Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr 1 )apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr 1 )apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170

Apelin receptor in GtoPdb v.2023.1

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [73] and subsequently updated [75]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36, apelin-13 and [Pyr1]apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) [88]. A second family of peptides discovered independently and named Elabela [13] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [97, 71]. The enzymatic pathways generating biologically active apelin and Elabela isoforms have not been determined but both propeptides include sites for potential proprotein convertase processing [81]. Structure-activity relationship Elabela analogues have been described [65, 90]. The stoichiometry of apelin receptor-heterotrimeric G protein complexes has been studied using cryogenic-electron microscopy [98]

Ghrelin receptor in GtoPdb v.2021.3

The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [19]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [74]. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin with equipotent biological activity [49]. A unique post-translational modification (octanoylation of Ser3, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [133] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [58]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [44]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [35, 68] inhibits ghrelin receptor-induced GH secretion and food intake [35]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [71]. In cell systems, the ghrelin receptor is constitutively active [45], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [93]

Ghrelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [18]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [70]. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin with equipotent biological activity [48]. A unique post-translational modification (octanoylation of Ser3, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [127] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [56]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [43]. In cell systems, the ghrelin receptor is constitutively active [44], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [88]

Ghrelin receptor in GtoPdb v.2023.1

The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [19]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [75]. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin with equipotent biological activity [50]. A unique post-translational modification (octanoylation of Ser3, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [134] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [59]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [45]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [36, 69] inhibits ghrelin receptor-induced GH secretion and food intake [36]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [72]. In cell systems, the ghrelin receptor is constitutively active [46], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [94]

Apelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [68]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36, apelin-13 and [Pyr1]apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [80]. A second family of peptides discovered independently and named Elabela [11] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [87, 67]. Structure-activity relationship Elabela analogues have been described [61]

Apelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [68]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36, apelin-13 and [Pyr1]apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [80]. A second family of peptides discovered independently and named Elabela [11] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [87, 67]. Structure-activity relationship Elabela analogues have been described [61]

Vascular effects of apelin in vivo in man

ObjectivesThis study was designed to establish the direct vascular effects of apelin in vivo in man.BackgroundApelin is the endogenous ligand for the previously orphaned G-protein–coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation.MethodsVascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a “nitric oxide clamp” (nitric oxide synthase inhibitor, L-NG-monomethylarginine [8 μmol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo.ResultsAlthough sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr1)apelin-13–mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7).ConclusionsAlthough having no apparent effect on venous tone, apelin causes nitric oxide–dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis