News Physiol Sci 16: 88-91, 2001;
1548-9213/01 $5.00
News in Physiological Sciences, Vol. 16, No. 2, 88-91,
April 2001
© 2001 Int. Union Physiol. Sci./Am. Physiol. Soc.
An Autocrine/Paracrine Mechanism Triggered by Myocardial Stretch Induces Changes in Contractility
Horacio E. Cingolani,
Néstor G. Pérez and
María C. Camilión de Hurtado
H. E. Cingolani, N. G. Pérez, and M. C. Camilión de Hurtado are at the Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
 |
Abstract
|
|---|
An autocrine/paracrine mechanism is triggered by stretching the myocardium. This mechanism involves release of angiotensin II, release/increased formation of endothelin, activation of the Na+/H+ exchanger, increase in intracellular Na+, and the increase in the Ca2+ transient that underlies the slow force response to stretch. The autocrine/paracrine mechanism could explain how changes in afterload alter cardiac contractility.
|
Introduction
|
|---|
Although the contractile performance of the heart is under continuous nervous, hormonal, and electrophysiological influence, the heart has intrinsic mechanisms by which it can adapt cardiac output to changing hemodynamic conditions. An increase in ventricular end diastolic volume (EDV), induced either by increasing aortic resistance to ejection or venous return, immediately leads to a more powerful contraction. This is the well known Frank-Starling mechanism that allows the heart to increase its output after the increase in venous return or to eject the same stroke volume against a greater afterload when an increase in arterial pressure takes place. However, over the next 10 or 15 min after the sudden stretch, there is a further increase in myocardial performance and EDV returns toward its original value (Fig. 1
). The time constant of the phenomenon will depend on several factors, such as species differences, temperature, coronary blood flow, and so forth. Von Anrep (15) showed in 1912 that a heart dilatation induced by clamping the heart outflow was followed by a decline in heart volume toward the initial volume. His interpretation was that, perhaps, the decrease in the flow to the adrenal glands induced the release of catecholamines and a positive inotropic effect. In 1959, Rosenblueth et al. (11) called attention to the fact that both an increase in heart rate (Bowditch effect) and an increase in afterload triggered increases in contractility of the isolated canine right ventricle. They coined the expression "the two-staircase phenomenon." Sarnoff et al. (13), in 1960, coined the term "homeometric autoregulation" to define the decrease in left ventricular EDV that occurs after the increase in diastolic volume induced by an increase in afterload. Since both reports (11, 13) were based on experiments performed in isolated hearts, the possibility of a positive inotropic effect due to the release of catecholamines by the adrenal glands was ruled out.
View larger version (14K):
[in this window]
[in a new window]
|
FIGURE 1. Schematic representation of a sudden increase in aortic pressure. Left: schematic changes in cardiac output (CO), aortic pressure (AP), and end diastolic volume (EDV) occurring after a sudden increase in AP. A few beats after the increase in AP, an increase in myofilament Ca2+ responsiveness allows the heart to eject the same stroke volume (SV) against a higher AP (Frank-Starling mechanism or heterometric autoregulation; points 1–2). The increase in EDV is followed by a progressive return to the initial value that develops during the next 10 min. The time constant will depend on several factors, such as species differences, temperature, coronary blood flow, and so forth. Since during this time neither AP nor SV are changing, the decrease in EDV (points 2–3) reflects an increase in contractility. Right: if the phenomenon is examined on the left ventricular function curves immediately after the increase in EDV, a change from point 1 to 2 on the control curve (Frank-Starling mechanism) takes place. After that, the shift to point 3 indicates a shift to a curve with a higher contractile state because the same SV is ejected at a lower EDV. The intermediate curves indicate the displacement (points 1–3) through a family of curves with a progressive increase in the inotropism. SW, stroke work.
|
|
In 1973, Parmley and Chuck (10) reproduced this phenomenon in isolated strips of ventricular myocardium. They showed that if the length of the muscle was increased, there were corresponding rapid and slow increases in developed force (1). The rapid change in force is thought to be the basis of the Frank-Starling mechanism and is induced by an increase in the myofilament Ca2+ sensitivity. The slow force response (SFR) to the change in length is due to a progressive increase in the Ca2+ transient (Fig. 2). These authors also ruled out the possibility of a release of catecholamines by the nerve endings as a mechanism playing a role in the development of the SFR, since it was also present in isolated muscles from reserpinized animals (10).
