Rat study finds beta-blocker plus 5-HT1A agonist reduces myocardial injury markers after infarction

In a controlled animal experiment involving 27 male Sprague-Dawley rats, one week of combined treatment with the beta-blocker bevantolol and the 5-hydroxytryptamine 1A receptor agonist tandospirone was associated with smaller myocardial infarcts, less tissue injury and fibrosis, fewer TUNEL-positive cells, and lower inflammatory markers than saline treatment after experimentally induced myocardial infarction. The study was published in PLOS One on October 14, 2026, and its findings do not establish clinical efficacy in humans.

Rats were randomly assigned to sham surgery, myocardial infarction with saline, or myocardial infarction followed by combined drug treatment, with nine animals in each group. Rats in the combination group received bevantolol at 10.5 mg/kg and tandospirone at 3.15 mg/kg by intragastric administration for seven days. Infarcted controls received 5 mL/kg of physiological saline. The doses were converted from human doses through a body-surface-area method, and tissues were collected after the final administration.

Investigators assessed infarct size using TTC/Evans blue staining. In this method, tissue unstained by Evans blue represented the ischemic area, while tissue not stained by TTC within that area represented infarction. Quantitative histological analyses used three biological replicates per group. Hematoxylin and eosin staining showed disorganized myocardium, inflammatory-cell infiltration, collagenous fibers, and visible scar in infarcted control rats. These abnormalities were less pronounced in rats receiving the combination, supporting the observation that combined treatment mitigated myocardial pathological damage after infarction.

Masson staining was used to quantify fibrosis through the collagen volume fraction, defined as the proportion of positively stained collagen area relative to total tissue area. Collagen volume fraction was higher after infarction than in sham-operated rats and lower with combined treatment than in saline-treated infarcted controls. TUNEL staining, which detects DNA fragmentation rather than apoptosis specifically, also showed a higher proportion of positive cells after infarction and a lower proportion following combined treatment. The investigators cautioned that TUNEL-positive cells can reflect multiple programmed cell-death pathways, including pyroptosis, so the assay did not quantify the separate contributions of apoptosis and pyroptosis to cardiomyocyte loss.

Enzyme-linked immunosorbent assays used six biological replicates per group to measure serum creatine kinase-MB and cardiac troponin I, serum and myocardial-tissue concentrations of interleukin-1β and interleukin-18, and myocardial-tissue concentrations of interleukin-1β and interleukin-18. Compared with sham-operated animals, infarcted controls had higher concentrations of the myocardial injury markers and inflammatory cytokines. The combined-treatment group had lower concentrations of all six measured analyte-location combinations than infarcted controls. Quantitative reverse-transcription polymerase chain reaction and Western blotting likewise showed higher myocardial interleukin-1β and interleukin-18 messenger RNA and protein expression after infarction and lower expression with the combination.

The investigators next examined NLRP3, cleaved Caspase-1, and the N-terminal domain of gasdermin D, designated GSDMD-N. Immunohistochemical staining, qRT-PCR, and Western blotting showed increased expression of these markers in infarcted controls relative to sham-operated rats and decreased expression in the combination group. These findings demonstrate lower molecular-marker expression following combined treatment; they do not, by themselves, prove that the treatment directly inhibited the pathway or that pathway suppression mediated the histological effects.

The study also assessed the precursor proteins pro-Caspase-1 and full-length GSDMD. Both were elevated after myocardial infarction. Their abundance was numerically lower in the combination group, but the differences from infarcted controls were not significant. By contrast, the ratios of cleaved Caspase-1 to pro-Caspase-1 and GSDMD-N to full-length GSDMD increased after infarction and were significantly reduced by combined treatment. The authors interpreted this pattern as consistent with less cleavage and activation of Caspase-1 and GSDMD rather than a major change in precursor-protein abundance.

Several limitations constrain the findings. The experiment did not include myocardial-infarction groups treated with bevantolol or tandospirone alone, so it cannot show that the combination was more effective than either drug or that the agents interacted synergistically. It also did not measure cardiac function, survival, or outcomes beyond the one-week treatment period, and it did not test post-infarction anxiety-like or depression-like behavior. Alternative stress-modulating drugs were not evaluated. The mechanistic interpretation remains bounded by the absence of a validated NLRP3-specific inhibitor or activator and definitive functional pyroptosis assays.

Cell-type-specific co-staining was also not performed, so the experiment could not identify which myocardial or inflammatory cell populations generated the pathway signals. These results therefore support an association between combined bevantolol and tandospirone treatment, reduced myocardial injury markers, and lower NLRP3/Caspase-1/GSDMD-associated marker expression in a short-term male rat infarction model. They do not demonstrate human clinical efficacy, long-term functional benefit, or a causal pathway mechanism.

Subject of Research: Short-term rat myocardial infarction study of bevantolol plus tandospirone and NLRP3/Caspase-1/GSDMD-associated markers

Article Title: Protection of beta-blocker and 5-hydroxytryptamine 1A receptor agonist on myocardial ischemia injury in rats by regulating the NLRP3/Caspase-1/GSDMD pathway

Article References: Chen, H., Li, Y., Liu, M., Chi, Y., & Zhang, L. (2026). Protection of beta-blocker and 5-hydroxytryptamine 1A receptor agonist on myocardial ischemia injury in rats by regulating the NLRP3/Caspase-1/GSDMD pathway. PLOS One, 21(10), e0360695. https://doi.org/10.1371/journal.pone.0360695

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360695

Keywords: rat myocardial infarction, bevantolol, tandospirone, beta-blocker, 5-HT1A receptor agonist, NLRP3 inflammasome, Caspase-1, GSDMD, myocardial inflammation, pyroptosis, Protection, hydroxytryptamine