Huatuo Zaizao Pills improve myocardial ischemia by inhibiting extracellular calcium influx

Abstract

Coronary heart disease (CHD), characterized by impaired coronary artery function, often results in myocardial ischemia, hypoxia, and necrosis, with clinical manifestations such as angina pectoris. Vascular smooth muscle cell (VSMC) hypercontraction, primarily regulated by intracellular calcium (Ca²⁺), plays a central role in pathological coronary vasoconstriction. This study aimed to evaluate the therapeutic effects of Huatuo Zaizao Pills (HTZZ) in alleviating myocardial ischemia caused by abnormal coronary artery contraction and to elucidate the underlying molecular mechanisms. A double-blind, multicenter, randomized, placebo-controlled clinical trial was conducted to assess the efficacy of HTZZ in patients with angina pectoris. In vivo, pituitrin-induced acute myocardial ischemia mice and spontaneously hypertensive rats (SHRs) were used to evaluate myocardial and vascular responses to HTZZ. In vitro, vasorelaxation mechanisms were investigated using isolated rat mesenteric arterial rings, patch clamp, calcium imaging, and [³H]-ryanodine binding assays. HTZZ significantly reduced the frequency and duration of angina attacks in clinical settings. It improved myocardial ischemia in mice and enhanced vascular elasticity and diastolic function in SHRs. Mechanistically, HTZZ induced vasodilation by inhibiting extracellular Ca²⁺ influx and reducing intracellular Ca²⁺ levels via suppression of L-type calcium channels (LTCCs) and ryanodine receptors (RyRs). Long-term HTZZ administration also downregulated LTCC expression at both the protein and mRNA levels. HTZZ effectively alleviates angina and myocardial ischemia by suppressing Ca ²⁺-mediated vasoconstriction through targeting LTCCs and RyRs. These findings highlight HTZZ as a promising therapeutic candidate for CHD characterized by coronary vasospasm and ischemia.

Keywords

Coronary heart disease / Huatuo Zaizao Pills / Vascular smooth muscle / Calcium channel / Ryanodine receptor / Vasodilation

Fundings

This study was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0537900), the National Multidisciplinary Cross-innovation Team Project in Traditional Chinese Medicine (No. ZYYCXTDD-D-202407), the National Natural Science Foundation of China (No. 82330011) and the China Postdoctoral Science Foundation (No. 2023MD744216).

Supporting information

Supporting information for this work can be obtained by contacting the corresponding authors via E-mail.

Declaration of competing interests

Guangzhou Baiyunshan Qixing Pharmaceutical Co. Ltd. donated the study drugs, including Huatuo Zaizao Pills and the placebo for the clinical research, but had no role in the data acquisition, statistical analysis and interpretation of the results. Ms. Na Ning is the employee of Guangzhou Baiyunshan Qixing Pharmaceutical Co. Ltd. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Nannan Wang is the employee of Guangzhou Baiyunshan Zhongyi Pharmaceutical Co. Ltd.

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