AJP - Heart AJP: Gastrointestinal and Liver Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 287: H1194-H1199, 2004. First published May 6, 2004; doi:10.1152/ajpheart.00563.2003
0363-6135/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/3/H1194    most recent
00563.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leite-Moreira, A. F.
Right arrow Articles by Brás-Silva, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leite-Moreira, A. F.
Right arrow Articles by Brás-Silva, C.

Inotropic effects of ETB receptor stimulation and their modulation by endocardial endothelium, NO, and prostaglandins

Adelino F. Leite-Moreira and Carmen Brás-Silva

Department of Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal

Submitted 16 June 2003 ; accepted in final form 4 May 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Endothelin (ET)-1 acts on ETA and ETB receptors. The latter include ETB1 (endothelial) and ETB2 (muscular) subtypes, which mediate opposite effects on vascular tone. This study investigated, in rabbit papillary muscles (n = 84), the myocardial effects of ETB stimulation. ET-1 (10–9 M) was given in the absence or presence of BQ-123 (ETA antagonist). The effects of IRL-1620 (ETB1 agonist, 10–10–10–6 M) or sarafotoxin S6c (ETB agonist, 10–10–10–6 M) were evaluated in muscles with intact or damaged endocardial endothelium (EE); intact EE, in the presence of NG-nitro-L-arginine (L-NNA); and intact EE, in the presence of indomethacin (Indo). Sarafotoxin S6c effects were also studied in the presence of BQ-788 (ETB2 antagonist). ET-1 alone increased 64 ± 18% active tension (AT) but decreased it by 4 ± 2% in the presence of BQ-123. In muscles with intact EE, sarafotoxin S6c alone did not significantly alter myocardial performance. Sarafotoxin S6c (10–6 M) increased, however, AT by 120 ± 27% when EE was damaged and by 39 ± 8% or 23 ± 6% in the presence of L-NNA or Indo, respectively. In the presence of BQ-788, sarafotoxin S6c decreased AT (21 ± 3% at 10–6 M) in muscles with intact EE, an effect that was abolished when EE was damaged. IRL-1620 also decreased AT (22 ± 3% at 10–6 M) in muscles with intact EE, an effect that was abolished when EE was damaged or in the presence of L-NNA or Indo. In conclusion, the ETB-mediated negative inotropic effect is presumably due to ETB1 stimulation, requires an intact EE, and is mediated by NO and prostaglandins, whereas the ETB-mediated positive inotropic effect, observed when EE was damaged or NO and prostaglandins synthesis inhibited, is presumably due to ETB2 stimulation.

heart; endothelins; endothelial function; contractile function; nitric oxide

ENDOTHELIN (ET)-1 was originally detected in vascular endothelial cells (62), but there is now evidence that this peptide can be synthesized in endocardial endothelial cells and myocardial cells as well (33).

Plasma and salivary levels of ET-1 are elevated, correlate with the New York Heart Association functional classes, and are of prognostic value in congestive heart failure (30).

The predominantly abluminal release and short half-life of ET-1 in blood restricts its activity primarily to paracrine and autocrine actions (33). In mammalian tissues, two G protein-coupled receptor types, ETA and ETB, mediate these actions differentially (2, 48, 56). ETA receptor stimulation elicits vasoconstriction (35) and mitogenesis (41) and increases inotropism (22, 28). ETB receptor activation promotes vasodilatation mediated by nitric oxide (NO) (10, 20) and prostacyclin (10, 14) release and has growth-inhibitory effects (34, 42) associated with apoptosis (42; see Ref. 12 for a review). These receptors also mediate the pulmonary clearance of circulating ET-1 (17) and the reuptake of ET-1 by endothelial cells (43).

In the vasculature, ETA receptors are found in smooth muscle cells, whereas ETB receptors are localized on endothelial cells (ETB1) and in smooth muscle cells (ETB2). ETB1 and ETB2 receptor stimulation promote opposite effects on vascular tone: ETB1 receptors induce vasodilatation through the release of NO, whereas ETB2 receptors induce direct vasoconstriction (13, 56).

Even though ETB receptors have been shown to be present in atrial and ventricular myocardium of various animal species, including humans (1, 9), the myocardial effects of their selective stimulation are still poorly understood. We recently found that, in the presence of selective ETA receptor antagonism, ET-1 induced a small, although significant, negative inotropic effect (32). The investigation of these effects and their underlying mechanisms was, therefore, the main goal of the present study.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
This investigation conforms to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, Revised 1996).

