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 pr oduction of the second-messenger substance cyclic AMP and exert a posi tive inotropic action on rat ventricle in vitro, a direct action of th ese peptides on cardiomyocytes has not been established. In contrast t o hearts of other mammalian species, which possess VIP-preferring rece ptors, rat heart is unique in that the existence of a ''relatively non selective receptor'' at which both secretin and VIP may bind has been proposed. We wished to define the receptor(s) for secretin and VIP pre sent on rat ventricular cardiomyocytes using a homogenous suspension o f viable cells. With adenosine deaminase 5 U/ml and the phosphodiester ase (PDE) inhibitor isobutyl methylxanthine (IBMX) 1 mM, both secretin and VIP increased intracellular levels of cyclic AMP maximally and co ncentration dependently after 5 min: EC(50) values were 8 and 58 nM, r espectively. At maximally effective concentrations, secretin 1 mu M in creased intracellular levels of cyclic AMP fourfold above basal levels , whereas a 1.6-fold increase was induced by VIP 10 mu M. Maximum chan ges in cell length (dL) of isolated cardiomyocytes during electrically stimulated (0.5 Hz) contractions were determined in the presence of a denosine 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 n M increased the amplitude of cellular contractions maximally to a valu e 37% greater than that obtained without peptide, VIP 20 nM increased the amplitude of cellular contractions maximally to a value 19% greate r than that obtained without peptide. The EC(50) values were 470 and 7 00 pM for VIP and secretin, respectively. The selective antagonist at VIP-preferring receptors, 4-Cl DPhe-6 Leu-17 VIP 10 mu M did not antag onise the actions of VIP. In the presence of the selective antagonist at receptors for secretin, secretin 7-27 greater than or equal to 10 m u M, the concentration dependence of the effect of secretin on accumul ation of cellular cyclic AMP and contractile amplitude displayed a rig htward parallel shift: the pA2 value for secretin 7-27 was 4.96. Secre tin 7-27 also induced a rightward parallel shift of the concentration dependence of the actions of VIP. VIP 10 mu M was additive with low co ncentrations 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 respons e to low concentrations of secretin (<1 nM), but antagonised the respo nse at higher concentrations of secretin (>1 nM). In rat ventricular c ardiomyocytes, secretin and VIP directly stimulate a potent contractil e response that may be due to accumulation of cyclic AMP in these cell s. Rat ventricular cardiomyocytes are devoid of VIP-preferring recepto rs, and VIP behaves as a partial agonist at nonselective receptors on these cells.