Role of adrenergic receptors in shock

Abstract

Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)—hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02 mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets.

Centhaquine Increases Stroke Volume and Cardiac Output in Patients with Hypovolemic Shock

“…These findings align with studies in animal models of hypovolemic shock[10; 11; 23; 24; 25], leading to increased venous return, CO, MAP, and tissue perfusion and underscore the significance of venous return in managing shock[26], with centhaquine targeting this through α2B-AR agonism. Thus, the current study and other studies[22; 23; 24] highlight the importance of venous return for treating shock.…”

“…Interestingly, ARs are distributed distinctly in the arterial and venous systems and play a key role in coordinating the arterial and venous circulation. Most arteries and large veins (e.g., vena cava) are mainly regulated by α1/α2-ARs, while peripheral veins are regulated by α2B-ARs[25; 31; 32; 33]. The high abundance of α2B-ARs in the peripheral veins highlights their involvement in the constriction of these peripheral veins.…”

Acute hepatic rupture causing hemoperitoneum in a dog with anaphylaxis

“…However, once administered, no change in cardiovascular status ensued. It is considered likely that maximal sympathetic receptor stimulation was already present in an attempt to compensate for the patient's shock state (Geevarghese et al., 2023 ). Given the ultimate findings in this case, it is considered unlikely that administration of epinephrine alone would have produced cardiovascular stabilization of the patient, however, it is possible that stabilization might have been achieved with its more timely use in combination with the other treatments administered sooner.…”

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

“…We found that MCAO/R-injured rats had increased cell apoptosis in the cortex and hippocampus, as well as increased expression of Caspase-3 and p53, demonstrating that Caspase-3 and p53 expression levels are closely related to ischemic injury-caused neural apoptosis. α2-adrenergic receptors (α2-ARs) mediate various physiological functions, such as regulation of blood perfusion and oxygen supply (Geevarghese et al, 2023). There are three subtypes of α2-ARs distributed in the body, namely, α2A, α2B, and α2C, which are principally associated with presynaptic neurons and regulate the activity and neuronal release of norepinephrine (Alekseev et al, 2019;Lähdesmäki et al, 2004).…”