Experimental preparation. The study was performed in isolated right papillary muscles (n = 84) from male New Zealand White rabbits (Oryctolagus cuniculus; 2.0–3.0 kg). Rabbits were anesthetized with intravenous pentobarbital sodium salt (25 mg/kg). A left thoracotomy was performed, and beating hearts were quickly excised and immersed in modified Krebs-Ringer (KR) solution [composition (in mmol/l) 98 NaCl, 4.7 KCl, 2.4 MgSO4·7H2O, 1.2 KH2PO4, 4.5 glucose, 1.8 CaCl2·2H2O, 17 NaHCO3, 15 C2H3NaO3, 5 C2H3NaO2, and 0.02 atenolol] at 35°C with cardioplegic 2,3-butanedione monoxime (BDM; 3%) (40) and 5% newborn calf serum and gassed with 95% O2-5% CO2 to obtain a pH between 7.38 and 7.42.

After dissection, papillary muscles (length: 3.8 ± 0.1 mm, weight: 2.9 ± 0.2 mg, preload: 4.4 ± 0.2 mN) were mounted vertically in a 10-ml Plexiglas organ bath containing the above-described KR solution and attached to an electromagnetic length-tension transducer (University of Antwerp; Antwerp, Belgium). Preload was estimated according to muscle dimensions, and the electrical stimulus (0.6 Hz) was set at 10% above threshold. Twenty minutes later, bathing solutions were replaced by corresponding KR solutions without BDM. During the next 2 h, muscles were stabilized. Bathing solutions were then replaced by corresponding KR solutions without calf serum, and maximum physiological length (Lmax) was calculated. Protocols were initiated after two similar isotonic and isometric control twitches separated by a 10-min interval were obtained.

Experimental protocols. The myocardial effects of ET-1, sarafotoxin S6c (SRTXc), and IRL-1620 were studied. ET-1 (10–9 M) was given in the absence (n = 9) and presence (n = 9) of BQ-123 (10–5 M; selective ETA receptor antagonist). Concentration-response curves to the selective ETB receptor agonist SRTXc (10–10–10–6 M) were performed in muscles with 1) intact endocardial endothelium (EE; n = 6); 2) damaged EE (n = 7); 3) intact EE in the presence of the NO synthase inhibitor NG-nitro-L-arginine (L-NNA; 10–5 M, n = 8); 4) intact EE in the presence of the cyclooxygenase inhibitor indomethacin (Indo; 10–5 M, n = 7); 5) intact EE in the presence of the ETB2 antagonist BQ-788 (10–5 M, n = 6); and 6) damaged EE in the presence BQ-788 (10–5 M, n = 6). Concentration-response curves to another selective ETB receptor agonist, IRL-1620 (10–10–10–6 M), which predominantly activates endothelial ETB1 receptors (63), were evaluated in muscles with 1) intact EE (n = 7); 2) damaged EE (n = 8); 3) intact EE in the presence of the NO synthase inhibitor L-NNA (10–5 M, n = 5); and 4) intact EE in the presence of the cyclooxygenase inhibitor Indo (10–5 M, n = 6).

The EE was damaged by briefly (1 s) exposing the isolated papillary muscle to a weak solution (0.5%) of the detergent Triton X-100 (5).

Chemicals were obtained from Sigma Chemical (St. Louis, MO).

Data analysis. Isotonic and isometric twitches were recorded and analyzed. The selected parameters included active tension (AT; in mN/mm2), maximum velocity of tension rise (dT/dtmax; in mN·mm–2·s–1); maximum velocity of tension decline (dT/dtmin; in mN·mm–2·s–1); peak isotonic shortening (PS %Lmax); maximum velocity of shortening (dL/dtmax; in Lmax/s); maximum velocity of lengthening (dL/dtmin; in Lmax/s); and time to half relaxation (tHR; in ms).

Notwithstanding, only data obtained from isometric twitches are described, as the analysis of isotonic twitches yielded globally similar results. In the various protocols, results are given as the percent change from baseline. For the parameters that are expressed as negative values (e.g., dT/dtmin), such percent change refers to the absolute values.

When a pharmacological inhibitor (BQ-123; BQ-788, Indo or L-NNA) was used, the term baseline refers to the condition in the presence of those inhibitors before the addition of ET-1, SRTXc, or IRL-1620. Analysis of the effects of each of those inhibitors per se on myocardial performance revealed that only BQ-123, in the presence of an intact EE, significantly altered the contractile parameters, decreasing AT by 6.5 ± 1.2%, dT/dtmax by 8.5 ± 1.4%, and dT/dtmin by 7.2 ± 1.5%.

Statistical methods. Values are means ± SE. The effects of a single concentration of an individual drug on the various contractile parameters were analyzed by a paired t-test, whereas the effects of increasing concentrations were analyzed by one-way repeated-measures ANOVA. When significant differences were detected with the latter, the Student-Newman-Keuls test was selected to perform multiple comparisons. P < 0.05 was accepted as significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Mean values of the contractile parameters in papillary muscles with an intact EE (n = 63) were similar in all experimental protocols. Removal of the EE (n = 21) resulted in a negative inotropic effect (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Mean values of contractile parameters in papillary muscles with an intact or damaged EE

 
Effects of ET-1 on myocardial contractility.

