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Background: Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM., Methods: T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups., Results: Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ± 13.2 and 279.7 ± 17.8 mg/dL, respectively (p < 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ± 8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ± 25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ± 1.5 to 13.3 ± 2.8 mg (p < 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats., Conclusion: The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future., (Copyright © 2019. Published by Elsevier B.V.)

G protein-coupled receptors (GPCRs), such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, i.e. myocytes, fibroblasts and endothelial cells, play crucial roles in regulating cardiac function and morphology. Their importance in cardiac physiology and disease is reflected by the fact that, collectively, they represent the direct targets of over a third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of their structure, function and the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart disease therapy. Here, we review these signaling modalities employed by GPCRs known to be expressed in the cardiac myocyte membranes and to directly modulate cardiac contractility. We also highlight drugs and drug classes that directly target these GPCRs to modulate cardiac function, as well as molecules involved in cardiac GPCR signaling that have the potential of becoming novel drug targets for modulation of cardiac function in the future., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Milrinone (Win 47203) is a dipyridine related to amrinone, which is about 20-50 times as effective as amrinone when assayed on cardiac contractility. In dog heart-lung preparations, milrinone in a concentration of 0.25-0.5 microM produced a near maximal positive inotropic effect on a variety of acute heart failures. This dosage produced a minimal increase in heart rate and reduced the PR interval. Large doses of milrinone did not produce cardiac irregularities and in Nifedipine heart failure with ventricular irregularities, it eliminated these irregularities. Papaverine-induced heart failure was resistant to ouabain, epinephrine and milrinone therapy. In the presence of positive inotropic amounts of papaverine or theophylline, a pentobarbital heart failure was superimposed. This heart failure responded poorly to milrinone, although it responded to both the addition of epinephrine and ouabain. It is thus possible that milrinone, papaverine and theophylline have closely related sites of action.

Six actodigin (AY-22,241)-related semisynthetic glycosides (with the C-3 natural linkage of the lactone ring to the steroid nucleus, transposed to C-2) were assayed in failing hearts of canine heart-lung preparations. Two compounds, with additional small modifications in the steroid nucleus, were incapable of reversing heart failure. Two others, an isodigoxigenin and an isogitoxigenin derivative, were only slightly active. However, the two other actodigin-derived compounds, with methyl groups at the lactone C-4, were very active. Compound 5 had the methyl group in beta position and was 2.5 times more potent than actodigin. Compound 6, with the methyl group in alpha position, had a potency similar to that of actodigin. In the anesthetized and vagotomized dog, their toxic effects (to the point of atrioventricular dissociation) were short lasting and completely reversible. Both of these agents had a wide margin of safety (relationship between the minimal therapeutic, irregularity and lethal doses).

The antiarrhythmic efficacy of ajmaline has been evaluated in three experimental models of cardiac arrhythmias in the dog. These data have been related to the actions of the compound on several parameters of heart function and compared to results obtained in various clinical arrhythmias. Ajmaline was more effective in arrhythmias of the ectopic focus type than in the circus movement model. These results agreed with the pattern of clinical activity. The compound produced decreases in excitability and conduction and increased the functional refractory period in all heart tissues. These effects were most marked in the atrium. The drug also showed a moderate degree of anticholinergic activity. Both in the dogs and in the clinical cases, the agent showed an important hypotensive effect. In a group of experiments in which transmembrane potentials were recorded, the compound produced in all tissues a decrease in upstroke velocity and amplitude of the action potential; it also increased the duration of the action potential in atrial and ventricular muscle, but it decreased it in Purkinje fibers. The possible mechanism(s) of action of the drug is discussed in terms of the different hypotheses for cardiac arrhythmias.