Cyclooxygenase-2 inhibition as a new tool to combat angiogenesis inhibitor-induced hypertension and renal toxicity
| Autor: | Daan Van Dorst, Katrina Mirabito Colafella, Leni Van Doorn, Richard Van Veghel, Ingrid Garrelds, Ron Mathijssen, Jan Danser, Jorie Versmissen |
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| Přispěvatelé: | Internal Medicine, Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of Hypertension, 40(Suppl. 1). Lippincott Williams & Wilkins |
| ISSN: | 1473-5598 0263-6352 |
| Popis: | OBJECTIVE: Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI2) and thromboxane (TXA2). DESIGN AND METHOD: Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day), a PGI2 analogue (iloprost 100 mcg/kg/day), or a dual TXA2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n = 7-8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. RESULTS: SU induced a rapid increase in MAP (16 ± 2 vs. 3 ± 1 mmHg after vehicle on day 6, P < 0.001), which was blunted by celecoxib (10 ± 2 mmHg on day 6, P = 0.06 versus SU), temporarily attenuated by iloprost (on treatment days 1-2) and unaffected by picotamide. Wire myography demonstrated a trend towards increased vasoconstrictor response to endothelin-1 in iliac arteries after SU, which was prevented by celecoxib (P < 0.001). SU increased albuminuria (0.6 ± 0.1 vs. 0.3 ± 0.1 mg/24 h after vehicle; P < 0.001), and this was prevented by celecoxib only (0.4 ± 0.1 mg/24 h, P = 0.01 vs. SU). SU increased the PGI2/TXA2 ratio in both plasma (3.0 ± 1.1 vs. 0.6 ± 0.2 after vehicle, P = 0.02) and urine (23 ± 2.1 vs. 0.9 ± 0.2 after vehicle, P < 0.0001). CONCLUSIONS: In conclusion, selective COX-2 inhibition combats angiogenesis inhibitor-induced hypertension and renal toxicity. SU paradoxically increases the PGI2/TXA2 ratio, particularly in the kidney. Although this upregulation might initially be protective, it could eventually contribute to renal toxicity, most likely because PGI2 exerts deleterious effects in excessive concentrations. Targeting excessive renal PGI2 production might be another promising strategy to prevent renal toxicity during angiogenesis inhibition. |
| Databáze: | OpenAIRE |
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