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Ann Thorac Surg 2000;69:711-715
© 2000 The Society of Thoracic Surgeons

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Original Articles

Endothelin receptor pathway in human left ventricular myocytes: relation to contractility

^a Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA

Address reprint requests to Dr Spinale, Division of Cardiothoracic Surgery, Medical University of South Carolina, 114 Doughty St, Suite 625, Strom Thurmond Research Building, Charleston, SC 29403

Presented at the Forty-sixth Annual Meeting of the Southern Thoracic Surgical Association, San Juan, Puerto Rico, Nov 4–6, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Increased synthesis and release of the potent bioactive peptide endothelin-1 (ET-1) occurs during and after cardiac surgery. However, the cellular and molecular basis for the effects of ET-1 on human left ventricular (LV) myocyte contractility remains unknown.

Methods. LV myocyte contractility was examined from myocardial biopsies taken from patients (n = 30) undergoing elective coronary artery bypass. LV myocytes (n = 997, > 30/patient) were isolated using microtrituration and contractility examined by videomicroscopy at baseline and after ET-1 exposure (200 pmol/L). In additional studies, myocytes were pretreated to inhibit either protein kinase C (PKC) (chelerythrine, 1 µmol/L), the sodium/hydrogen (Na/H) exchanger (EIPA, 1 µmol/L), both PKC and the Na/H exchanger, or the ET_A receptor (BQ-123, 1 µmol/L), followed with ET-1 exposure.

Results. Basal myocyte shortening increased 37.8 ± 6.3% with ET-1 (p < 0.05). Na/H exchanger, PKC, and dual inhibition all eliminated the effects of ET-1. Furthermore, ET_A inhibition demonstrated that ET-1 effects on myocyte contractility were mediated through the ET_A receptor subtype.

Conclusions. ET-1 directly influences human LV myocyte contractility, which is mediated through the ET_A receptor and requires intracellular activation of PKC and stimulation of the Na/H exchanger.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
The endothelins are a family of 21 amino acid peptides that induce important physiologic responses, particularly in the cardiovascular system [1–3]. Specifically, endothelin-1 (ET-1) is the most potent endogenous influence with regard to changes in vascular resistance, and has been implicated to modulate myocardial contractility [1, 4]. The effects of ET-1 have been identified to occur through two distinct receptor subtypes, ET_A and ET_B [5, 6]. The ET_A receptor has been demonstrated in a number of cell types, which include smooth muscle cells and cardiac myocytes [1, 3, 5]. A high density of ET_B receptors exists on endothelial cells, but this receptor subtype has also been identified on vascular and nonvascular smooth muscle as well as on cardiac myocytes [4, 5]. While ET-1 has been shown to modulate myocardial contractile function in various multicellular animal preparations [6–8], and existence of ET_A and ET_B receptors have been demonstrated on the cardiomyocyte, the direct effects of ET-1 on normal isolated human left ventricular myocyte contractile performance has not been studied. Therefore, the first goal of the present study was to determine whether ET-1 exposure influences contractility in isolated normal human left ventricular myocytes. Furthermore, this study examined whether this effect was primarily mediated through the ET_A receptor.

While there are a number of intracellular events that occur after ET_A receptor activation, evidence has been accumulated that implicates protein kinase C (PKC) and the sodium-hydrogen (Na/H) exchanger in the signal transduction cascade after ET_A receptor activation [6–9]. A number of intracellular events are influenced by PKC activation; one of those events that may have particular relevance with regard to myocyte contractility is Na/H exchanger stimulation. The Na/H exchanger has been demonstrated to alter intracellular pH and calcium concentration, both potentially influencing myocyte contractility [7, 9]. However, whether and to what degree this signaling pathway is functional after ET_A receptor activation, and the relation to contractile performance in isolated normal human left ventricular myocytes, remains unexplored. Accordingly, the second goal of this study was to interrupt the PKC-Na/H exchanger mediated pathways after ET-1 exposure on human myocytes in order to determine if this pathway is obligatory for the effects of ET-1 upon myocyte contractility.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Isolated human left ventricular myocytes were obtained from biopsies in patients undergoing elective coronary artery bypass surgery as described previously [10]. Isolated left ventricular (LV) myocyte contractility was then examined under basal conditions by video microscopy as developed by this laboratory [10, 11]. After this, myocytes were then randomly assigned to treatment protocols in order to define the effects of ET-1 on contractility as well as the basis for these effects.

