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Am J Physiol Heart Circ Physiol 291: H2013-H2017, 2006. First published May 26, 2006; doi:10.1152/ajpheart.00167.2006
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Contrasting inotropic responses to {alpha}1-adrenergic receptor stimulation in left versus right ventricular myocardium

Guan-Ying Wang,1,3 Diana T. McCloskey,1,3 Sally Turcato,1,3 Philip M. Swigart,2,3 Paul C. Simpson,2,3 and Anthony J. Baker1,3

Departments of 1Radiology and 2Medicine, University of California, San Francisco; and 3Veterans Affairs Medical Center, San Francisco, California

Submitted 14 February 2006 ; accepted in final form 15 May 2006


   ABSTRACT
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The left ventricle (LV) and right ventricle (RV) have differing hemodynamics and embryological origins, but it is unclear whether they are regulated differently. In particular, no previous studies have directly compared the LV versus RV myocardial inotropic responses to {alpha}1-adrenergic receptor ({alpha}1-AR) stimulation. We compared {alpha}1-AR inotropy of cardiac trabeculae from the LV versus RV of adult mouse hearts. As previously reported, for mouse RV trabeculae, {alpha}1-AR stimulation with phenylephrine (PE) caused a triphasic contractile response with overall negative inotropy. In marked contrast, LV trabeculae had an overall positive inotropic response to PE. Stimulation of a single subtype ({alpha}1A-AR) with A-61603 also mediated contrasting LV/RV inotropy, suggesting differential activation of multiple {alpha}1-AR-subtypes was not involved. Contrasting LV/RV {alpha}1-AR inotropy was not abolished by inhibiting protein kinase C, suggesting differential activation of PKC isoforms was not involved. However, contrasting LV/RV {alpha}1-AR inotropic responses did involve different effects on myofilament Ca2+ sensitivity: submaximal force of skinned trabeculae was increased by PE pretreatment for LV but was decreased by PE for RV. For LV myocardium, {alpha}1-AR-induced net positive inotropy was abolished by the myosin light chain kinase inhibitor ML-9. This study suggests that LV and RV myocardium have fundamentally different inotropic responses to {alpha}1-AR stimulation, involving different effects on myofilament function and myosin light chain phosphorylation.

myosin light chain phosphorylation; phenylephrine; calcium; myofilament

THE LEFT VENTRICLE (LV) and right ventricle (RV) differ considerably. The LV is a thick-walled pressure pump that drives blood at high pressure through the systemic circulation. The RV has a thin free wall and acts as a volume pump to drive blood at low pressure through the pulmonary circulation. Recent studies indicate that the LV and RV derive from different cardiogenic progenitor populations (2). Despite these functional, structural, and molecular differences, it is not clear whether the LV and RV are regulated differently. beta-Adrenergic receptor stimulation mediates positive inotropy for both LV and RV myocardium (6). However, no previous studies have directly compared the LV versus RV myocardial inotropic responses to {alpha}1-adrenergic receptor ({alpha}1-AR) stimulation.

Therefore, we determined LV and RV myocardial responses to {alpha}1-AR stimulation and found them to be fundamentally different. Furthermore, we investigated whether different LV/RV {alpha}1-AR inotropic responses involved differential activation of {alpha}1-AR-subtypes or downstream protein kinase C isoforms, or involved different effects on myofilament function.


   MATERIALS AND METHODS
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Trabeculae. Hearts were removed from anesthetized male and female FVB mice (23–28 g) and flushed with modified Krebs-Henseleit, as previously described (16). The RV or LV was opened and a free-running trabecula dissected out (one per heart). The width, thickness, and cross-sectional area of trabeculae from the RV (147 ± 17 µm, 96 ± 8 µm, and 0.013 ± 0.002 mm2, n = 18) and LV (123 ± 11 µm, 99 ± 8 µm, and 0.011 ± 0.002 mm2, n = 23) were not different (P > 0.05). Trabeculae were mounted in a muscle chamber between a micromanipulator and force transducer, and sarcomere length was set to 2.1 µm (16). Trabeculae were superfused with Krebs-Henseleit solution (2 mM bath [Ca2+], at 22°C) and field stimulated (0.5 Hz pacing frequency and voltage 1.5x threshold) (16).

Inotropic responses. After 30-min equilibration, the nonselective {alpha}1-AR agonist phenylephrine (PE, 10 µM) or {alpha}1A-AR-selective agonist A-61603 (10 nM) or the PKC activator phorbol 12,13-dibutyrate (PDBu, 1 µM) was added to the superfusate. The beta-AR antagonist timolol (10 µM) and, for some experiments, PKC inhibitor bisindolylmaleimide (BIM, 3 µM) or myosin light chain kinase inhibitor ML-9 (40 µM) were present 30 min before and throughout agonist stimulation.

