Three ghrelin receptor agonists rapidly lowered blood pressure in rats through a novel vascular receptor that is distinct from the known GHSR1a ghrelin receptor and is not activated by ghrelin itself.
Novel vascular receptor identifiedThree ghrelin receptor agonists lowered blood pressure through a receptor that is NOT the known ghrelin receptor — the effect wasn't blocked by ghrelin antagonists and wasn't mimicked by ghrelin itself.
What the researchers found
Three GHSR1a agonists (ulimorelin, capromorelin, CP464709) caused rapid blood pressure decreases in anesthetized rats. This effect was NOT blocked by GHSR1a antagonists (JMV2959 or YIL781) at doses that blocked other ghrelin receptor effects. Neither ghrelin nor unacylated ghrelin mimicked the hypotensive effect. The blood pressure drop preceded changes in sympathetic nerve activity and was not reduced by ganglionic blockade or baroreceptor denervation, indicating a direct vascular mechanism. Ulimorelin relaxed isolated mesenteric artery and aorta segments, with relaxation also resistant to GHSR1a antagonists. These findings indicate a novel vascular receptor activated by small-molecule GHSR1a agonists but not by the peptide ghrelin.
Why it matters
This study reveals that some drugs designed to target ghrelin receptors (for appetite stimulation or GI motility) have unexpected cardiovascular effects through a completely different receptor system. This matters for drug safety — blood pressure drops are a clinically important side effect. It also identifies a new blood vessel receptor that could become a target for blood pressure medications, potentially opening a novel therapeutic avenue for hypertension.
How the study worked
In vivo blood pressure studies in anesthetized rats using direct arterial monitoring, with pharmacological antagonism (JMV2959, YIL781), ganglionic blockade (hexamethonium), and sino-aortic denervation. Ex vivo relaxation studies on isolated rat mesenteric artery and aorta segments. In vitro GHSR1a activation assays in transfected HEK293 cells confirming drug potency at the known receptor. Multiple agonists and antagonists used to dissect the pharmacology.
What this study cannot tell us
The study was conducted entirely in rats, and the novel receptor has not been identified or characterized molecularly. The blood pressure effects were studied under anesthesia, which may alter cardiovascular pharmacology. The receptor identity remains unknown — it could be a known receptor with unexpected pharmacology or a truly novel entity. Translation to human cardiovascular physiology is uncertain. The study used only small-molecule agonists; a broader panel of ghrelin-related peptides was not tested.
How to read the evidence
This is a rigorous preclinical pharmacology study using multiple complementary approaches (in vivo, ex vivo, in vitro) with appropriate controls and antagonists. The novel receptor claim is well-supported by the pharmacological evidence. However, the receptor has not been molecularly identified and findings are limited to rats.
When this study was published
Published in 2014 in the British Journal of Pharmacology, this study made a fundamental pharmacological discovery. The novel receptor it identified has yet to be molecularly characterized, leaving an open research question.
The bigger picture
The discovery of novel receptors for existing drug molecules is rare and important. This finding suggests the ghrelin signaling system is more complex than previously thought, with multiple receptor subtypes mediating different physiological effects. It parallels discoveries in other peptide systems where synthetic ligands have revealed 'orphan' or previously unknown receptors, expanding our understanding of peptide pharmacology.
Questions still open
- What is the molecular identity of this novel vascular receptor that responds to ghrelin receptor agonists but not to ghrelin itself?
- Could this receptor be a therapeutic target for developing new blood pressure-lowering drugs?
- Do ghrelin receptor agonist drugs used clinically (like relamorelin) have unrecognized cardiovascular effects through this novel receptor?
Common questions
Does ghrelin affect blood pressure?
What does the discovery of a novel ghrelin-related receptor mean?
Read the original research
Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor.
British journal of pharmacology, 171(5), 1275-86
Citation
Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela M; Ferens, Dorota; Ban, Kung; Baell, Jonathan; Nguyen, Trung V; Rivera, Leni R; Brock, James A; Furness, John B. (2014). Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor.. British journal of pharmacology, 171(5), 1275-86. https://doi.org/10.1111/bph.12527