Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure
Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular m...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Journal of Pharmacological Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861322000718 |
| _version_ | 1797990046190534656 |
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| author | Ahasanul Hasan Farzana Zerin Sreelakshmi N. Menon Md. Ashraful Alam Raquibul Hasan |
| author_facet | Ahasanul Hasan Farzana Zerin Sreelakshmi N. Menon Md. Ashraful Alam Raquibul Hasan |
| author_sort | Ahasanul Hasan |
| collection | DOAJ |
| description | Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mechanism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by concurrent inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 (by 1 μM DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 μM linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa by 1 μM apamin, IKCa 10 μM TRAM-34, and BKCa by 10 μM paxilline, respectively), ATP-sensitive (KATP) channels (by 10 μM glibenclamide), or SERCA pump (by 0.1 μM thapsigargin). Inhibition of SGLTs (by 1 μM phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that canagliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure. |
| first_indexed | 2024-04-11T08:30:08Z |
| format | Article |
| id | doaj.art-8200b91bcfa14674be40422ddd894600 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-04-11T08:30:08Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-8200b91bcfa14674be40422ddd8946002022-12-22T04:34:33ZengElsevierJournal of Pharmacological Sciences1347-86132022-12-011504211222Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressureAhasanul Hasan0Farzana Zerin1Sreelakshmi N. Menon2Md. Ashraful Alam3Raquibul Hasan4Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, United StatesDepartment of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, United StatesDepartment of Pharmaceutical Sciences, North South University, Dhaka 1229, BangladeshDepartment of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, United States; Corresponding author. Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341, United States.Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is reported to produce beneficial cardiovascular effects including a reduction in arterial contractility, and blood pressure. However, whether canagliflozin could directly relax resistance mesenteric arteries, underlying molecular mechanism and its role in regulating systemic blood pressure remain unclear. Here, we investigated the mechanism of regulation of small mesenteric artery contractility and its relevance for blood pressure regulation. Our pressure myography data showed that canagliflozin application rapidly produces a concentration-dependent vasodilation in mesenteric arteries. Such vasodilation was inhibited by concurrent inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 (by 1 μM DPO-1), KV2.1 (by 100 nM guangxitoxin), and KV7 (by 10 μM linopirdine) but not by the inhibition of small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa by 1 μM apamin, IKCa 10 μM TRAM-34, and BKCa by 10 μM paxilline, respectively), ATP-sensitive (KATP) channels (by 10 μM glibenclamide), or SERCA pump (by 0.1 μM thapsigargin). Inhibition of SGLTs (by 1 μM phlorizin or the inhibition of endothelial signaling did not alter canagliflozin-evoked vasodilation. Consistently, acute canagliflozin treatment (4 mg/kg body weight) lowered systemic blood pressure in vivo. Overall, our data suggests that canagliflozin stimulates KV1.5, KV2.1, and KV7 channels, leading to vasodilation and a reduction of systemic blood pressure.http://www.sciencedirect.com/science/article/pii/S1347861322000718CanagliflozinMesenteric arteriesVoltage-gated K+ channelsVasorelaxationBlood pressure |
| spellingShingle | Ahasanul Hasan Farzana Zerin Sreelakshmi N. Menon Md. Ashraful Alam Raquibul Hasan Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure Journal of Pharmacological Sciences Canagliflozin Mesenteric arteries Voltage-gated K+ channels Vasorelaxation Blood pressure |
| title | Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure |
| title_full | Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure |
| title_fullStr | Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure |
| title_full_unstemmed | Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure |
| title_short | Mechanism of canagliflozin-induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure |
| title_sort | mechanism of canagliflozin induced vasodilation in resistance mesenteric arteries and the regulation of systemic blood pressure |
| topic | Canagliflozin Mesenteric arteries Voltage-gated K+ channels Vasorelaxation Blood pressure |
| url | http://www.sciencedirect.com/science/article/pii/S1347861322000718 |
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