Secretin and vasoactive intestinal peptide are potent stimulants of cellular contraction and accumulation of cyclic AMP in rat ventricular cardiomyocytes.
Although secretin and vasoactive intestinal peptide (VIP) stimulate production of the second-messenger substance cyclic AMP and exert a positive inotropic action on rat ventricle in vitro, a direct action of these peptides on cardiomyocytes has not been established. In contrast to hearts of other mammalian species, which possess VIP-preferring receptors, rat heart is unique in that the existence of a "relatively nonselective receptor" at which both secretin and VIP may bind has been proposed. We wished to define the receptor(s) for secretin and VIP present on rat ventricular cardiomyocytes using a homogeneous suspension of viable cells. With adenosine deaminase 5 U/ml and the phosphodiesterase (PDE) inhibitor isobutyl methylxanthine (IBMX) 1 mM, both secretin and VIP increased intracellular levels of cyclic AMP maximally and concentration dependently after 5 min: EC50 values were 8 and 58 nM, respectively. At maximally effective concentrations, secretin 1 microM increased intracellular levels of cyclic AMP fourfold above basal levels, whereas a 1.6-fold increase was induced by VIP 10 microM. Maximum changes in cell length (dL) of isolated cardiomyocytes during electrically stimulated (0.5 Hz) contractions were determined in the presence of adenosine deaminase 2.5 U/ml. Under these conditions, both secretin and VIP produced a concentration-dependent positive contractile response that became maximal 5 min after addition of the peptide. Secretin 50 nM increased the amplitude of cellular contractions maximally to a value 37% greater than that obtained without peptide. VIP 20 nM increased the amplitude of cellular contractions maximally to a value 19% greater than that obtained without peptide. The EC50 values were 470 and 700 pM for VIP and secretin, respectively. The selective antagonist at VIP-preferring receptors, 4-Cl DPhe-6 Leu-17 VIP 10 microM did not antagonise the actions of VIP. In the presence of the selective antagonist at receptors for secretin, secretin 7-27 > or = 10 microM, the concentration dependence of the effect of secretin on accumulation of cellular cyclic AMP and contractile amplitude displayed a rightward parallel shift: the pA2 value for secretin 7-27 was 4.96. Secretin 7-27 also induced a rightward parallel shift of the concentration dependence of the actions of VIP. VIP 10 microM was additive with low concentrations of secretin (< 10 nM) in stimulating production of cyclic AMP but antagonised this response at higher concentrations of secretin (> 10 nM). Similarly, VIP 2 and 20 nM enhanced the contractile response to low concentrations of secretin (< 1 nM), but antagonised the response at higher concentrations of secretin (> 1 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
Bell
D
D
Department of Therapeutics and Pharmacology, Queen's University of Belfast, Northern Ireland.
McDermott
B J
BJ
D000818:Animals; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012633:Secretin / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013552:Swine; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
D012633:Secretin; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP