H2S treatment reverts cardiac hypertrophy and increases SERCA2a activity but does not fully restore cardiac Ca2+ handling in hypertensive rats

Hydrogen sulfide (H₂S) has been proposed to play a cardioprotective role, particularly due to its ability to revert left ventricular hypertrophy (LVH) and mitigate cardiac dysfunction in various cardiomyopathies, including hypertensive heart disease. However, the extent to which cardioprotection by H₂S involves improvement in Ca²⁺ handling remains unclear. Although H₂S has been reported to influence the function of key Ca²⁺ handling proteins, most studies have focused on acute administration of H₂S donors in isolated cardiomyocytes, rather than in a therapeutic context. In this study, we used a rat model of hypertension induced by abdominal aortic coarctation (AAC) to evaluate the therapeutic potential of NaHS, an H₂S donor, on LVH and Ca²⁺ handling. After 8 weeks of AAC, hypertensive rats developed moderate LVH, which was accompanied by a reduction in both the amplitude and the rate of rise of systolic Ca²⁺ transients, as well as a decrease in sarcoplasmic reticulum (SR) Ca²⁺ load. Despite the reduced SR Ca²⁺ load, the frequency of diastolic Ca²⁺ sparks remained high, while the incidence and propagation rate of spontaneous Ca²⁺ waves significantly increased, suggesting enhanced diastolic SR Ca²⁺ leak, most likely due to hypersensitivity of ryanodine receptors (RyR2) to Ca²⁺. On the other hand, NaHS administration during the final 4 weeks of AAC reverted both LVH and hypertension, and increased SR Ca²⁺ reuptake mediated by the SR Ca²⁺ ATPase (SERCA2a). However, NaHS treatment failed to restore the amplitude and rate of rise of systolic Ca²⁺ transients or SR Ca²⁺ load. Furthermore, SR Ca²⁺ leak might have worsened, since spontaneous Ca²⁺ waves increased. In conclusion, NaHS treatment does not appear to normalize all Ca²⁺ handling properties during hypertensive LVH. On the contrary, NaHS may exert an arrhythmogenic effect, likely due to enhanced SERCA2a activity under conditions of unresolved RyR2 Ca²⁺ hypersensitivity.