Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure marked increase in endothelin-1. Production in the failing heart

被引:275
作者
Sakai, S
Miyauchi, T
Sakurai, T
Kasuya, Y
Ihara, M
Yamaguchi, I
Goto, K
Sugishita, Y
机构
[1] UNIV TSUKUBA,INST CLIN MED,DEPT INTERNAL MED,TSUKUBA,IBARAKI 305,JAPAN
[2] UNIV TSUKUBA,INST BASIC MED SCI,DEPT PHARMACOL,TSUKUBA,IBARAKI 305,JAPAN
[3] BANYU PHARMACEUT CO LTD,TSUKUBA RES INST,TSUKUBA,IBARAKI,JAPAN
关键词
endothelin; heart failure; heart rate; genes; contractility;
D O I
10.1161/01.CIR.93.6.1214
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Although it was demonstrated that circulating endothelin-l (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelin(A) (ET(A)) receptor antagonist, on both heart rate and myocardial contractility in rats with CHF. Methods and Results We used the left coronary artery-ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression of prepro-ET-l mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500+/-41 versus 102+/-10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243+/-20 versus 155+/-17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg . kg(-1). min(-1) for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP/dt(max) (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats. Conclusions In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor-mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.
引用
收藏
页码:1214 / 1222
页数:9
相关论文
共 55 条
[1]   DIFFERENTIAL CHANGES IN LEFT AND RIGHT VENTRICULAR SR CALCIUM-TRANSPORT IN CONGESTIVE-HEART-FAILURE [J].
AFZAL, N ;
DHALLA, NS .
AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 262 (03) :H868-H874
[2]   CLONING AND EXPRESSION OF A CDNA-ENCODING AN ENDOTHELIN RECEPTOR [J].
ARAI, H ;
HORI, S ;
ARAMORI, I ;
OHKUBO, H ;
NAKANISHI, S .
NATURE, 1990, 348 (6303) :730-732
[3]  
BAKER KM, 1992, ANNU REV PHYSIOL, V54, P227, DOI 10.1146/annurev.ph.54.030192.001303
[4]   EFFECTS OF NOREPINEPHRINE INFUSION ON MYOCARDIAL HIGH-ENERGY PHOSPHATE CONTENT AND TURNOVER IN THE LIVING RAT [J].
BITTL, JA ;
BALSCHI, JA ;
INGWALL, JS .
JOURNAL OF CLINICAL INVESTIGATION, 1987, 79 (06) :1852-1859
[5]  
CLOZEL M, 1994, J PHARMACOL EXP THER, V270, P228
[6]  
CLOZEL M, 1994, CIRCULATION S1, V88, P316
[7]   CONTRIBUTION OF VASOPRESSIN TO VASOCONSTRICTION IN PATIENTS WITH CONGESTIVE-HEART-FAILURE - COMPARISON WITH THE RENIN-ANGIOTENSIN SYSTEM AND THE SYMPATHETIC NERVOUS-SYSTEM [J].
CREAGER, MA ;
FAXON, DP ;
CUTLER, SS ;
KOHLMANN, O ;
RYAN, TJ ;
GAVRAS, H .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1986, 7 (04) :758-765
[8]   IS ENDOTHELIN-INDUCED VASOCONSTRICTION MEDIATED ONLY BY ET(A) RECEPTORS IN HUMANS [J].
DAVENPORT, AP ;
MAGUIRE, JJ .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1994, 15 (01) :9-11
[9]   EVIDENCE FOR A ROLE OF AN INTRACARDIAC RENIN-ANGIOTENSIN SYSTEM IN NORMAL AND FAILING HEARTS [J].
DOSTAL, DE ;
BAKER, KM .
TRENDS IN CARDIOVASCULAR MEDICINE, 1993, 3 (02) :67-74
[10]   SECRETORY MECHANISM OF IMMUNOREACTIVE ENDOTHELIN IN CULTURED BOVINE ENDOTHELIAL-CELLS [J].
EMORI, T ;
HIRATA, Y ;
OHTA, K ;
SHICHIRI, M ;
MARUMO, F .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1989, 160 (01) :93-100