Abstract: SA-PO1018
Ticagrelor Reduces Urinary Concentration and Arginine Vasopressin (AVP) Levels: Potential Use in AVP Excess States
Session Information
- Fluid and Electrolytes: Basic - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid and Electrolytes
- 901 Fluid and Electrolytes: Basic
Authors
- Kishore, Bellamkonda K., Univ. of Utah and VA Medical Center, Salt Lake City, Utah, United States
- Hansson, Kenny M., AstraZeneca, Cardiovascular, Renal and Metabolism iMED, Mölndal, Sweden
- Carlson, Noel G., Univ. of Utah and VA Medical Center, Salt Lake City, Utah, United States
- Zhang, Yue, Univ. of Utah and VA Medical Center, Salt Lake City, Utah, United States
Background
Previously we showed that blockade of P2Y12 receptor by thienopyridine anti-thrombotic drugs (clopidogrel or prasugrel) increases urinary concentration and AVP levels. However, it is not clear whether non-thienopyridine drugs, such as ticagrelor, have similar effects on urine concentration and AVP levels.
Methods
Groups of B6D2 mice (N = 5/group) were fed regular chow containing different concentrations of ticagrelor (0.15, 0.20 and 0.25%) for 14 or 21 days and euthanized. Urine output, osmolality and AVP levels were determined prior to and at the end of treatment. Terminal plasma ticagrelor levels were assayed by LC-MS/MS. The effect of ticagrelor (0.5, 2 or 10 µM) added in vitro on dDAVP (synthetic analog of AVP; 20 nM)-induced AQP2 and AQP3 mRNA expression in primary cultures of rat inner medullary collecting duct (IMCD) cells was assessed.
Results
Administration of ticagrelor to mice caused increased urine output associated with decreased urine osmolality and AVP levels. (see Table). There was significant negative correlation between the plasma ticagrelor and urinary AVP (P < 0.04). But, blockade of P2Y12 receptor in cultured IMCD cells by ticagrelor caused dose dependent enhancement of AQP2 and APQ3 mRNA expression.
Conclusion
The observed decrease in urinary AVP excretion appears to be due to an unexpected off-target effect on hypothalamic AVP production/secretion. However, the in vitro effect on IMCD cells was an expected one based on our previous studies on P2Y12 receptor blockade. Hence, it appears that the off-target effect of ticagrelor on AVP production in vivo has apparently overridden its targeted effect on IMCD cells. Thus, our results suggest that the off-target effect of ticagrelor may find potential use in conditions associated with AVP excess, such as ADPKD, congestive heart failure, cirrhosis of liver, diabetic ketoacidosis, and cardiorenal syndrome, among others.
Terminal Plasma and Urine Data (mean ± SE)
| Ticagrelor in Chow (%, w/w)* | 0.15 | 0.20 | 0.25 |
| Plasma Ticagrelor (μM) | 1.30 ± 0.15 | 2.49 ± 0.21 | 5.30 ± 0.90 |
| Urine Output per day** | 164 ± 35 | 169 ± 62 | 203 ± 75 |
| Urine Osmolality** | 75 ± 9 | 69 ± 11# | 44 ± 13# |
| Urine AVP per day** | 79 ± 8 | 76 ± 19 | 33 ± 6# |
*after 21 days of treatment; **as percent of respective day 0 values (14 days of treatment); #signficantly different from the respective day 0 values
Funding
- Veterans Affairs Support – AtraZeneca AB