symptoms, or anunstable blood pressure

19. History of cerebrovascular abnormalities (e.g., prior stroke, transient ischemicattacks, epilepsy)

20. Known history of atherosclerosis of the carotid arteries (i.e., plaque formation)

21. History of concussion and or other loss of consciousness within the preceding 30days

22. Autonomic dysfunction (e.g., Shy-Drager Syndrome, Bradbury-Eggleston syndrome, sinusarrhythmia, idiopathic orthostatic hypotension, fainting disorder)

23. Respiratory illnesses (e.g., chronic asthma (including exercise-induced asthma),Chronic Obstructive Pulmonary Disease, Reactive Airway Disease)

24. Any prior history of anaphylaxis, not just prior reactions to the materials used inthis study

25. Severe phobia of needles

26. Latex allergy aa) Known allergies or sensitivities to substances used in the study (e.g., Lidocaine HCL, sodium nitroprusside, acetylcholine, phentolamine, L-NAME,TUDCA, or related drugs) bb) Donated blood within the last 60 days cc) History orfamily history of abnormal blood clotting, clots in deep veins in the legs orpelvis, or blood clots to the lungs dd) History of alcohol or drug abuse whichinhibits the subject's ability to complete this study ee) Individuals who have hadmastectomies ff) History of methemoglobinemia gg) Current diagnosis of anemia hh)Current Fever (oral temp >99.5 °F/ 37.5 °C) ii) Current use of PDE3 inhibitors (e.g., Viagra) or soluble guanylate cyclase (sGC) stimulators (e.g., riociguat), orunwillingness to withhold medication for 2 weeks prior to laboratory testing jj)Current diagnosis of cancer kk) Cardiac surgery or cardiac events (e.g., coronaryartery bypass graft surgery, myocardial infarction, heart failure) ll) Diagnosis ofneurological disease or cognitive dysfunction