View larger version (18K):
[in this window]
[in a new window]
|
FIGURE 2. After stretching a papillary muscle from 92 to 98% of length at maximal force (Lmax), a sudden increase in force immediately occurs (A; from a to b) because of an increase in myofilament Ca2+ responsiveness. After that, a progressive increase in force develops during the next 10–15 min, the slow force response (SFR), which is due to an increase in the Ca2+ transient (B) secondary to the increase in intracellular Na+ concentration ([Na+]i; D, control). The SFR, the increase in [Na+]i, and the increase in Ca2+ transient are abolished by blocking the angiotensin II (ANG II) AT1 receptors with losartan (C and D). The SFR, the increase in [Na+]i, and the increase in the Ca2+ transient can also be prevented by blocking the endothelin (ET)-1 ETA receptors with BQ 123 and by inhibition of the Na+/H+ exchanger (NHE). C and D are modified from Ref. 2.
|
|
Although the cellular and molecular bases of the Frank-Starling mechanism (or heterometric autoregulation) are well known and involve an increase in the response of cardiac myofilaments to the activator Ca2+ (6), the mechanism of the von Anrep effect (homeometric autoregulation) is less well understood. It is known that the increase in cardiac contractility that develops during 10–15 min after the muscle stretch does not involve changes in myofilament Ca2+ sensitivity and can be quantitatively explained by a progressive increase in the Ca2+ transient. However, the source for this increase in Ca2+ is less well understood. The increase in Ca2+ transient (2, 9) can be explained neither by an increased release of Ca2+ by the sarcoplasmic reticulum (9) nor by an increased transsarcolemmal Ca2+ current (7). The mechanism leading to the increase in the Ca2+ transient was clarified by recent experiments that demonstrated a link between Ca2+ influx and an autocrine/paracrine response to muscle stretch (2, 5).
Our first contact with this phenomenon was the finding of stretch-induced myocardial alkalinization by the activation of the Na+/H+ exchanger (NHE) in cat papillary muscles bathed in a HCO3–-free medium (5). At that time we did not pay attention to the mechanical changes evoked by stretch-induced activation of the NHE, but we were able to detect and characterize the autocrine/paracrine cascade of events leading to the activation of the NHE that follows the stretch. The release of preformed angiotensin II (ANG II) by stretching cultured cardiac myocytes from neonatal rats has previously been reported by Sadoshima and Izumo (12). Furthermore, the presence of endothelin (ET) in the culture medium was also detected after stretching neonatal rat cardiomyocytes (8). The main contribution of our report was, therefore, to detect the autocrine/paracrine mechanism in an adult cardiac multicellular preparation (5). Since neonatal and adult cardiomyocytes have different receptors and intracellular signaling pathways, our findings might have important implications for the mechanisms involved in the development of cardiac hypertrophy.
The NHE regulates intracellular pH (pHi) by exchanging intracellular H+ for extracellular Na+. Stimulation of the NHE could potentially increase force by two mechanisms: the increase in pHi would increase myofilament Ca2+ sensitivity and the increase in intracellular Na+ concentration ([Na+]i) would increase Ca2+ influx via the Na+/Ca2+ exchanger (NCX). However, when we performed experiments under more physiological conditions using HCO3–-containing buffers, little or no change in pHi was detected (2). The explanation for the lack of change in pHi can be found in the fact that many growth factors like ANG II and ET simultaneously activate at least two different pHi-regulatory mechanisms, one being an alkalinizer and the other an acidifier (4, 14). Figure 3 illustrates the fact that ANG II, through release/formation of ET, simultaneously stimulates the NHE and the Na+-independent Cl–/HCO3– anion exchanger, thus minimizing the changes in pHi. However, the anion exchanger cannot compensate for the increase in [Na+]i. Therefore, the activation of the NHE can be detected by an increase in pHi only in the absence of HCO3– in the medium, but there will still be an increase in [Na+]i.
