Negative Inotropic Effect of BGP-15 on the Human Right Atrial Myocardium

Figures

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  Figure 1. An isolated-organ bath with a (white) tissue holder placed on its top (left panel), and a trabecula carnea, indicated by a double-pointed red arrow, on a finger (right upper panel) and on a tissue holder (right lower panel).

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  Figure 2. Scheme of protocols of the present study. E/c: concentration-response curve; ISO: isoproterenol; EC50: half maximal effective concentration; BGP-15: O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime hydrochloride.

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  Figure 3. The contractile force of the human right atrial samples at the end of the wash-out period after the third adenosine E/c curve. The upper panel shows the individual values (with the overall mean ± SEM, and with the mean values for the Direct and Indirect groups), while the lower panel denotes the different data sets (mean + SEM). The open columns represent samples that were subjected to isoproterenol (ISO) in a later phase of the experiments. In contrast, the filled columns denote samples without any subsequent ISO treatment. E/c: concentration-response; SEM: standard error of the mean; PROP: propranolol; BGP-15: O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime hydrochloride.

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  Figure 4. The effect of adenosine (Ado) on the human right atrial samples (based on the third adenosine concentration-response (E/c) curve), not stimulated (Direct group) or stimulated (Indirect group) with isoproterenol (ISO) in a later phase of the experiments. The axis x shows the common logarithm of the molar concentration of adenosine, and the axis y denotes the effect as a percentage decrease of the initial contractile force. (As any ISO treatment occurred subsequently, herein direct negative inotropic effects are shown in each group.) The symbols represent the effect of adenosine averaged within the groups or subgroups (±SEM). BGP-15, PROP, Weak and Strong in the name of the subgroups refer to events occurred in a later phase of the investigation. SEM: standard error of the mean; BGP-15: O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime hydrochloride; PROP: propranolol.

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  Figure 5. The effect of isoproterenol (ISO) on the human right atrial samples. The axis x shows the common logarithm of the molar concentration of ISO, and the axis y denotes the effect as a percentage increase of the initial contractile force (in addition to the original level). The symbols represent the effect of ISO averaged within the different data sets (±SEM), and, on the left panel, the individual responses of two samples (Extremely strong resp. I. and Extremely strong resp. II). The right panel shows the Indirect group and its two subgroups. Asterisks indicate the significance level of differences between responses of the two subgroups to the specific ISO concentrations (**: p < 0.01; ***: p < 0.001). SEM: standard error of the mean.

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  Figure 6. Relationship of the initial contractile force of the human right atrial samples in the Indirect group (measured in millinewton at the end of the wash-out period following the third adenosine E/c curve) with the maximal positive inotropic effect of isoproterenol (ISO) (left panel), furthermore with the potency of ISO (characterized by the negative common logarithm of the half maximal effective ISO concentration) (right panel). Closed symbols indicate samples in the Strong subgroup, whereas open symbols denote samples in the Weak subgroup. Dotted lines show the fitted linear function, while dotted curves represent the 95% confidence interval bands. (Since, there was no statistically significant correlation between parameters indicated in the panels, regression lines and bands are only illustrations).

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  Figure 7. The effect of BGP-15 (upper and left panels) and propranolol (PROP) (upper and right panels) on the human right atrial samples without (Direct group) or with (Indirect group) a previous stimulation with isoproterenol (ISO). The axis x denotes the common logarithm of the molar concentration of the chemical, and the axis y shows the effect as a percentage decrease of the initial contractile force. The symbols represent the effect averaged within the groups (±SEM). The “Direct group” in the left panel and the right panel means the BGP-15 subgroup and the PROP subgroup, respectively. Of course, the “Indirect group” always refers to the whole Indirect group. Asterisks indicate the significance level of differences between responses of the groups (*: p < 0.05; **: p < 0.01). SEM: standard error of the mean; BGP-15: O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime hydrochloride.

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  Figure 8. The effect of BGP-15 (left panel) and propranolol (PROP) (right panel) on the human right atrial samples subjected to a previous isoproterenol (ISO) stimulation (Indirect group), dichotomized according to the response to ISO (weak or strong) based on a previously generated ISO concentration-response (E/c) curve. The axis x denotes the common logarithm of the molar concentration of the chemical, and the axis y indicates the effect as a percentage decrease of the initial contractile force. The symbols represent the effect averaged within the (sub)groups (±SEM). Asterisks show the significance level of differences between responses of the two subgroups of the Indirect group (*: p < 0.05). SEM: standard error of the mean; BGP-15: O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime hydrochloride.

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  Figure 9. Comparison of effects of adenosine (Ado; upper panel), isoproterenol (ISO; left panel) and BGP-15 (right panel) on the human right atrial samples after dichotomization of data of the Indirect group according to the presence (DM) or absence (non-DM) of known diabetes mellitus (both types). The effect of adenosine is direct, while the effect of BGP-15 is indirect (i.e. occurred in the absence and presence of ISO, respectively). The axis x shows the common logarithm of the molar concentration of the agent in question, and the axis y indicates the effect as a percentage decrease (Ado, BGP-15) or increase (ISO) of the initial contractile force. The symbols represent the effect values averaged within the data sets (±SEM). Asterisks show the significance level of differences between responses of the diabetic (DM) and non-diabetic (non-DM) data sets of the Indirect group (*: p < 0.05; **: p < 0.01). SEM: standard error of the mean; BGP-15: O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime hydrochloride.