Abstract
There are studies which indicate that some fluorobenzene derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action at cardiovascular level is very confusing. To clarify these phenomena in this study, a new fluorobenzene derivative was synthesized to evaluate its biological activity on perfusion pressure and left ventricular pressure. The Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the fluorobenzene derivative [0.001 nM]. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the fluorobenzene derivative was evaluated by measuring left ventricular pressure in absence or presence of following compounds; ouabain, digoxin, levosimendan, cyclopiazonic acid and thapsigargin. The results showed that the fluorobenzene derivative significantly increased the perfusion pressure and coronary resistance in comparison with the control conditions. Additionally, other data indicate that fluorobenzene derivative increase perfusion pressure in a form similar to ouabain and digoxin; however, this effect was different compared with levosimendan. Other results showed that biological activity induced by the fluorobenzene on left ventricular pressure was significantly inhibited by both cyclopiazonic acid [50 mM] and thapsigargin [300 mM]. These data suggest that positive inotropic activity induced by the fluorobenzene on perfusion pressure and left ventricular pressure was via changes of biological activity both Na,K-ATPase and Ca+2-ATPase. This phenomenon is a particularly interesting because the positive inotropic activity induced by this fluorobenzene derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.
Highlights
Congestive heart failure is one of the main health problems worldwide [1,2,3]
This has led to studies comparing the effect of dobutamine with levosimendan; the results showed an improvement in hemodynamic function with levosimendan compared to the group treated with dobutamine [10]
Other data showed a yield of 67% for the compound 3 (Fluoro-cyclobutenyl-2-ol derivative, Figure 1) with melting point of 80-82 °C. 1H NMR and 13C NMR spectra for the compound 3 are showed in the table 1
Summary
Congestive heart failure is one of the main health problems worldwide [1,2,3]. Since several years ago several drugs with positive inotropic activity have been used for the treatment of congestive heart failure [4, 5]. The use of digoxin (ATP-ase inhibitor) in patients with heart failure; its narrow therapeutic window and even slight exposure changes have been associated with adverse reactions; this has resulted in close monitoring of digoxin serum levels in patients with heart failure [6,7,8] This problem has resulted in the use of other therapeutic alternatives such as dobutamine (adrenergic agonist); its poor oral bioavailability results in this drug being administered intravenously [9]. It has been observed that high doses of levosimendan in patients with episodes of myocardial infarction may induce changes in the inotropic effect by inhibiting the activity of some phosphodiesterases [11]. The milrinone at a dose of 0.75 μg / kg per minute increased cardiac output and reduce systemic vascular resistance in patients with
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