View larger version (24K):
[in this window]
[in a new window]
|
FIGURE 3. Proposed mechanism for the effect of stretch on intracellular pH (pHi) regulatory mechanisms. The stretch induces the release of preformed ANG II, which, in an autocrine/paracrine fashion, induces the release or increase in formation of ET. ET will activate the NHE and the Na+-independent Cl–/HCO3– anion exchanger (AE). Since the AE does not transport Na+ in any direction, the simultaneous activation of both pHi regulatory mechanisms will prevent the increase in pHi but not the increase in [Na+]i. However, an increase in pHi after stretch can take place in the absence of HCO3– (HEPES buffer). Since the first step of the autocrine/paracrine mechanism is the release of endogenous ANG II, similar effects can be obtained by the exogenous addition of this peptide. (pHi records shown at bottom were modified from Camilión de Hurtado et al., Circ Res 82: 473-481, 1998).
|
|
An increase in [Na+]i is known to induce an increase in intracellular Ca2+ levels through the NCX. The increase in intracellular Ca2+ may result from either a decrease in Ca2+ efflux through the NCX or an increase in Ca2+ entry through the NCX operating in the reverse mode. The fact that the increase in Ca2+ transient after the stretch takes place without an increase in diastolic Ca2+ (2, 9) suggests that the increase in [Na+]i is driving the NCX in reverse mode. If we keep in mind that the mechanism of the increase in [Na+]i is the activation of the NHE by ET and that ET and ANG II have also been reported to activate the NCX (3), both mechanisms (increase in [Na+]i and activation of the NCX) would be contributing to the described phenomenon. However, the increase in [Na+]i seems to be mandatory since its suppression by inhibition of the NHE (2) prevented the SFR.
The SFR can be abolished by interfering with any step of the autocrine/paracrine cascade that follows myocardial stretch: blocking the effects of ANG II through the AT1 receptors, blocking the effects of ET through the ETA receptors, or preventing NHE activation. Figure 2
shows that the increase in the Ca2+ transients that occurs during the development of the SFR was abolished by losartan (ANG II-AT1 receptor antagonist). The fact that BQ 123 (selective ETA receptor antagonist) also abolished the increase in the Ca2+ transients and the SFR (2) is a reflection of the cross-talk between ET and ANG II. Figure 4 summarizes the sequence of events that follows myocardial stretch.
View larger version (14K):
[in this window]
[in a new window]
|
FIGURE 4. Schematic representation of the proposed cascade of events following myocardial stretch. Endogenous ANG II is released from the myocytes activating AT1 receptors in an autocrine fashion. Stimulation of AT1 receptors induces the release/formation of ET, which will simultaneously activate the NHE and the AE through the ETA receptors. The stimulation of the AE prevents the expected increase in pHi by the NHE activation but does not prevent the increase in [Na+]i. The increase in [Na+]i will possibly drive the Na+/Ca2+ exchanger (NCX) in the reverse mode, determining the increase in the Ca2+ transient. Notice that although this figure schematizes the stretch-induced mechanism as autocrine, we cannot rule out the possibility of endothelial cells or fibroblasts contributing in a paracrine fashion.
|
|
These studies emphasize that the heart makes use of a dual mechanism for adapting its work output to changing hemodynamic conditions. First there is a rapid increase in myofilament Ca2+ sensitivity, which is dependent on stretch. This is followed by a slow increase in the amount of Ca2+ released into the cytosol with each action potential, a response that results from a stretch-induced local release of ANG II and ET. Both mechanisms working together bring about a change in ventricular work output with little change in ventricular filling pressure. A potentially important clinical issue raised by these findings is the extent to which the adaptive ability of the heart is impaired by blockers of ANG II and ET receptors.