Patients and myocardial collection
Patients (n = 30) were enrolled in this study, and informed consent was obtained after approval by the Institutional Review Board of the Medical University of South Carolina (December 1994). These patients were scheduled for elective coronary artery bypass surgery, and LV function was assessed to be within normal limits by echocardiography or ventriculography as demonstrated by a mean LV ejection fraction of 50% ± 1%. The patient population was similar with respect to age (62 ± 2 years), target vessels for revascularization (4 ± 1), and preoperative medications. After routine induction of anesthesia and median sternotomy, the pericardium was opened, and a 5 x 4 x 3-mm deep epicardial biopsy of the anterior LV free wall was obtained as previously described by this laboratory [10]. Briefly, using a no. 11 scalpel, the myocardial specimen was excised and immediately placed in an ice-cold oxygenated HEPES-buffered, balanced salt solution (pH 7.4), and transferred to the isolation laboratory within 30 minutes. The biopsy site was then closed with pledgeted-supported 3-0 suture, and the coronary artery bypass surgery completed as planned. There were no complications from this biopsy procedure.

LV myocyte isolation and contractility measurements
The LV biopsies were subjected to a microtrituration isolation technique as previously described by this laboratory [10, 11]. Briefly, the LV myocardium was gently agitated in an oxygenated collagenase (400 U/mL, Type II; Worthington Biochemical Corp, Lakewood, NJ)/hyaluronidase (0.5 mg/mL; Sigma Chemical Co, St. Louis, MO) solution at 35°C. After 60 minutes, the liberated LV myocytes were suspended in oxygenated cell culture media (pH-7.4, Medium 199; Gibco BRL, Life Technologies, Rockville, MD) at 37°C. The LV myocytes were washed in the standard cell culture media four times and then suspended in fresh oxygenated media.

For contractility measurements, the isolated LV myocytes were placed in a thermostatically regulated chamber containing normothermic, oxygenated cell culture media and field stimulated at 1 Hz (S48; Astro-Med Inc, West Warwick, RI). Myocytes that displayed a homogeneous contraction profile were selected for study. The myocyte contraction profiles initially were imaged using a charge-coupled device (TM-640; Pulnix, Sunnyvale, CA), converted to a voltage signal, digitized, and input to a computer at 240 Hz (Pentium 90; Magitronic, Atlanta, GA). Parameters computed from the digitized profiles included percent shortening, velocity of shorten-ing, relengthening velocity, and time to 50% relaxation (Tau₅₀).

Experimental protocol
Basal contractile function measurements were performed, and then myocytes randomly assigned to treatment protocols, as schematically shown in Figure 1. These treatments were: (1) vehicle only; (2) the PKC inhibitor chelerythrine (1 µmol/L; LC Laboratories, Woburn, MA); (3) the Na/H exchanger inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (1 µmol/L; Sigma Chemical Co); (4) combined PKC and Na/H exchanger inhibition; or (5) the ET_A receptor antagonist BQ-123 (1 µmol/L; American Peptide Corp, Sunnyvale, CA). Contractile measurements were then performed, which provided a means to examine the effects, if any, of the inhibitors used in these studies in the absence of exogenous ET-1. After these treatment interventions, contractile function was again measured, and then myocytes were exposed to ET-1 (200 pmol/L; Sigma Chemical Co), for 1 minute, and measurements repeated. This ET-1 concentration and exposure time were selected by initial dose response studies, as well as that used previously for isolated myocyte preparations [12]. The concentrations for the inhibitors used were likewise based on previous studies or dose-response studies [7, 8, 13].