Myofilament function. After {alpha}1-AR inotropic responses fully developed, some trabeculae were demembranated using 1% Triton X-100, and in vitro myofilament function was assessed using steady-state contractions at various bath [Ca2+] as recently described (16). For each experiment, the sigmoidal relationship between steady-state force (F) and [Ca2+] was fit to the Hill equation: F = Fmax x [Ca2+]nH/([Ca2+]nH+EC50nH), where Fmax is the maximum Ca2+-activated force, EC50 is the [Ca2+] at which F is 50% of Fmax, and nH is the Hill coefficient reflecting the slope of the Ca2+-force relationship at EC50.

Statistical analysis. Data are means ± SE. Groups were compared using Student’s t-test or two-way repeated-measures ANOVA with a Tukey post hoc test.


   RESULTS
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For RV trabeculae (Fig. 1A), nonsubtype-selective {alpha}1-AR stimulation with PE caused a triphasic contractile response with overall negative inotropy, consistent with previous studies (7–9, 14). A brief rise of force (phase 1) was followed by a marked fall of force (phase 2) and then partial force recovery (phase 3). In marked contrast, LV trabeculae (Fig. 1B) had an overall positive inotropic response to PE that was also triphasic. The pooled data (Fig. 1C) show that the small rise of force in phase 1 was similar in RV and LV trabeculae. In contrast, the fall of force in phase 2 was much greater in RV compared with LV trabeculae, and the nadir of force decline was later. The rise of force in phase 3 was similar for RV and LV trabeculae, and the time of force plateau was similar. RV and LV trabeculae had similar baseline developed force (systolic minus diastolic force) (7.6 ± 0.8 mN/mm2, n = 18 vs. 7 ± 0.7 mN/mm2, n = 23, P > 0.05).


Figure 1
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  		Fig. 1. Representative slow-time base records of electrically paced contractions of trabeculae from mouse right ventricle (RV) (A) and left ventricle (LV) (B). Arrows show addition of {alpha}1-adrenergic receptor ({alpha}1-AR) agonist phenylephrine (10 µM PE, with beta-AR antagonist timolol present throughout). The 3 phases of {alpha}1-AR inotropic responses are indicated. C: summary of changes in developed force versus time from PE addition during 3 phases of inotropic response.

 
Previous studies suggest that {alpha}1-AR subtypes mediate opposing inotropic responses in rat LV myocytes (5). To investigate {alpha}1-AR subtype function, we used the {alpha}1A-AR-subtype-selective agonist A-61603. Like nonselective {alpha}1-AR stimulation with PE, A-61603 also mediated contrasting LV/RV inotropic responses, with net positive inotropy in LV trabeculae but net negative inotropy in RV trabeculae (Fig. 2A). Thus differing {alpha}1-AR inotropic responses of RV versus LV myocardium existed at the level of a single {alpha}1-AR subtype response.


Figure 2
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  		Fig. 2. A: summary of changes in developed force versus time from A-61603 addition during 3 phases of inotropic response. B: inotropic responses of RV and LV trabeculae to PE [before and after inhibition of PKC with bisindolymaleimide (BIM)] and inotropic responses to PKC activation [with phorbol 12,13-dibutyrate (PDBu)] (beta-AR antagonist present throughout) (number of experiments indicated in columns).

 
Stimulation of {alpha}1-ARs can activate multiple PKC isoforms (11). To investigate the role of PKC, we used the nonselective inhibitor BIM, which did not block {alpha}1-AR inotropic responses for either RV or LV myocardium (Fig. 2B), suggesting that PKC was not involved in {alpha}1-AR inotropy. To confirm that PKC was inhibited by BIM, BIM completely blocked the inotropic response to the PKC activator PDBu (not shown). Moreover, PKC activation with PDBu caused negative inotropic responses in both RV and LV (Fig. 2B), in contrast to the differing LV/RV responses to {alpha}1-AR stimulation.

Previously, we found that {alpha}1-AR-mediated negative inotropy in RV trabeculae involved decreased myofilament Ca2+ sensitivity (7). Therefore, we determined whether {alpha}1-AR stimulation caused different effects on myofilament Ca2+ sensitivity for LV and RV trabeculae. On reaching phase 3 of the inotropic response to PE, trabeculae were skinned. When compared with untreated controls, PE treatment before skinning caused the relationship between skinned fiber force and [Ca2+] to shift to the left for LV trabeculae but, in contrast, shift to the right for RV trabeculae (Fig. 3). Thus PE treatment before skinning caused greater myofilament Ca2+ sensitivity in LV versus RV trabeculae. Consistent with this, fitting to the Hill equation showed that PE treatment before skinning caused lower EC50 ([Ca2+] at half-maximal force) for LV versus RV trabeculae (Fig. 3B). Moreover, the Fmax for skinned RV trabeculae was reduced by PE pretreatment versus untreated controls (Fig. 3B).


