Positive and negative contractile effects of neuropeptide Y on ventricular cardiomyocytes

Abstract

The potency of neuropeptide Y (NPY) to cause negative and positive contractile responses in rat ventricular cardiomyocytes was investigated. In these cells, NPY was found to activate the transient outward K+ current (Ito) and the slow inward Ca2+ current (Isi). As reported before (H. M. Piper, B. C. Millar, and J. R. McDermott, Naunyn Schmiedeberg's Arch. Pharmacol. 340: 333-337, 1989), NPY attenuated the increase in the contractile response induced by isoprenaline (10(-7) M). This effect of NPY could be abolished by 1) the presence of the inhibitor of Ito, 4-aminopyridine (4-AP, 0.5 mM); 2) pretreatment of the cells with pertussis toxin (1 microgram/ml for 6 h); and 3) the presence of the 19-amino acid COOH-terminal fragment of NPY, NPY-(18-36) (10(-6) M). In the absence of isoprenaline, but in the presence of 4-AP, NPY exerted a stimulatory effect on the cardiomyocytes. This effect could be abolished 1) by using the inhibitor of the Isi, verapamil (10(-8) M), but not 2) by pretreatment with pertussis toxin, nor 3) by coincubation with NPY-(18-36). The results indicate that in the rat the antiadrenergic negative contractile effect of NPY results from its action on the Ito. Blockade of this current by 4-AP unmasks a positive contractile effect of NPY that is related to activation of the Isi.

Induction of Hypertrophic Responsiveness of Cardiomyocytes to Neuropeptide Y in Response to Pressure Overload

“…NPY is predominantly found as a cotransmitter with noradrenaline in the sympathetic innervation, although an appreciable amount of NPY is localized separately in intrinsic myocardial neurons (McDermott et al, 1993) and non-neuronal sources, including platelets (Ogawa et al, 1992) and cardiomyocytes (Millar et al, 1991). PYY 3-36 represents a major molecular form of PYY in human plasma (Grandt et al, 1992).…”

Modulation of Contractile Function through Neuropeptide Y Receptors during Development of Cardiomyocyte Hypertrophy

“…Use of the selective Y 2 receptor agonists, PYY 3-36 and NPY , inferred Y 2 receptor involvement (McDermott et al, 1997), but the finding that long C-terminal fragments of both PYY and NPY also exhibit high affinity for the Y 5 receptor subtype (Hu et al, 1996) emphasizes the need for clarification of receptor subtypes involved in NPY-stimulated cardiomyocyte contraction. NPY alone does not influence the basal level of contraction of cardiomyocytes, but in the presence of 4-aminopyridine, which selectively inhibits I to in these cells, a positive response to NPY is unmasked (Millar et al, 1991). This has been observed also in chicken cardiomyocytes in the absence of rectifier current blockade (Jacques et This work was supported by the British Heart Foundation.…”

“…Ventricular cardiomyocytes were isolated from spontaneously hypertensive rats (SHRs) pre-LVH (12 weeks), during development (16 weeks Mammalian myocardium contains large quantities of neuropeptide Y (NPY) (Onuoha et al, 1999), mainly colocalized with noradrenaline in perivascular sympathetic neurons innervating cardiac tissue (Franco-Cereceda et al, 1985;Allen et al, 1986). NPY has been implicated in left ventricular hypertrophy (LVH), an initial compensatory response of the heart to pressure overload precipitated by hypertension (Agabiti-Rosei and Muiesan, 2001) because increased plasma levels of the peptide are found in hypertension, myocardial infarction, and heart failure (Maisel et al, 1989) and correlate with severity of LVH (Hulting et al, 1990).NPY can both decrease and increase the contractile response of electrically stimulated rat ventricular cardiomyocytes (Piper et al, 1989;Millar et al, 1991). The negative effect, observed in isoproterenol-treated cells, is due primarily to stimulation of the transient outward current (I to ) and mediated through an inhibitory G protein/adenylate cyclase pathway (Kassis et al, 1987;Piper et al, 1989;Millar et al, 1991).…”

“…NPY can both decrease and increase the contractile response of electrically stimulated rat ventricular cardiomyocytes (Piper et al, 1989;Millar et al, 1991). The negative effect, observed in isoproterenol-treated cells, is due primarily to stimulation of the transient outward current (I to ) and mediated through an inhibitory G protein/adenylate cyclase pathway (Kassis et al, 1987;Piper et al, 1989;Millar et al, 1991).…”

“…The negative effect, observed in isoproterenol-treated cells, is due primarily to stimulation of the transient outward current (I to ) and mediated through an inhibitory G protein/adenylate cyclase pathway (Kassis et al, 1987;Piper et al, 1989;Millar et al, 1991). Use of the selective Y 2 receptor agonists, PYY 3-36 and NPY , inferred Y 2 receptor involvement (McDermott et al, 1997), but the finding that long C-terminal fragments of both PYY and NPY also exhibit high affinity for the Y 5 receptor subtype (Hu et al, 1996) emphasizes the need for clarification of receptor subtypes involved in NPY-stimulated cardiomyocyte contraction.…”