View larger version (11K): [in this window] [in a new window]   Fig 1. A schematic of the isolated human LV myocyte contractile function studies. After basal contractility measurements, LV myocytes were randomly assigned to one of five treatments protocols: (1) vehicle only; (2) PKC inhibition (PKCi); (3) Na/H exchange inhibition (Na/Hi); (4) PKCi + Na/Hi; or (5) ETA receptor blockade (ETAi). After the treatment interventions, myocyte contractile function was examined after exposure to ET-1 (200 pmol/L).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Normal human LV myocytes were successfully isolated from all myocardial biopsies, and 997 LV myocytes (33 ± 5 myocytes/biopsy) were subjected to contractility measurements. Basal indices of myocyte contraction and relaxation were similar to those reported previously [10]. Specifically, indices of LV myocyte contraction such as percent shortening was 2.59% ± 0.05%, and shortening velocity was 43.06 ± 0.83 µm/s. An index of LV myocyte relaxation such as Tau₅₀ was 98.33 ± 1.98 ms, and relengthening velocity was 36.03 ± 0.90 µm/s. The effects of ET-1 on these parameters of myocyte contractile performance are summarized in Figures 2 and 3. Myocyte percent and velocity of shortening increased from basal values with exposure to ET-1. Indices of myocyte relaxation such as Tau₅₀ and relengthening velocity increased significantly with ET-1.

View larger version (16K): [in this window] [in a new window]   Fig 2. ET-1 increased indices of myocyte contraction from baseline. PKC (PKCi) or sodium/hydrogen exchange (Na/Hi) inhibition blocked the effect of ET-1 and resulted in a negative effect on myocyte shortening velocity. Combined Na/Hi and PKCi induced similar effects. ETA receptor blockade (ETAi) attenuated the effects of ET-1. (*p < 0.05 vs baseline; + p < 0.05 vs ET-1).

View larger version (22K): [in this window] [in a new window]   Fig 3. LV myocyte time to 50% relaxation (Tau50) and relengthening velocity increased with ET-1. PKC (PKCi) or sodium/hydrogen exchange (Na/Hi) inhibition reduced the ET-1-mediated effects on Tau50, but this did not reach statistical significance. Combined treatment significantly reduced myocyte Tau50 from ET-1-only values. ETA receptor blockade attenuated the increase in ET-1-mediated Tau50. Myocyte relengthening velocity was prolonged with ET-1 receptor blockade, and this effect was abolished with any of the pretreatment protocols. (*p < 0.05 vs baseline; + p < 0.05 vs ET-1).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
ET-1 is a potent bioactive peptide that promotes a number of physiologic effects, particularly in the cardiovascular system. Increased levels of ET-1 have been identified in clinical settings such as cardiac surgery and cardiopulmonary bypass [14–16]. While ET-1 has been shown to influence myocardial contractility in multicellular animal preparations, the effects of ET-1 on isolated normal human left ventricular (LV) myocyte contractility and the signaling pathway that mediates these effects remains unexplored [1, 4, 6–8]. Accordingly, the goal of the present study was to examine the direct effects of ET-1 on isolated normal human LV myocytes and to determine factors involved in the signal transduction pathway producing those effects. The important findings of the present study were twofold. First, ET-1 exposure produced a positive inotropic effect on normal human LV myocytes that was mediated by the ET_A receptor. Second, this study demonstrated that in normal human LV myocytes, the effects of ET-1 were dependent upon the activational state of protein kinase C (PKC) and stimulation of the sodium-hydrogen (Na/H) exchanger.

To our knowledge, this is the first study that has examined isolated normal human LV myocyte contractile performance with exposure to ET-1. Past studies using multicellular preparations have identified that ET-1 can influence contractile behavior [6–8]. In the present study, ET-1 increased myocyte shortening to a greater degree than that of shortening velocity. Past studies have demonstrated that ET-1 can cause temporal changes in the contraction cycle [7, 12]. For example, Meyer and associates demonstrated that the time to 50% relaxation and the rate of rise in developed tension were prolonged in human atrial strips exposed to ET-1 [7]. In the present study, the time to 50% relaxation and relengthening velocity in isolated myocytes were both prolonged with ET-1. The fundamental basis by which myocyte shortening occurs is through an enhanced rate and/or number of myofilament cross-bridges formed. Therefore, these findings suggest that contributory factors for increased myocyte shortening with ET-1 include an increased rate of cross-bridge formation (velocity of shortening) and changes in the temporal profile of the contraction process that would result in increased calcium exposure to the myofilament apparatus.

