Testing conception of engagement of imidazoline receptors in imidazoline drugs effects on isolated rat heart atria.

Recently, attention has been payed to the role of imidazolines in physiology of the heart. However, no systematic comparative studies were reported regarding the activity of a representative set of specific ligands towards imidazoline receptors in the heart preparations. The aim of this project was to test effects of a set of ligands on the pharmacological function of putative imidazoline receptors in isolated rat heart atria. Known imidazoline drugs with a postulated high affinity to imidazoline I(1) receptor: AGN192403, rilmenidine, moxonidine and clonidine were used. The specific ligands of imidazoline I(2) receptor: 2-BFI, BU239 and putative natural ligand for imidazoline I(1), I(2) and I(3) receptors, agmatine, were tested also. The spontaneously beating right and left atria, driven electrically, were studied. Dose-response curves for amplitude and rate of the contractions of the atria were produced by administration of increasing doses of the agents. Phentolamine as alpha(1)/alpha(2) adrenergic receptors blocker and idazoxan as I(2)/I(1)/alpha(2) receptors blocker were added in order to inhibit ino- and chronotropic effects of the compounds studied. The -log EC(50) parameters were calculated. The positive inotropic effect on left atria were evoked with the rank order of potency: agmatine >> clonidine > BU239 > rilmenidine > or = moxonidine and these effects were generally diminished by idazoxan. Moxonidine produced a weak positive inotropic effect potentiated by idazoxan. Rilmenidine and moxonidine were assumed to act as partial agonists of imidazoline I(1) receptor. AGN192403 did not change the amplitude of beating of left atria. The positive chronotropic effects on spontaneously beating right heart atria were with in the following order of potency: BU239 > or = agmatine >>> clonidine > AGN192403. Idazoxan markedly antagonized chronotropic effect of both BU239 and agmatine. 2-BFI weakly diminished the rate of beating of atria; moxonidine and rilmenidine had no effect. In conclusion, imidazoline receptors of the I(1) subtype may be involved in inotropic reaction of the agents studied, but this effect depends mainly on the alpha(2)/alpha(1) adrenergic receptors. Engagement of I(2) imidazoline receptors, along with the alpha(2) adrenergic ones, in chronotropic activity of isolated right atria of rat has been demonstrated.