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Dual L/T calcium channel blocker exerts both antihypertensive and renoprotective effects in L-NAME-induced
Peter Muiruri Kamau1, Yang Chen1, Xiaopei Yang2
1National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Key Laboratory of Genetic Evolution & Animal Models, New Cornerstone Science Laboratory, Key Laboratory of Bioactive Peptides of Yunnan Province, Sino-African Joint Research Center, and National Resource Center for Non-Human Primates, Engineering Laboratory of Peptides of Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, No. 17, Longxin Road, Kunming 650201, Yunnan, PR China; University of Chinese Academy of Sciences, Kunming College of Life Science, Beijing 100049, China.
Insights
Toddaculin effectively lowers blood pressure and protects kidneys in hypertensive mice by inhibiting L-type and T-type calcium channels. This natural compound shows promise as a dual-action antihypertensive and renoprotective agent.
Area of Science:
- Pharmacology
- Nephrology
- Cardiovascular Medicine
Background:
- Renal hypertension, often stemming from kidney disease and atherosclerosis, can lead to kidney failure.
- Current renoprotective therapies are limited, necessitating research into novel agents.
- Dual blockade of L-type and T-type calcium channels presents a promising therapeutic strategy for hypertension.
Purpose of the Study:
- To investigate the antihypertensive and renoprotective effects of toddaculin, a T-type calcium channel inhibitor.
- To evaluate toddaculin's impact on L-type and T-type calcium channels (CaV1.2 and CaV3.1) and its mechanism in vascular smooth muscle cells.
- To assess toddaculin's efficacy in an in vivo model of L-NAME-induced hypertension.
Main Methods:
- Utilized conserved amino acid sequence comparison, electrophysiological recordings, and Flex Station to analyze toddaculin's interaction with CaV1.2 and CaV3.1 channels.
- Assessed intracellular calcium ([Ca2+]i) using fluo-4-AM and investigated toddaculin's effects on vascular smooth muscle cells (VSMCs) and rat aortic rings.
- Employed a mouse model of L-NAME-induced hypertension to evaluate in vivo antihypertensive and renoprotective properties.
Main Results:
- Toddaculin equally and dose-dependently inhibited both CaV3.1 and CaV1.2 channels, with L1047A and L1456A identified as potential key binding sites.
- Demonstrated toddaculin-induced reduction in intracellular calcium in VSMCs and dose-dependent relaxation of aortic rings.
- Observed significant blood pressure reduction and renoprotective effects of toddaculin in a mouse model of L-NAME-induced hypertension.
Conclusions:
- Toddaculin acts as a dual inhibitor of CaV1.2 and CaV3.1 calcium channels.
- Toddaculin exhibits antihypertensive effects by relaxing vascular smooth muscle and reducing blood pressure.
- Toddaculin demonstrates therapeutic potential as an antihypertensive drug with significant renoprotective properties.
Abstract:
Renal hypertension, a common form of secondary hypertension, results from kidney disease. It arises due to the narrowing of arteries connected to the kidneys, often caused by atherosclerosis. Over time, this condition can lead to kidney failure. Therapeutics for kidney protection are currently limited, prompting continual search for new renoprotective agents in the context of hypertension. Dual blockage of both L-type and T-type calcium channels has shown promise in the treatment of hypertension when compared to selective calcium channel blockers. Toddaculin has been proven to be a potent inhibitor of the T-type channel. Conserved amino acid sequence comparison, electrophysiological recordings, and Flex Station were used to evaluate and compare toddaculin effect on the CaV3.1 and CaV1.2 channels and their respective residues, transiently expressed in HEK293T cells. Intracellular Ca2+ was assessed using the molecular probe fluo-4-AM. They specifically investigated the impact of toddaculin on vascular smooth muscle cells (VSMCs). Toddaculin's myogenic effects were assessed using aortic rings isolated from rats within an organ bath system. In an in vivo context, a mouse model with L-NAME-induced hypertension was employed to investigate toddaculin's anti-hypertensive and renoprotective properties. We found that L1047A in CaV1.2, and L1456A in CaV3.1 are potential key binding sites for toddaculin, and that toddaculin inhibited CaV3.1 and CaV1.2 equally and dose-dependently. Toddaculin-induced decline of [Ca2+]i cultured VSMCs under a laser scanning confocal microscopy. Aortic rings exposed to toddaculin demonstrated dose-dependent relaxation following KCl-induced contraction. Moreover, toddaculin exhibited significant blood pressure reduction and renoprotective effects against L-NAME-induced renal injury in mice. This finding provides an evident therapeutic potential of toddaculin as an antihypertensive drug candidate with a renoprotective effect.
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