Abstract
Cardiovascular morbidity and mortality carry great socioeconomic burden worldwide that mandates the development of new, efficacious therapeutic agents with limited adverse effects. O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime (BGP-15) is a known, well-tolerable drug candidate that exerts beneficial effects in several disease models. As BGP-15 has a significant structural similarity with propranolol, it arose that BGP-15 might also have a direct effect on the heart. Thus, in the present work, we investigated the effect of BGP-15 and propranolol on the contractility of isolated, paced, human right atrial samples (obtained from patients undergone open-heart surgery), with or without previous isoproterenol (ISO) stimulation (evoking an indirect or direct effect, respectively). We found that both BGP-15 and propranolol exerted direct as well as indirect negative inotropic effects on the atrial myocardium, reaching similar maximal response. However, BGP-15 had considerably smaller potency than propranolol regarding both types of negative inotropy. In addition, BGP-15, in contrast to propranolol, had a significantly greater indirect negative inotropic effect on samples exhibiting strong response to ISO. Moreover, the indirect negative inotropic effect of BGP-15 was significantly greater on samples derived from diabetic patients than on samples obtained from non-diabetic ones. Our results suggest that the enhanced ISO sensitivity is associated with the diabetic state, and BGP-15 exerts greater negative inotropic effect on the human atrial myocardium in both conditions (as compared to the atrial tissue that is not ISO oversensitive and/or diabetic). Additionally, the negative inotropic effects of BGP-15 and propranolol seem to be mediated by in part different molecular pathways in the atrial myocardium.
Highlights
The prevalence of cardiovascular diseases (CVDs)—including high blood pressure, atrial fibrillation (AF), and heart failure—is continuously increasing worldwide, predominantly in the developed countries
The major finding of the present study is that BGP-15, a derivative of the non-selective β-blocker propranolol, exerted both direct and indirect negative inotropic effects on the ex vivo human right atrial myocardium
The negative inotropy elicited by BGP-15 can be characterized with a considerably smaller potency than that exerted by propranolol, they possess practically the same maximal value
Summary
The prevalence of cardiovascular diseases (CVDs)—including high blood pressure, atrial fibrillation (AF), and heart failure—is continuously increasing worldwide, predominantly in the developed countries. Improper (e.g., sedentary) lifestyle, stress, and obesity all contribute to the likelihood of developing CVDs [1]. In 2014, every third person older than 20 years suffered from high blood pressure in the USA. In 10 years (until 2015), the mortality rate attributable to high blood pressure increased by 10.5%, showing a deteriorating trend [1]. Beyond prevention, the therapy of CVDs must be addressed. Most of the widely available therapeutic options have limited efficiency or are accompanied by several undesirable effects [2,3,4]
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