Administration of ET-1 (10–9 M) to isolated papillary muscles induced positive inotropic and lusitropic effects: AT increased by 64.2 ± 18.2%, dT/dtmax increased by 58.6 ± 20.2%, dT/dtmin increased by 38.9 ± 13.2%, and tHR increased by 3.9 ± 2.1%. In contrast, in the presence of the ETA receptor antagonist BQ-123 (10–5 M), ET-1 induced small but significant negative inotropic and lusitropic effects: AT decreased by 4.3 ± 2.4%, dT/dtmax decreased by 5.0 ± 2.6%, and dT/dtmin increased by 6.5 ± 3.4%. tHR did not change significantly in this experimental condition.

Myocardial effects of selective ETB receptor stimulation by SRTXc and IRL-1620.

Concentration-response curves to SRTXc and IRL-1620 for AT, dT/dtmax, and dT/dtmin, in the various experimental conditions, are illustrated in Figs. 1–3.



View larger version (15K):
[in this window]
[in a new window]
  		Fig. 1. Concentration-response curves for the effect of sarafotoxin S6c (SRTXc) on contractile parameters in the various experimental conditions: intact (n = 6) or damaged (n = 7) endocardial endothelium (EE) or intact EE in the presence of NG-nitro-L-arginine (L-NNA, n = 8) or indomethacin (Indo, n = 7). A: active tension (AT). B: peak rate of tension rise (dT/dtmax). C: peak rate of tension decline (dT/dtmin). Values are means ± SE (as %baseline). *P < 0.05 vs. baseline.

 


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 3. Concentration-response curves for the effect of IRL-1620 on contractile parameters in the various experimental conditions: intact (n = 7) or damaged (n = 8) EE or intact EE in the presence of L-NNA (n = 5) or Indo (n = 6). A: AT. B: dT/dtmax. C: dT/dtmin. Values are means ± SE (as %baseline). *P < 0.05 vs. baseline.

 
When given alone to muscles with an intact EE, SRTXc did not significantly alter myocardial performance, although there was a trend for negative inotropic and lusitropic effects at the two higher concentrations. In these conditions, 10–6 M SRTXc decreased AT by 7.8 ± 4.8%, dT/dtmax by 6.8 ± 7%, and dT/dtmin by 7.1 ± 3.8%. In contrast, when the EE was damaged, or in the presence of L-NNA or Indo, SRTXc induced instead positive inotropic and lusitropic effects (Fig. 1), which were highly significant at 10–6 M. At this concentration, when the EE was damaged, SRTXc increased AT by 119.2 ± 27.2%, dT/dtmax by 85.9 ± 31.9%, and dT/dtmin by 95.0 ± 21.0%. At the same concentration, in the presence of L-NNA, SRTXc increased AT by 38.8 ± 8.0%, dT/dtmax by 51.4 ± 11.2%, and dT/dtmin by 35.2 ± 11.5%, whereas in the presence of Indo, SRTXc increased AT by 23.4 ± 6.0%, dT/dtmax by 27.8 ± 7.0%, and dT/dtmin by 16.0 ± 8.2%. The positive inotropic effect elicited by SRTXc, both in muscles with damaged EE and muscles with intact EE in the presence of L-NNA or Indo, started immediately after the addition of the drug and reached a stable maximum 16–19 min later. The effect could be completely, albeit slowly, washed out, taking 90–120 min to return to baseline.

When given in the presence of BQ-788 to muscles with an intact EE, SRTXc induced concentration-dependent negative inotropic and lusitropic effects, which were significant over the entire range of concentrations, decreasing at 10–6 M: AT, 20.7 ± 2.5%; dT/dtmax, 19.1 ± 2.5%; and dT/dtmin, 17.1 ± 3.0%. On the other side, when the EE was damaged, the positive inotropic and lusitropic effects of SRTXc observed in the absence of BQ-788 were abolished in the presence of this blocker (Fig. 2).



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 2. Concentration-response curves for the effect of SRTXc in the presence of BQ-788 on contractile parameters in muscles with intact (n = 6) or damaged (n = 6) EE. A: AT. B: dT/dtmax. C: dT/dtmin. Values are means ± SE (as %baseline). *P < 0.05 vs. baseline.