Figure 3
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  		Fig. 3. Force-Ca2+ relationships of in vitro skinned trabeculae. A: pooled data from LV and RV trabeculae with PE pretreatment and without (control) PE. Lines show fit of pooled data to the Hill equation. With PE, group data from LV were significantly different from RV (P < 0.05, 2-way repeated measures ANOVA; results from Turkey post hoc tests are shown). Control LV and RV did not differ and are combined. B: summary of fitting data for each experiment to the Hill equation (16). C: {alpha}1-AR inotropic responses versus submaximal force of skinned trabeculae. *P < 0.05, **P < 0.01.

 
At 1 µM bath [Ca2+], pretreatment with PE caused higher force for skinned LV trabeculae (23 ± 3 mN/mm2, n = 5, P = 0.02) but lower force for skinned RV trabeculae (7 ± 1 mN/mm2, n = 5, P = 0.02) compared with untreated controls (14 ± 2 mN/mm2, n = 6). These different effects of PE pretreatment on skinned fiber contractions resembled the different LV/RV inotropic responses to PE. Indeed, for the subset of trabeculae used for skinned fiber studies, there was a significant positive linear relationship (P < 0.001) between {alpha}1-AR inotropy (measured before skinning) versus subsequent skinned fiber force (Fig. 3C).

In rat LV papillary muscle, {alpha}1-AR-induced positive inotropy was abolished by the myosin light chain kinase inhibitor ML-9, but the transient phase of negative inotropy was not abolished (1). Consistent with this, for LV trabeculae, {alpha}1-AR-induced net positive inotropy was abolished by ML-9 and converted to net negative inotropy (Fig. 4A, P < 0.05, paired t-test). Moreover, negative inotropy in phase 2 was not abolished but instead was more pronounced (P < 0.05), and the nadir occurred later (P < 0.001).


Figure 4
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  		Fig. 4. Summary of changes in developed force versus time from PE addition during 3 phases of inotropic response both before and after treatment with the myosin light chain kinase inhibitor ML-9. A: LV trabeculae; B: RV trabeculae.

 
For RV myocardium, the effects of ML-9 were less pronounced. The partial recovery of force during phase 3 of {alpha}1-AR inotropy was eliminated by ML-9 (Fig. 4B). Moreover, the nadir of force decline for phase 2 was delayed (P < 0.05). As previously reported (1), beta-AR-mediated positive inotropy was not affected by ML-9 (not shown).


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
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The novel finding here was that under identical conditions, {alpha}1-AR stimulation caused net negative inotropy in RV trabeculae but net positive inotropy in LV trabeculae. Different LV/RV inotropy also arose from stimulation of only one of the three major {alpha}1-AR subtypes in the heart ({alpha}1A-AR) suggesting that differential activation of {alpha}1-AR-subtypes was not involved. Different LV/RV {alpha}1-AR inotropy was not abolished by PKC inhibition, suggesting that ventricle-specific activation of different PKC isoforms was not involved. However, with prior {alpha}1-AR stimulation, submaximal force of skinned fibers was increased in LV trabeculae but decreased in RV trabeculae versus untreated controls. Thus contrasting effects on myofilament function may explain, at least in part, contrasting LV/RV {alpha}1-AR inotropy.

Phosphorylation of myosin light chain 2 (MLC-2) sensitizes cardiac myofilaments to Ca2+ (3) and has been implicated in {alpha}1-AR-induced positive inotropy (1). For LV trabeculae, we found that the MLC-2 kinase inhibitor ML-9 abolished the late phase of positive {alpha}1-AR inotropy and resulted in overall negative {alpha}1-AR inotropy. Likewise for RV trabeculae, ML-9 abolished the late phase of positive {alpha}1-AR inotropy. However, with ML-9, the overall {alpha}1-AR inotropic response was reduced more in LV (48%, Fig. 4A) than in RV trabeculae (19%, Fig. 4B). These results are consistent with a role for MLC-2 phosphorylation in {alpha}1-AR-induced positive inotropy (3) and suggest that this mechanism may be more important in LV versus RV myocardium. Interestingly, a marked gradient of MLC-2 phosphorylation across the myocardium was reported (4); it will be interesting to know if this gradient extends to the LV versus RV.

With ML-9, the time to the nadir of negative {alpha}1-AR inotropy in phase 2 was prolonged and was similar for both RV and LV trabeculae. This suggests that without ML-9 the transient negative inotropy in phase 2 was abbreviated due to the ensuing positive inotropy in phase 3. Thus, for LV trabeculae, {alpha}1-AR-induced positive inotropy in phase 3 may contribute to the briefer negative inotropy in phase 2 relative to RV trabeculae.

