Ghrelin and Hexarelin Reduce Infarct Size in Isolated Ischemic Rat Hearts via PKC
Background
Cardiac ischemia-reperfusion injury remains a leading cause of myocardial damage, and identifying endogenous cardioprotective mechanisms is a major research priority. GHSR (growth hormone secretagogue receptor) has been identified in cardiac tissue, yet its functional role in the heart was previously unknown. Both endogenous peptides like ghrelin and synthetic secretagogues such as hexarelin activate this receptor, making them candidates for cardiac protection independent of growth hormone secretion. Understanding whether these agents can limit infarct size through direct myocardial mechanisms — rather than systemic GH release — could open new therapeutic avenues for ischemic heart disease.
Study Design
Isolated working rat hearts were exposed to ghrelin 20 nM, hexarelin 1 µM, or MK-0677 (dose not specified in abstract) under aerobic conditions and during a protocol of 30 minutes of ischemia followed by 120 minutes of reperfusion. Infarct size was estimated using triphenyltetrazolium chloride (TTC) staining. Desacylated ghrelin served as a negative control for ghrelin's acylation-dependent activity. The protein kinase C inhibitor chelerythrine was co-administered with hexarelin to probe the mechanistic pathway. Hemodynamic performance was also assessed under aerobic baseline conditions.
Results
Under aerobic conditions, none of the secretagogues — ghrelin, hexarelin, or MK-0677 — produced any significant hemodynamic effects, indicating the compounds do not acutely alter baseline cardiac contractile performance. In the ischemia-reperfusion model, hexarelin 1 µM significantly reduced infarct size as quantified by TTC staining, establishing a clear cardioprotective signal for the synthetic peptidyl secretagogue. Ghrelin 20 nM was also protective in the same model, while desacylated ghrelin — which lacks biological activity — did not modify ischemic injury, confirming that acylation is required for cardioprotection.
The non-peptidyl secretagogue MK-0677 was entirely ineffective at reducing infarct size, dissociating
GHSRoccupancy from the cardioprotective mechanism seen with peptidyl agents.
The protein kinase C (PKC) inhibitor chelerythrine partly abolished hexarelin's protection, implicating PKC activation as a key downstream mediator of the cardioprotective effect.
Key Findings
- Hexarelin 1 µM significantly reduced infarct size after 30 min ischemia + 120 min reperfusion
- Ghrelin 20 nM was cardioprotective; desacylated ghrelin had no effect
- MK-0677 (non-peptidyl GHSR agonist) failed to reduce infarct size
- Chelerythrine (PKC inhibitor) partly abolished hexarelin's cardioprotection
- No secretagogue produced significant hemodynamic changes under aerobic conditions
Why It Matters
The cardioprotection afforded by ghrelin and hexarelin appears to be independent of growth hormone secretion, meaning GH-axis side effects are unlikely to be required for — or necessarily coupled to — the cardiac benefit. For clinicians and researchers, this positions hexarelin and ghrelin as candidates for peri-ischemic cardiac protection rather than purely as GH secretagogues. The ineffectiveness of MK-0677 despite its GHSR agonism suggests receptor-subtype selectivity or peptide-specific signaling bias is critical — stacking MK-0677 with hexarelin for cardiac ends may not be additive. Translation to humans requires significant further work; current evidence is limited to an ex vivo isolated rodent heart preparation with no in vivo pharmacokinetic data.