|
Acknowledgments
|
|---|
H. E. Cingolani, N. G. Pérez, and M. C. Camilión de Hurtado are Established Investigators of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
|
References
|
|---|
-
Allen DG and Kentish JC. The cellular basis of the length-tension relationship in cardiac muscle. J Mol Cell Cardiol 17: 821–840, 1985.[Web of Science][Medline]
-
Alvarez BV, Pérez NG, Ennis IL, Camilión de Hurtado MC, and Cingolani HE. Mechanisms underlying the increase in force and calcium transient that follows stretch of cardiac muscle: a possible explanation of the Anrep effect. Circ Res 85: 716–722, 1999.[Abstract/Free Full Text]
-
Ballard C and Somaffer S. Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin 1. J Mol Cell Cardiol 28: 11–17, 1996.[Web of Science][Medline]
-
Camilión de Hurtado MC, Alvarez BV, Ennis IL, and Cingolani HE. Stimulation of myocardial Na+-independent Cl–-HCO3– exchanger by angiotensin II is mediated by endogenous endothelin. Circ Res 86: 622–627, 2000.[Abstract/Free Full Text]
-
Cingolani HE, Alvarez BV, Ennis IL, and Camilión de Hurtado MC. Stretch-induced alkalinization of feline papillary muscle. An autocrine-paracrine system. Circ Res 83: 775–780, 1998.[Abstract/Free Full Text]
-
Hofmann PA and Fuchs F. Bound calcium and force development in skinned cardiac muscle bundles: effect of sarcomere length. J Mol Cell Cardiol 20: 667–677, 1988.[Web of Science][Medline]
-
Hongo K, White E, Le Guennec JY, and Orchard CH. Changes in [Ca2+]i, [Na+]i and Ca2+ current in isolated rat ventricular myocytes following an increase in cell length. J Physiol (Lond) 491: 609–619, 1996.[Abstract/Free Full Text]
-
Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F, and Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 92: 398–403, 1993.
-
Kentish JC and Wrzosek A. Changes in force and cytosolic Ca2+ concentration after length changes in isolated rat ventricular trabeculae. J Physiol (Lond) 506: 431–444, 1998.[Abstract/Free Full Text]
-
Parmley WW and Chuck L. Length-dependent changes in myocardial contractile state. Am J Physiol 224: 1195–1199, 1973.
-
Rosenblueth A, Alanais J, Lopez E, and Rubio R. The adaptation of ventricular muscle to different circulatory conditions. Arch Int Physiol Biochim 67: 358–373, 1959.[Web of Science][Medline]
-
Sadoshima J and Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J 12: 1681–1692, 1993.[Web of Science][Medline]
-
Sarnoff SJ, Mitchell JH, Gilmore JP, and Remensnyder JP. Homeometric autoregulation in the heart. Circ Res 8: 1077–1091, 1960.[Abstract/Free Full Text]
-
Thomas RC. Cell growth factors. Bicarbonate and pHi response. Nature 337: 601, 1989.[Medline]
-
Von Anrep G. On the part played by the suprarenals in the normal vascular reactions on the body. J Physiol (Lond) 45: 307–317, 1912.
This article has been cited by other articles:
|
|
|
|
 
Y.-H. Yi, P.-Y. Ho, T.-W. Chen, W.-J. Lin, V. Gukassyan, T.-H. Tsai, D.-W. Wang, T.-S. Lew, C.-Y. Tang, S. J. Lo, et al.
Membrane Targeting and Coupling of NHE1-Integrin{alpha}IIb{beta}3-NCX1 by Lipid Rafts following Integrin-Ligand Interactions Trigger Ca2+ Oscillations
J. Biol. Chem.,
February 6, 2009;
284(6):
3855 - 3864.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. von Lewinski, J. Kockskamper, D. Zhu, H. Post, A. Elgner, and B. Pieske
Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na+-Contraction Coupling
Circ Heart Fail,
January 1, 2009;
2(1):
47 - 55.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. L. Ennis, C. D. Garciarena, N. G. Perez, R. A. Dulce, M. C. Camilion de Hurtado, and H. E. Cingolani
Endothelin isoforms and the response to myocardial stretch
Am J Physiol Heart Circ Physiol,
June 1, 2005;
288(6):
H2925 - H2930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Browe and C. M. Baumgarten
Angiotensin II (AT1) Receptors and NADPH Oxidase Regulate Cl- Current Elicited by {beta}1 Integrin Stretch in Rabbit Ventricular Myocytes
J. Gen. Physiol.,
August 30, 2004;
124(3):
273 - 287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Reyes, G. L. Freeman, D. Escobedo, S. Lee, M. E. Steinhelper, and M. D. Feldman
Enhancement of Contractility With Sustained Afterload in the Intact Murine Heart: Blunting of Length-Dependent Activation
Circulation,
June 17, 2003;
107(23):
2962 - 2968.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. E Cingolani, N. G Perez, B. Pieske, D. von Lewinski, and M. C Camilion de Hurtado
Stretch-elicited Na+/H+ exchanger activation: the autocrine/paracrine loop and its mechanical counterpart
Cardiovasc Res,
March 15, 2003;
57(4):
953 - 960.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Introduction
References