 
Figure 3 illustrates concentration-response curves to the other ETB agonist, IRL-1620. When the EE was intact, this agent promoted concentration-dependent negative inotropic and lusitropic effects. At 10–6 M, it decreased AT by 22.1 ± 2.6%, dT/dtmax by 14.4 ± 2.0%, and dT/dtmin by 11.1 ± 6.1%. This effect was abolished when the EE was damaged or in the presence of L-NNA or Indo. The negative inotropic effect elicited by IRL-1620 in muscles with intact EE started immediately after the addition of the drug and reached a stable maximum 20–25 min later. The effect could be completely washed out, taking 30–35 min to return to baseline.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study showed that in the presence of selective ETA antagonism, ET-1 induces negative inotropic and lusitropic effects and an earlier onset of relaxation, indicating that they are presumably due to ETB stimulation.

Previous reports also described a negative inotropic effect of ET-1. The relative contribution of ETA and ETB receptors to this effect remains, however, unclear. Most of these studies showed an initial transient negative, followed by a sustained positive inotropic effect (7, 11, 37, 46, 57, 58). This pattern was mainly reported in atrial tissue (11, 37, 46), being observed in ventricular tissue only with higher concentrations of ET-1 (57, 58). In our study, 10–9 M of ET-1 produced a sustained positive inotropic effect that began immediately after its administration, whereas the sustained negative inotropic effect was observed only when ET-1 was given in the presence of an ETA receptor antagonist. In mouse ventricular tissue, ET-1 also induced a long-lasting negative inotropic effect, which was, however, attributed to ETA stimulation (24) and seemed to be specific of this animal species (24, 47). Some authors attributed the negative inotropic of ET-1 to concomitant {beta}-adrenoceptor stimulation (6, 11, 64), a mechanism that presumably did not contribute to the effects we observed because our experiments were performed in the presence of the {beta}-blocking agent atenolol.

In the vasculature, ETB receptors are localized on endothelial cells (ETB1) and in smooth muscle cells (ETB2), which promote opposite effects on vascular tone: ETB1 receptors induce vasodilatation through the release of NO (10, 20) and prostaglandins (10, 14), whereas ETB2 receptors induce direct vasoconstriction through mechanisms that are not yet clear (13, 56).

To investigate whether a similar distribution of ETB receptor subtypes occurs in the heart (ETB1 in EE cells and ETB2 in cardiomyocytes), we analyzed in muscles with intact and damaged EE the myocardial effects of two distinct ETB agonists: 1) SRTXc, which, activating both ETB1 and ETB2 subtypes, acts predominantly on muscular ETB2 receptors (61, 63); and 2) IRL-1620, which selectively activates endothelial ETB1 receptors (9, 63). The results of these studies support our hypothesis. In fact, in muscles with an intact EE, both agents induced negative inotropic and lusitropic effects, although they were of larger magnitude with IRL-1620 and did not even reach statistical significance with SRTXc. Therefore, in the heart, IRL-1620 apparently also selectively activates endothelial ETB1 receptors because its effects disappeared when the EE damaged. On the other side, the nonsignificant negative inotropic and lusitropic effects elicited by SRTXc observed were reversed when the EE was damaged or when the synthesis of NO or prostaglandins was inhibited. Cardiac endothelium, both vascular and endocardial, regulates performance of underlying cardiac muscle, through the release of several substances, namely, ET-1, NO, and prostaglandins (see Ref. 4 for a review).

The inotropic and lusitropic effects of SRTXc may be explained by the balance between its effects on endothelial (ETB1) and muscular (ETB2) receptor stimulation. In the presence of an intact EE, ETB1 effects equilibrate, or slightly exceed, those of ETB2 stimulation, and therefore SRTXc promotes small and nonsignificant negative inotropic and lusitropic actions. In the presence of BQ-788, which preferentially antagonizes ETB2 receptors (25, 63), the balance favors ETB1 effects, and therefore increased and highly significant negative inotropic and lusitropic actions are observed over the entire range of SRTXc concentrations. When the EE is damaged, SRTXc acts preferentially on ETB2 receptors and elicits positive inotropic and lusitropic actions, which were observed with concentrations of 10–8 M or higher, although it only reached statistical significance at the concentration of 10–6 M. Such effects are blocked when BQ-788 is concomitantly administered. Finally, when the synthesis of NO or prostaglandins is inhibited, it is conceivable that the balance might be also shifted toward the effects of ETB2 stimulation.

NO released either from cardiac endothelial cells or generated within cardiac myocytes can directly influence cardiac contractile function (52). Both endothelium-derived NO and exogenous NO donors induce an earlier onset of myocardial relaxation and/or reduce diastolic tone (18, 44). These effects have been observed in a variety of preparations and species, including rat cardiac myocytes (31, 54, 60); ferret (55), cat (38), and human (16) papillary muscles; isolated ejecting guinea pig hearts (18); and normal human subjects undergoing diagnostic cardiac catheterization (44, 45). Although NO is generally considered to have negative inotropic properties, some studies have suggested that it might increase or decrease inotropism depending on the concentration of NO (29, 38, 50), the integrity of endocardial endothelium (38), the rate of NO release (3), and the presence of cholinergic (38) or {beta}-adrenergic stimulation (36, 38, 49). The negative inotropic and relaxant effects of NO have largely been attributed to a cGMP-mediated reduction in myofilament Ca2+ responsiveness, via activation of PKG (60) and possibly subsequent phosphorilation of troponin I (31).

