Abstract
Kappa-opioid agonists (KOAs) enhance cardiac performance, as well as reduce infarct size and prevent deleterious cardiac remodeling following myocardial infarction. Additionally, KOAs promote diuresis; however, there has been limited development of KOAs as a class due to the promotion of untoward central nervous system (CNS)-mediated side effects. Our laboratory has developed a peripherally-restricted, orally-active, KOA (JT09) for the treatment of pain and cardiovascular disease. Peripherally-restricted KOAs possess a limited side-effect profile and demonstrate potential in preventing heart failure. The aim of this study was to assess the diuretic activity of lead compound JT09 relative to vehicle control and Tolvaptan through single oral administration to adult male Sprague–Dawley rats. JT09-administered rats demonstrated significantly increased urine output relative to vehicle control. However, the effect persisted for 8 h, whereas Tolvaptan-administered rats demonstrated diuretic activity for 24 h. Relative to Tolvaptan, urine output was significantly reduced in JT09 administered animals at all-time points, suggesting that the overall diuretic effect of JT09 is less profound than Tolvaptan. Additionally, JT09-administered rats demonstrated alterations in clinical chemistry; reduced urine specific gravity; and increased urine pH relative to vehicle control. The following study establishes a preliminary diuretic profile for JT09.
Highlights
Cardiovascular disease (CVD) is the leading cause of death in the United States, accounting for over 800,000 deaths per year [1]
Most common medications of use include β-adrenergic receptor antagonists (β-blockers), which reduce blood pressure, as well as reduce cardiac inotropy and chronotropy [2]; Angiotensin converting enzyme (ACE)-inhibitors, which block the conversion of angiotensin I to angiotensin II, reducing blood pressure and mitigating deleterious cardiovascular remodeling; Angiotensin receptor antagonists, which act similar to ACE-inhibitors by blocking the activity of angiotensin II; and diuretics, which help relieve the symptoms of congestive heart failure by reducing volume overload and reducing left ventricular pre-load and systemic vascular resistance [3]
This study was performed to assess the diuretic activity of test item, JT09, through single oral administration to Sprague–Dawley rats, relative to vehicle control and Tolvaptan
Summary
Cardiovascular disease (CVD) is the leading cause of death in the United States, accounting for over 800,000 deaths per year [1]. Treatment for HF includes lifestyle changes and combination therapy with a variety of medications. Most common medications of use include β-adrenergic receptor antagonists (β-blockers), which reduce blood pressure, as well as reduce cardiac inotropy (contractility) and chronotropy (heart rate) [2]; Angiotensin converting enzyme (ACE)-inhibitors, which block the conversion of angiotensin I to angiotensin II, reducing blood pressure and mitigating deleterious cardiovascular remodeling; Angiotensin receptor antagonists, which act similar to ACE-inhibitors by blocking the activity of angiotensin II; and diuretics, which help relieve the symptoms of congestive heart failure by reducing volume overload and reducing left ventricular pre-load and systemic vascular resistance [3]
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