Effects of a new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo(1,2-a)pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020) on contractile force and cyclic AMP metabolism in canine ventricular muscle.

Abstract

Abstract-E-1 020, a newly synthesized imidazopyridinylpyridine or imidazopyridine derivative (structurally closely related to the bipyridine derivative milrinone) in creased the force of contraction and cyclic AMP levels in a concentration-dependent manner in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37°C. The concentration-response curve for the increase in force of contraction by E-1020 was biphasic. The maximal positive inotropic effect (PIE) of E-1020 is comparable to that of milrinone, and its potency is 3-fold less than that of milrinone, but 10-fold higher than that of amrinone. The time course of increases in force of contraction induced by E-1020 was coincident with that of cyclic AMP accumulation. The concentration-response curve for the PIE of E-1020 was superimposable to that of cyclic AMP accumulation. A Q-adrenoceptor antagonist, (±)-bupranolol (3x10-7 mol/I), did not affect the PIE of E-1020. The increase in the force of contraction and accumulation of cyclic AMP produced by E-1020 were inhibited by a muscarinic receptor agonist, carbachol. The relationship between the force of contraction and cyclic AMP levels in the presence of E-1020 was not modified by addition of carbachoi or isoproterenol. E-1020 shifted the concentration-response curve for isoproterenol to the left. E-1020 shortened the total duration of contraction and relaxation time of isometric contractions. These findings indicate that cyclic AMP is essentially involved in the PIE of E-1020 on the canine ventricular muscle, although the possible involvement of a cyclic AMP independent mechanism can not be excluded.

Signal Transduction and Ca2+ Signaling in Intact Myocardium

“…Phosphodiesterase (PDE) inhibitors elicit the positive inotropic effect via a mechanism similar to that of β-adrenoceptor stimulation because they act by activation of the cAMP/ PKA signaling pathway (27 -43). A number of agents such as papaverine (27,28), cilostamide and isobutylmethylxanthine (29), amrinone (30), milrinone (32), vesnarinone (31), OPC-8490 (36), ZSY-39 (33), Ro-1724 (34), olprinone (35), Y-20487 (37), and UK-1745 (38) belong to the same family, which induce a positive inotropic effect by themselves and are able to enhance the effect of β-adrenoceptor stimulation (except UK-1745). Some of them are very effective in the treatment of cardiac pump dysfunction in acute and decompensated heart failure (39 -43).…”

Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors

“…PDEIII-Is cause a prompt increase in cAMP in cardiomyocytes, which is maximized within 10 minutes, 3 followed by a rapid activation of PKA. Furthermore, PKA activation is reported to cause sufficient augmentation of p38 MAPK activity through a protein tyrosine phosphatase, completely independently of PKC activation.…”

“…3 The former effect reduces vascular resistance, and the latter increases myocardial contractility to improve hemodynamic status, 4 with less cardiac oxygen demand than catecholamines. 5 It has been shown, 6 however, that long-time exposure to either inotropic or cardiotonic agents fails to provide any better outcomes.…”

“…6 Treatment with PDEIII-Is or catecholamines increases intracellular calcium levels ([Ca 2ϩ ] i ) in cardiomyocytes. 3 We have reported that a transient increase in myocardial [Ca 2ϩ ] i mimics the infarct size limitation by ischemic preconditioning via protein kinase C (PKC) activation. 11 Therefore, transient pretreatment with PDEIII-Is may reduce infarct size, which may be mediated through the transient increase in intracellular cAMP or [Ca 2ϩ ] i and PKC activation.…”

Synthesis of 4,6-dimethyl-3-cyano-2-pyridone catalysed by amino acids

“…Polazeći od derivata 2-piridona kao kuplujuće komponente sintetisane su različite serije azo boja i pigmenata sa odličnom sposobnošću bojenja sintetičkih vlakana [1,2]. Osim toga 2-piridonski prsten predstavlja deo strukture i biološki aktivnih jedinjenja pri čemu je jedan od derivata identifikovan kao inhibitor reverzne transkriptaze HIV-1 virusa [3], dok su derivati sa kardiotoničnom i kardiovaskularnom aktivnošću komercijalizovani kao lekovi Milrinone ® i Amrinone ® [4,5].Zbog raznovrsnosti primene jedinjenja koja u svojoj strukturi sadrže 2-piridinsko jezgro razvijen je izvestan broj različitih sinteza. Kada je u pitanju hemijska sinteza može se naći nekoliko pristupa, a mehanizmi se razvrstavaju prema veličini fragmenata ugljenikovog niza od kojih sinteza počinje [6].…”