ET-1 also stimulates the release of prostaglandins, namely, prostacyclin, as shown in bovine and human vascular endothelial cells (14, 27) and in isolated (26) and in vivo rabbit hearts (59). Prostaglandins act through their specific receptors that are coupled via G proteins to second messenger systems, mainly cAMP and possibly inositol 1,4,5-trisphosphate (51). Direct myocardial actions of prostaglandins are still not clear, because both negative (51) and positive (39) inotropic effects were shown in isolated papillary muscles. The positive inotropic effect of EE-released prostaglandins was, however, observed only when NO synthesis was inhibited (39). This interaction between EE-released NO and prostaglandins might help to explain why, in our study, inhibition of the synthesis of NO or prostaglandins resulted in positive inotropic and lusitropic effects of ETB stimulation and why such effects were of larger magnitude when NO rather than prostaglandin synthesis was inhibited.

In conclusion, the present study, therefore, adds to our knowledge about the myocardial effects of ETB receptor stimulation. It shows that ETB1 stimulation induces a negative inotropic effect, which requires an intact EE and is mediated by NO and prostaglandins. When the EE was damaged, ETB2 stimulation induced a positive inotropic effect. The differential effects of ETB stimulation, in the presence and absence of an intact EE, indicate that the analysis of such effects might be used as an experimental tool, unavailable to date, to test the functional integrity of the EE.

These findings might be potentially relevant for the pathophysiology of cardiovascular diseases characterized by increased ET-1 levels and endothelial dysfunction (e.g., heart failure). They might also help to better interpret eventual differences between the therapeutic effects of selective and nonselective ETA receptor antagonists, which are being currently tested.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by grants from Calouste Gulbenkian Foundation and Fundação para a Ciência e Tecnologia (POCTI/CBO/47519/02; partially funded by Fundo Europeu de Desenvolvimento Regional), through the Cardiovascular R&D Unit (51/94-FCT).


   ACKNOWLEDGMENTS
 
The authors are sincerely grateful to Antónia Teles for technical support.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. F. Leite-Moreira, Dept. of Physiology, Faculty of Medicine, Alameda Professor HernÂni Monteiro, 4200-319 Porto, Portugal (E-mail: amoreira{at}med.up.pt).

