Abstract
Hippocampal cholinergic neurostimulating peptide (HCNP), which derives from phosphatidylethanolamine-binding protein (also named Raf kinase inhibitor protein), enhances acetylcholine synthesis in the hippocampal medial septal nuclei. It is present in the chromaffin secretory granules of the adrenal cells and under stress is cosecreted with peptide hormones and catecholamines. Using the isolated rat heart perfused according to Langendorff to reveal the cardiotropic action of HCNP on the mammalian heart, we showed that rat HCNP exerts, at concentrations of 5 × 10-13 to 10-6 M, a negative inotropism under basal conditions (left ventricular pressure variations ranging from -8.34 ± 0.94% to -21 ± 3.5%) and enhances the cholinergic-mediated negative inotropy through direct interaction with G-protein-coupled muscarinic receptor pathway. Under adrenergic stimulation (isoproterenol), the peptide exerts an antiadrenergic action. The analysis of the percentage of rate pressure product variations in terms of EC50 values of isoproterenol alone (-8.5 ± 0.3; r2 = 0.90) and in the presence of rat HCNP at 0.01 nM (-6.9 ± 0.36; r2 = 0.88) revealed a competitive type of antagonism of the peptide. HCNP does not affect either heart rate or coronary pressure. The evidence that HCNP in mammals may play a novel role as an inhibitory cardiac modulator throughout an involvement of the myocardial G-protein-coupled receptor pathway provides new insights regarding the neurohumoral control of heart function under normal and physiopathological conditions.
Footnotes
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This work was supported by MURST 60% (to B.T. and M.C.C.), by the “Dottorato di Ricerca in Biologia Animale” (to T.A.), by the Egide Program (Galilée; to B.T., T.A., and M.C.C.), and by the Vinci Program (to T.A.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.102103.
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ABBREVIATIONS: HCNP, hippocampal cholinergic neurostimulating peptide; ACh, acetylcholine; PEBP, phosphatidylethanolamine-binding protein; ISO, isoproterenol; KHs, Krebs-Henseleit solution; PTx, pertussis toxin; AFDX116, 11-((2-diethylamino)methyl)-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyrido(2,3-b)(1-4) benzodiazepine-6-one; rHCNP, rat HCNP; HR, heart rate; LVP, left ventricular pressure; LVP, left ventricular pressure; RPP, rate pressure product; +(LVdP/dt)max, maximal rate of left ventricular pressure contraction; CP, coronary pressure; ANOVA, analysis of variance.
- Received January 31, 2006.
- Accepted April 6, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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