The inotropic response to {alpha}1-AR stimulation has remained uncertain because it has varied considerably among studies and may be influenced by experimental conditions (12). The present study indicates that use of RV versus LV myocardium is a major experimental factor that can dramatically influence {alpha}1-AR inotropy. In mouse myocardium the present results may reconcile some previously conflicting findings. We and others have shown that {alpha}1-AR stimulation causes a negative inotropic response in mouse RV trabeculae and muscle strips (7–9, 14).In contrast, we and others recently found that {alpha}1-AR stimulation causes a positive inotropic response in Langendorff-perfused mouse hearts (10, 15). These differing results may reflect contrasting LV/RV {alpha}1-AR inotropy because the trabeculae and muscle strips were derived from the RV, whereas Langendorff-perfused hearts reported on LV function.

The myocardial properties of RV trabeculae or papillary muscles are often assumed to be representative of myocardium throughout the heart. However, the LV and RV are different in both ontogeny and hemodynamics. The present findings reveal fundamentally different LV/RV myocardial responses to {alpha}1-AR stimulation. Comparison of our findings in mice to other species will be important. Mice are similar to humans in cardiac {alpha}1-AR abundance (whereas {alpha}1-AR abundance is much higher in rats) (13).

Although the relationship between the present findings and in situ heart function is unclear, contrasting LV/RV {alpha}1-AR inotropy could lead to complex hemodynamic regulation. Thus greater understanding of the functional effects of {alpha}1-AR stimulation is critical. For example, with heart failure, {alpha}1-ARs should become more activated because catecholamines are elevated and beta-ARs downregulated.


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This study was supported by National Heart, Lung, and Blood Institute Grants HL-68738 (to A. J. Baker) and HL-31113 (to P. C. Simpson) and an Established Investigator Award from the American Heart Association (to A. J. Baker).


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. J. Baker, VA Medical Center, Cardiology Division (111C), 4150 Clement St., San Francisco, CA 94121 (e-mail: Anthony.Baker{at}ucsf.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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  1. Andersen GG, Qvigstad E, Schiander I, Aass H, Osnes JB, and Skomedal T. {alpha}1-AR-induced positive inotropic response in heart is dependent on myosin light chain phosphorylation. Am J Physiol Heart Circ Physiol 283: H1471–H1480, 2002.[Abstract/Free Full Text]
  2. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, and Evans S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5: 877–889, 2003.[CrossRef][ISI][Medline]
  3. Clement O, Puceat M, Walsh MP, and Vassort G. Protein kinase C enhances myosin light-chain kinase effects on force development and ATPase activity in rat single skinned cardiac cells. Biochem J 285: 311–317, 1992.[ISI][Medline]
  4. Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, and Epstein ND. The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation. Cell 107: 631–641, 2001.[CrossRef][ISI][Medline]
  5. Gambassi G, Spurgeon HA, Ziman BD, Lakatta EG, and Capogrossi MC. Opposing effects of {alpha}1-adrenergic receptor subtypes on Ca2+ and pH homeostasis in rat cardiac myocytes. Am J Physiol Heart Circ Physiol 274: H1152–H1162, 1998.[Abstract/Free Full Text]
  6. Janssen PM, Stull LB, Leppo MK, Altschuld RA, and Marban E. Selective contractile dysfunction of left, not right, ventricular myocardium in the SHHF rat. Am J Physiol Heart Circ Physiol 284: H772–H778, 2003.[Abstract/Free Full Text]
  7. McCloskey DT, Rokosh DG, O'Connell TD, Keung EC, Simpson PC, and Baker AJ. Alpha(1)-adrenoceptor subtypes mediate negative inotropy in myocardium from alpha(1A/C)-knockout and wild type mice. J Mol Cell Cardiol 34: 1007–1017, 2002.[CrossRef][ISI][Medline]
  8. Montgomery DE, Wolska BM, Pyle WG, Roman BB, Dowell JC, Buttrick PM, Koretsky AP, Del Nido P, and Solaro RJ. {alpha}-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI. Am J Physiol Heart Circ Physiol 282: H2397–H2405, 2002.[Abstract/Free Full Text]
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  10. Petrashevskaya NN, Bodi I, Koch SE, Akhter SA, and Schwartz A. Effects of alpha1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression. Cardiovasc Res 63: 561–572, 2004.[Abstract/Free Full Text]
  11. Rohde S, Sabri A, Kamasamudran R, and Steinberg SF. The alpha(1)-adrenoceptor subtype- and protein kinase C isoform-dependence of norepinephrine's actions in cardiomyocytes. J Mol Cell Cardiol 32: 1193–1209, 2000.[CrossRef][ISI][Medline]
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