The present study demonstrated that PKC activation is necessary for inducing the contractile effects of ET-1 on isolated LV myocytes. Previous reports have demonstrated that ET-1 can cause translocation of PKC in rat-isolated myocyte preparations, indicative of activation [17]. In a rat ventricular myocyte preparation, Kramer and associates demonstrated that the inotropic effects of ET-1 were attenuated by PKC inhibition [8]. Furthermore, PKC has been implicated to modulate a number of calcium homeostatic processes [18, 19]. Therefore, it is likely that through the modulation of PKC, ET-1 alters calcium availability to the myofilament apparatus and is a basic mechanism for the contractile performance observed in the isolated human LV myocyte. In human right atrial appendages, ET-1 increased inositol phosphate production, which in turn can modulate intracellular calcium homeostasis [20]. The present study did not directly measure whether the signaling cascade involving inositol phosphate production plays an obligatory role in inducing ET-1-mediated contractility. In addition, it must be recognized that pharmacological inhibition of PKC can induce a number of intracellular events that in and of itself may alter contractile performance independent of the effects of ET-1 stimulation. In light of the findings from the present study, future studies that more carefully quantify this specific component of the ET-1 intracellular transduction pathway in human LV myocytes would be warranted.

Past studies have also implicated a role of the Na/H exchanger the ET-1-mediated effects on contractility [7–9]. The present study clearly demonstrated an important role of the Na/H exchanger in the ET-1-mediated increases in normal human LV myocyte contractility. Past studies have demonstrated that ET_A receptor activation can induce alterations in PKC, which in turn stimulate the Na/H exchanger [7, 9]. The net result of stimulation of the Na/H exchanger would be the extrusion of protons, and thereby increased intracellular pH, which in turn would enhance myofilament sensitivity to calcium. Furthermore, the subsequent increase in intracellular sodium produced by Na/H exchanger activation would in turn promote calcium influx through the sodium-calcium exchanger, further increasing intracellular calcium levels. These components of the ET-1-mediated signal transduction cascade will collectively serve to increase myocyte contractile performance. The observations of the present study, as well as those of past studies, have thus provided a working hypothesis by which ET-1 modulates LV myocyte contractile function, and has been summarized in Figure 4.

View larger version (26K): [in this window] [in a new window]   Fig 4. Occupancy of the ETA receptor results in the stimulation of phospholipase C (PLC) and subsequent formation of inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 mediates an increased calcium availability to the myofilament apparatus. DAG stimulates protein kinase C (PKC), which in turn activates the sodium-hydrogen exchanger (Na/H) and alkalinizes the intracellular compartment. This change in pH will increase myofilament sensitivity to calcium. Activation of the Na/H increases intracellular sodium concentration, which will drive the sodium-calcium exchanger (Na/Ca) and increase intracellular calcium concentrations. These intracellular events will ultimately result in increased myofilament cross-bridge formation and, hence, myocyte contractility.

There are several limitations that must be recognized regarding the isolated myocyte preparation used in the present study. First, biopsies were obtained from patients with normal LV ejection performance, and therefore presumably normal LV myocytes were obtained. Therefore, whether ET-1 exerts differential effects in the setting of preexisting LV dysfunction was not addressed. Second, this isolated myocyte system is devoid of in vivo influences such as paracrine and endocrine effects that may modulate contractile behavior. In addition, the myocytes were studied in the unloaded state, and whether alterations in load would influence the contractile behavior to ET-1 remains to be established. Finally, the present study employed one concentration of ET-1 that may or may not represent physiologic concentrations. However, recent studies directly measuring myocardial interstitial levels of the bioactive peptide angiotensin II demonstrated 100-fold higher concentrations as compared with plasma levels [21]. These findings suggest that interstitial compartmental levels of ET-1 may potentially be much higher than those in the circulating plasma; thus, the ET-1 concentration used in the present study likely holds relevance. Future studies that directly determine myocardial interstitial levels of ET-1 in the setting of cardiac surgery will be necessary in order to more carefully address this issue. Nevertheless, the present study clearly demonstrated that ET-1 has a direct effect on human LV myocyte contractility requiring functional activation of both PKC and the Na/H exchanger, which is independent of a number of vascular effects that may occur with increased ET-1 synthesis and release during cardiac surgical procedures [14–16].

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James L. Zellner Fred A. Crawford, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldberg, A. T. Articles by Spinale, F. G. Search for Related Content PubMed PubMed Citation Articles by Goldberg, A. T. Articles by Spinale, F. G. Related Collections Related Article