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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Allen BG, Phuong LL, Farhat H, and Chevalier D. Both endothelin-A and endothelin-B receptors are present on adult rat cardiac ventricular myocytes. Can J Physiol Pharmacol 81: 95–104, 2003.[CrossRef][Web of Science][Medline]
  2. Arai H, Hori H, Aramori A, Ohkubo H, and Nakanishi S. Cloning and expression of cDNA encoding an endothelin receptor. Nature 348: 730–732, 1990.[CrossRef][Medline]
  3. Balligand JL, Kelly RA, Marsden PA, Smith TW, and Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signalling system. Proc Natl Acad Sci USA 90: 347–351, 1993.[Abstract/Free Full Text]
  4. Brutsaert DL. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev 83: 59–115, 2003.[Abstract/Free Full Text]
  5. Brutsaert DL, Meulemans AL, Spido KR, and Sys SU. Effects of damaging endocardial surface on the mechanical performance of isolated cardiac muscle. Circ Res 62: 358–366, 1988.[Abstract/Free Full Text]
  6. Chu L and Endoh M. Biphasic inotropic response to endothelin-1 in the presence of various concentrations of norepinephrine in dog ventricular myocardium. J Cardiovasc Pharmacol 36, Suppl 2: S9–S14, 2000.
  7. Cirino M, Martin E, Yano M, and Rodger IW. Cardiovascular and renal actions of the endothelin B receptor in pigs. J Cardiovasc Pharmacol 29: 704–712, 1997.[CrossRef][Web of Science][Medline]
  8. Concas V, Laurent S, Brisac AM, Perret C, and Safar M. Endothelin has potent direct inotropic and chronotropic effects in cultured cells. J Hypertens 7: S96–S97, 1989.
  9. Davenport A. International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev 54: 219–226, 2002.[Abstract/Free Full Text]
  10. De Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, and Vane JR. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by release of prostacyclin and endothelium-derived relaxation factor. Proc Natl Acad Sci USA 85: 9797–9800, 1988.[Abstract/Free Full Text]
  11. Dhein S, Giessler C, Wangemann T, Silber RE, Zerkowski HR, and Brodde OE. Differential pattern of endothelin-1-induced inotropic effects in right atria and left ventricles of the human heart. J Cardiovasc Pharmacol 36: 564–569, 2000.[Web of Science][Medline]
  12. D'Orleans-Juste P, Labonte J, Bkaily G, Choufani S, Plante M, and Honore J. Function of the endothelin (B) receptor in cardiovascular physiology and pathophysiology. Pharmacol Ther 95: 222–238, 2002.
  13. Douglas SA, Meek TD, and Ohlstein EH. Novel receptor antagonists welcome a new era in endothelin biology. Trends Pharmacol Sci 15: 313–316, 1994.[CrossRef][Medline]
  14. Filep JG, Battistini B, Cote YP, Beaudoin AR, and Sirois P. Endothelin 1 induces prostacyclin release from bovine aortic endothelial cells. Biochem Biophys Res Commun 177: 171–176, 1991.[CrossRef][Web of Science][Medline]
  15. Firth JD, Roberts FC, and Raine AEG. Effect of endothelin on the function of isolated perfused working rat heart. Clin Sci (Lond) 79: 221–226, 1990.[Medline]
  16. Flesch M, Kilter H, Cremers B, Lenz O, Sudkamp M, Kuhn-Regnier F, and Bohm M. Acute effects of nitric oxide and cyclic GMP on human myocardial contractility. J Pharmacol Exp Ther 281: 1340–1349, 1997.[Abstract/Free Full Text]
  17. Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, and Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 199: 1461–1465, 1994.[CrossRef][Web of Science][Medline]
  18. Grocott-Mason Fort S, Lewis MJ, and Shah AM. Myocardial relaxant effect of exogenous nitric oxide in the isolated ejecting heart. Am J Physiol Heart Circ Physiol 266: H1699–H1705, 1994.[Abstract/Free Full Text]
  19. Hattori Y, Nakaya H, Nishihara J, and Kanno M. A dual component positive inotropic effect of endothelin-1 in guinea-pig left atria: a role of protein kinase C. J Pharmacol Exp Ther 266: 1202–1212, 1993.[Abstract/Free Full Text]
  20. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, and Marumo F. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 91: 1367–1373, 1993.[Web of Science][Medline]
  21. Hu JR, von Harsdorf R, and Lang RE. Endothelin has potent inotropic effects in rat atria. Eur J Pharmacol 158: 275–278, 1988.[CrossRef][Web of Science][Medline]
  22. Ishikawa T, Li LM, Shinmi O, Kimura S, Yanagisawa M, Goto K, and Masaki T. Characteristics of binding of endothelin-1 and endothelin-3 to rat hearts. Developmental changes in mechanical responses and receptor subtypes. Circ Res 69: 918–926, 1991.[Abstract/Free Full Text]
  23. Ishikawa T, Yanagisawa M, Kimura S, Goto K, and Masaki T. Positive inotropic action of novel vasoconstrictor peptide endothelin on guinea-pig atria. Am J Physiol Heart Circ Physiol 255: H970–H973, 1988.[Abstract/Free Full Text]
  24. Izumi M, Miyamoto S, Hori M, Ozaki H, and Karaki H. Negative inotropic effect of endothelin-1 in the mouse right ventricle. Eur J Pharmacol 396: 109–117, 2000.[CrossRef][Web of Science][Medline]
  25. Jones RD, Wanstall JC, Gambino A, and Morice AH. The effect of the endothelin ETA receptor antagonist CI-1020 on hypoxic pulmonary vasoconstriction. Eur J Pharmacol 374: 367–375, 1999.[CrossRef][Web of Science][Medline]
