Sepsis is a syndrome of immune imbalance involving multiple organs, which can lead to abnormalities in various organs of the body, among which the heart is the most severely damaged. Cardiac dysfunction induced by sepsis is the main cause of poor prognosis in patients with sepsis. The treatment of heart dysfunction has also become a major effort of clinicians. As a beta blocker with super-short effect, esmolol has been proven to have a protective effect on the heart many times, and is widely used in clinical practice. In this experiment, samples were obtained through the classical modeling method and drug intervention method, and relevant factors were detected, and the expected results were finally obtained.
It is a well known technique to induce sepsis in the rat model by caecal ligation and puncture. It is also quite reasonable to apply it in this study. ELISA and Western Blot show that after CLP intervention, inflammatory cytokines CA, TNF-α, IL–6, MyD88 and NF-KB were significantly increased compared with the sham group, similar to a septic patient’s clinical pathological process of inflammatory activation. In the use of esmolol after the intervention, the content of the above inflammatory factors decreased, which was statistically significant. This indicates that esmolol has the effect of inhibiting the inflammatory response during sepsis, and can reduce the damage of inflammation to the body in the early stage. As for the cardiac function factor cTnI, compared with the CLP group, esmolol can increase the content of cTnI and improve the cardiac function of patients to a certain extent.
Then,we studied the improvement of the beta receptor pathway with esmolol. As mentioned earlier in this article, beta receptors have positive inotropic effects that maintain the general physiological function of the heart by exciting GPCRs, that is β-AR—Gs—AC—cAMP—PKA pathway. However, when sepsis occurs, the early "sympathetic storm" causes the beta receptors to be continuously excited by catecholamines, and the GPCRs are transformed into the β-AR—Gs—Ca2+一CaMKII pathway, which triggers apoptosis and cardiac dysfunction. It can be seen from ELISA results that, compared with the Sham group, the levels of G protein pathway factors AC, cAMP and PKA in the CLP group are significantly increased, while the levels of these factors are decreased in the ES group. This suggests that when sepsis occurred, esmolol, as beta blockers, can compete for catecholamine binding sites and inhibit the early onset of the "sympathetic storm" of sepsis. In other words, it can inhibit the pathologic apoptotic pathway mediated by catecholamines, thus playing a protective role on the heart.
Previous data have shown that β-arrestin is involved in the process of reducing the incidence of left heart failure in patients and improving the cardiac function of patients with myocardial fibrosis to a certain extent[23][24]. There are also studies that show that β-arrestin can protect the myocardium in two ways. First, it is involved in the degradation, internalization, and circulation of β-AR mediated by G protein of the classical pathway, and it inhibits the apoptotic pathway induced by overactivated beta receptors in the early stage of sepsis. As previously stated, this desensitization cannot occur without both beta-arrestin and beta-ARK. Secondly, it can also act as a signaling molecule to participate in the beta receptor pathway, that is, it can bind to the beta receptor to activate the extracellular signal-regulated kinase (ERK)., inhibiting the proliferation and apoptosis of cardiomyocytes, thereby improving cardiac function. In this experiment, western blot showed that compared with the CLP group, the levels of β1-AR, β2-AR, β-arrestin-1 and β-arrestin-2 in the myocardial tissue of the ES group were significantly increased. It is suggested that in the early stage of sepsis, esmolol can activate the β-arrestin pathway to trigger the desensitization of beta receptors and prevent their over-activation thereby increasing the expression level of beta receptors and ultimately reducing the occurrence of cardiac dysfunction. Previous studies have shown that βARK is involved in the occurrence of myocyte hypertrophy[25], while the results of our experiment are just the opposite of the previous protein expression, indicating that esmolol can play a protective role in myocytes by reducing the expression of βARK.
In addition, our pathological results showed that, among the myocardial cell injuries in each time period, the sham group was the least severe, followed by the ES group, and the CLP group was the most severe. It also visually demonstrated the cardiomyocyte protective effect of esmolol. We analyzed the apoptotic area of cardiomyocytes under electron fluorescence microscopy, and the immunofluorescence results also showed the same conclusion.
Finally, as shown in the figure of survival rate analysis, esmolol did make a significant contribution to the improvement of rat mortality and indirectly indicating a protective function in cardiomyocytes.
In general, from the perspective of desensitization of the β receptor in the pathogenesis of SIMD, we have explored its mechanism from the whole, tissue, and cellular levels. Taking βARK1, β-arrestin-1 and β-arrestin-2 as the key observational indicators, we have provided a new target for clinical treatment of SIMD, providing a new theoretical basis for esmolol to improve SIMD, and providing theoretical support for clinical reduction of sepsis mortality and improvement of prognosis. All of these have not been or only rarely been previously studied.
Of course, there are still many deficiencies in this study. For example, the literature selected in this study is limited, and the data on the relationship between esmolol and beta receptor pathway is relatively insufficient. The theoretical aspect is not yet systematic and mature, it is still in the preliminary research stage. The experimental scheme is not perfect, and the sample size is limited. We also fail to face the above research from the genetic level. These defects will become our future research direction.