Background
Postoperative obstructive jaundice is associated with multiple organ dysfunction syndrome [
1‐
3]. Specifically, the cardiovascular instability caused by defects in myocardial performance and vascular reactivity is thought to be an important mechanism in the pathophysiology of multiple organ dysfunction syndrome [
4,
5]. In 1986, Green [
5] reported impaired left ventricular performance in dogs with cholemia, and called this hepatic cardiomyopathy "jaundiced heart"[
4]. The jaundiced heart is also characterized by defective vascular reactivity attributed to altered beta-adrenergic receptor signaling [
6], membrane fluidity, and down regulation of cardiac beta-adrenoceptor density and affinity [
7].
Propofol is a widely employed intravenous anesthetic used to induce and maintain anesthesia. It is characterized by rapid onset/offset of effect and rapid elimination from the body [
8,
9]. However, propofol can also induce cardiovascular depression, manifested primarily by decreased arterial blood pressure [
10] due to inhibition of the sympathetic nervous system [
11], a negative inotropic effect [
12], and reduced preload [
13].
The effect of propofol on myocardial performance in patients with obstructive jaundice is unclear. Therefore, in the present study, 7-day bile duct ligation (BDL) was used as a model of obstructive jaundice to evaluate the effect of propofol on cardiac function in vivo. In ex vivo experiments, the direct effects of propofol on the isolated heart of BDL rats were assessed to exclude the vasodilator effect of propofol and the associated neurohormonal adaptation in vivo [
14,
15].
Discussion
In the present study, we could not confirm impaired cardiac performance in a rat model of obstructive jaundice because the in vivo and ex vivo results were inconsistent. However, an important and novel finding is that the inhibitory effects of propofol on myocardial function were comparable in rats that underwent BDL and rats that underwent the sham operation at low and intermediate doses (12.5 and 25 μmol/L). At the highest dose of propofol tested (50 μmol/L), stronger effects on cardiac function were observed in rats with obstructive jaundice.
A propofol concentration of 2 to 4 μM was clinically relevant according to a previous study [
19], and researchers proved that higher than > 10 μM propofol in vitro might cause cardiovascular depression [
20]. To compare the hemodynamic effects of propofol between cholestatic rat hearts and controls, we use d relatively high concentrations (12.5, 25, and 50 μmol/L) of propofol ex vivo because propofol at < 10 μM did not suppress the KATP channel or display a myocardial depression effect [
21]. The present study did not confirm our hypothesis that propofol depresses myocardial performance in the jaundiced heart compared with the normal, healthy heart. This finding may be attributed to a number of factors. First, most animal and human studies have shown that propofol induces dose-dependent cardiovascular depression. Furthermore, clinically relevant concentrations of propofol do not significantly depress myocardial contractility and evidence suggests that its pharmacological properties may be due in part to enhanced sensitivity of the myofilaments to Ca
2+, despite reduced uptake of Ca
2+ uptake into the sarcoplasmic reticulum [
22,
23]. Moreover, propofol is a cardioprotective agent and may protect the myocardium from injury such as that caused by ischemia-reperfusion [
24,
25]. Inhibition of the mitochondrial permeability transition pore is a recently reported mechanism underlying the protective action of propofol on the myocardium [
24,
26]. In addition, accumulation of bile acids is a causative factor for jaundiced heart [
5]. Bile acids exert negative chronotropic and inotropic effects on the heart via mitochondrial damage [
12,
27]. These factors especially the enhanced sensitivity of the myofilaments to Ca
2+ and the inhibition of the mitochondrial permeability transition pore, may protect against cardiovascular depression and account for the minimal responsiveness of BDL-treated rats to low and intermediate concentrations of propofol.
Another interesting observation was the opposite in vivo and ex vivo results of basal cardiac contractility in the BDL group. In the ex vivo experiments, hearts from the BDL-treated rats exhibited impaired contractility and a reduction in the maximum pressure in the left ventricle, whereas BDL-treated rats showed significantly increased LVSEP, +dP/dt
max and -dP/dt
max in vivo. The mechanism underlying this phenomenon is unclear, but may involve neural or humoral adaptations. Dabagh [
28] reported increased concentrations of norepinephrine and epinephrine during the development of cholestasis. Poo [
29] found elevated renin and angiotensin II at 1 week after establishment of obstructive jaundice in rats. In our in vivo experiments, increased LVSEP, +dP/dt
max and -dP/dt
max , were associated with myocardial contractility, suggesting up regulation of the sympathetic nervous system. In addition, LVEDP which directly relates to the cardiac preload might remain unchanged possibly not owing to the depletion of body fluid in obstructive jaundice [
30,
31]. However, the lower heart rate may be caused in part by accumulated bile acids, which impair cardiac function by affecting calcium uptake from the sarcoplasmic reticulum [
32,
33]. Recent research has focused on the overproduction of nitric oxide, which results in bradycardia after BDL [
34,
35]. Despite enhanced cardiac contractility in vivo, our experiment showed that a high dose of propofol produced stronger inhibition of cardiac function in BDL-treated rats, unmasking latent cardiac dysfunction. These results are consistent with those of previous studies reporting that BDL-treated rats show hemodynamic instability [
5].
There are also limitations in our study. To assess left ventricular inotropism, three load-dependent indices of left ventricular contractility (LVESP, LVEDP, and ± dP/dt
max ) were used. It must be underscored that these indices may also be influenced by left ventricular loading conditions [
36]. Load-independent indices of left ventricular contractility, such as construction of pressure-volume curves in both systole and diastole would greatly enhance the validity and interpretation of our results. It would enable more specific measurement of the left ventricular performance independent of both loading conditions and HR [
37]. Thus, the data of our study must be interpreted with caution when using propofol at mild to intermediate doses in obstructive jaundice.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
HR: data mining and analysis in fulfillment of his MD thesis. LY and ZL: idea, experimental design and part of animal studies. CC and KT: conception and help with statistics. CC: conception writing of the paper. JS and WC: ex vivo experiment. WY: idea, experimental design and part of animal studies. All authors read and approved the final version of the manuscript.