  26. Karwatowska-Prokopczuk E and Wennmalm A. Effects of endothelin on coronary flow, mechanical performance, oxygen uptake, and formation of purines and on outflow of prostacyclin in the isolated rabbit heart. Circ Res 66: 46–54, 1990.[Abstract/Free Full Text]
  27. Kato K, Sawada S, Toyoda T, Kobayashi K, Shirai K, Yamamoto K, Tamagaki T, Yamagami M, Yoneda M, Takada O, Uno M, Tsuji H, and Nakagawa M. Influence of endothelin on human platelet aggregation and prostacyclin generation from human vascular endothelial cells in culture. Jpn Circ J 56: 422–431, 1992.[Medline]
  28. Kelso EJ, McDermott BJ, Silke B, and Spiers JP. Endothelin A receptor subtype mediates endothelin-induced contractility in left ventricular cardiomyocytes isolated from rabbit myocardium. J Pharmacol Exp Ther 294: 1047–1052, 2000.[Abstract/Free Full Text]
  29. Kojda G, Kottemberg K, Nix P, Schluter KD, Piper HM, and Noack E. Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. Circ Res 78: 91–101, 1996.[Abstract/Free Full Text]
  30. Krum H, Denver R, Tzanidis A, and Martin P. Diagnostic and therapeutic potential of the endothelin system in patients with chronic heart failure. Heart Fail Rev 6: 341–352, 2001.[CrossRef][Medline]
  31. Layland J, Li JM, and Shah AM. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J Physiol 540: 457–467, 2002.[Abstract/Free Full Text]
  32. Leite-Moreira AF, Bras-Silva C, Pedrosa CA, and Rocha-Sousa AA. ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and Na+/H+ exchanger-mediated effect. Am J Physiol Heart Circ Physiol 284: H1332–H1339, 2003.[Abstract/Free Full Text]
  33. Luscher TF and Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102: 2434–2440, 2000.[Abstract/Free Full Text]
  34. Mallat A, Fouassier L, Preaux AM, Gal CS, Raufaste D, Rosenbaum J, Dhumeaux D, Jouneaux C, Mavier P, and Lotersztajn S. Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway. J Clin Invest 96: 42–49, 1995.[Web of Science][Medline]
  35. Marsault R, Feolde E, and Frelin C. Receptor externalisation determines sustained contractile responses to endothelin-1 in the rat aorta. Am J Physiol Cell Physiol 264: C687–C693, 1993.[Abstract/Free Full Text]
  36. Mery PF, Pavoine C, Belhassen L, Pecker F, and Fischmeister R. Nitric oxide regulates cardiac Ca2+ current: involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. J Biol Chem 268: 26286–26295, 1993.[Abstract/Free Full Text]
  37. Meyer M, Lehnart S, Pieske B, Schlottauer K, Munk S, Holubarsch C, Just H, and Hasenfuss G. Influence of endothelin-1 on human atrial myocardium-myocardial function and subcellular pathways. Basic Res Cardiol 91: 86–93, 1996.[Web of Science][Medline]
  38. Mohan P, Brutsaert DL, Paulus WJ, and Sys SU. Myocardial contractile response to nitric oxide and cGMP. Circulation 93: 1223–1229, 1996.[Abstract/Free Full Text]
  39. Mohan P, Brutsaert DL, and Sys SU. Myocardial performance is modulated by interaction of cardiac endothelium derived nitric oxide and prostaglandins. Cardiovasc Res 29: 637–640, 1995.[CrossRef][Web of Science][Medline]
  40. Mulieri LA, Hasenfuss G, Ittleman F, Blanchard EM, and Alpert NR. Protection of human left ventricular myocardium from cutting injury with 2,3-butanedione monoxime. Circ Res 65: 1441–1444, 1989.[Abstract/Free Full Text]
  41. Ohlstein EH, Arleth A, Bryan H, Elliot JD, and Sung CP. The selective endothelin ETA receptor antagonist BQ123 antagonizes endothelin-1-mediated mitogenesis. Eur J Pharmacol 225: 347–350, 1992.[CrossRef][Web of Science][Medline]
  42. Okazawa M, Shiraki T, Ninomiya H, Kobayashi S, and Masaki T. Endothelin-induced apoptosis of A375 human melanoma cells. J Biol Chem 267: 12584–12592, 1998.
  43. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, and Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured endothelial cells. Biochem Biophys Res Commun 209: 483–489, 1995.[CrossRef][Web of Science][Medline]
  44. Paulus WJ, Vantrimpont PJ, and Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Circulation 89: 2070–2078, 1994.[Abstract/Free Full Text]
  45. Paulus WJ, Vantrimpont PJ, and Shah AM. Paracrine coronary endothelial control of left ventricular function in humans. Circulation 92: 2119–2126, 1995.[Abstract/Free Full Text]
  46. Russel FD and Molennar P. The human heart endothelin system: ET-1 synthesis, storage, release and effect. Trends Pharmacol Sci 21: 353–359, 2000.[CrossRef][Medline]
  47. Sakurai K, Norota I, Tanaka H, Kubota I, Tomoike H, and Endoh M. Negative inotropic effects of angiotensin II, endothelin-1 and phenylephrine in indo-1 loaded adult mouse ventricular myocytes. Life Sci 70: 1173–1184, 2002.[CrossRef][Web of Science][Medline]
  48. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, and Masaki T. Cloning of a cDNA encoding a non-iso-peptide-selective subtype of the endothelin receptor. Nature 348: 732–735, 1990.[CrossRef][Medline]
  49. Sandirasegarane L and Diamond J. The nitric oxide donors, SNAP and DEA/NO, exert a negative inotropic effect in rat cardiomyocytes which is independent of cyclic GMP elevation. J Mol Cell Cardiol 31: 799–808, 1999.[CrossRef][Web of Science][Medline]
  50. Sarkar D, Vallance P, Amirmansour C, and Haring SE. Positive inotropic effects of NO donors in isolated guinea-pig and human cardiomyocytes independent of NO species and cyclic nucleotides. Cardiovasc Res 48: 430–439, 2000.[Abstract/Free Full Text]
  51. Schror K and Hohlfeld TH. Inotropic actions of eicosanoids. Basic Res Cardiol 87: 2–11, 1992.[CrossRef][Web of Science][Medline]
  52. Shah AM and MacCarthy PA. Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther 86: 49–86, 2000.[CrossRef][Web of Science][Medline]
  53. Shah AM, Lewis MJ, and Henderson AH. Inotropic effects of endothelin in ferret ventricular myocardium. Eur J Pharmacol 163: 365–367, 1989.[CrossRef][Web of Science][Medline]
  54. Shah AM, Spurgeon HA, Sollott SJ, Talo A, and Lakatta EG. 8-Bromo cyclic GMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res 74: 970–978, 1994.[Abstract/Free Full Text]
  55. Smith JA, Shah A, and Lewis MJ. Factors released from endocardium of the ferret and pig modulate myocardial contraction. J Physiol 439: 1–14, 1991.[Abstract/Free Full Text]
  56. Sudjarwo SA, Hori M, Tanaki T, Matsuda Y, Okada T, and Karaki H. Subtypes of ETA and ETB receptors mediating venous smooth muscle contraction. Biochem Biophys Res Commun 200: 627–633, 1994.[CrossRef][Web of Science][Medline]
  57. Takanashi M and Endoh M. Concentration- and time-dependence of phosphoinositide hydrolysis induced by endothelin-1 in relation to the positive inotropic effect in the rabbit ventricular myocardium. J Pharmacol Exp Ther 262: 1189–1194, 1992.[Abstract/Free Full Text]
  58. Talukder MAH, Norota I, Sakurai K, and Endoh M. Inotropic response of rabbit ventricular myocytes to endothelin-1: difference from isolated papillary muscles. Am J Physiol Heart Circ Physiol 281: H596–H605, 2001.[Abstract/Free Full Text]
  59. Thiemermann C, Lidbury PS, Thomas GR, and Vane JR. Endothelin 1 releases prostacyclin and inhibits ex vivo platelet aggregation in the anesthetized rabbit. J Cardiovasc Pharmacol 13, Suppl 5: S138–S141, 1989.
  60. Vila-Petroff MG, Younes A, Egan J, Lakatta EG, and Sollott SJ. Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res 84: 1020–1031, 1999.[Abstract/Free Full Text]
  61. Williams DL Jr, Jones KL, Pettibone DJ, Lis EV, and Clineschmidt BV. Sarafotoxin S6c: an agonist which distinguishes between endothelin receptor subtypes. Biochem Biophys Res Commun 175: 556–561, 1991.[CrossRef][Web of Science][Medline]
  62. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, and Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415, 1988.[CrossRef][Medline]
  63. Yoneyama T, Hori M, Makatani M, Yamamura T, Tanaka T, Matsuda Y, and Karaki H. Subtypes of endothelin ETA and ETB receptors mediating tracheal smooth muscle contraction. Biochem Biophys Res Commun 207: 668–674, 1995.[CrossRef][Web of Science][Medline]
  64. Zhu Y, Yang HT, and Endoh M. Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle. Am J Physiol Heart Circ Physiol 273: H119–H127, 1997.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Exp PhysiolHome page
P. Castro-Chaves, R. Fontes-Carvalho, M. Pintalhao, P. Pimentel-Nunes, and A. F. Leite-Moreira
Angiotensin II-induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart
Exp Physiol, June 1, 2009; 94(6): 665 - 674.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. Mazza, A. Gattuso, C. Mannarino, B. K. Brar, S. F. Barbieri, B. Tota, and S. K. Mahata
Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart
Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H113 - H122.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. P. Lourenco, R. Roncon-Albuquerque Jr., C. Bras-Silva, B. Faria, J. Wieland, T. Henriques-Coelho, J. Correia-Pinto, and A. F. Leite-Moreira
Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats
Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1587 - H1594.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
C. Bras-Silva and A. F. Leite-Moreira
Obligatory role of the endocardial endothelium in the increase of myocardial distensibility induced by endothelin-1.
Experimental Biology and Medicine, June 1, 2006; 231(6): 876 - 881.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
C. Bras-Silva, A. P. Fontes-Sousa, C. Moura, J. C. Areias, and A. F. Leite-Moreira
Impaired Response to ETB Receptor Stimulation in Heart Failure: Functional Evidence of Endocardial Endothelial Dysfunction?
Experimental Biology and Medicine, June 1, 2006; 231(6): 893 - 898.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/3/H1194    most recent
00563.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (9)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leite-Moreira, A. F.
Right arrow Articles by Brás-Silva, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leite-Moreira, A. F.
Right arrow Articles by Brás-Silva, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.