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

Abstract

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.

Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide

“…Cardiac endothelial cells are potential targets for IMD in the heart and therefore likely modulators of its myocardial action. In fact, the role of these cells in the paracrine modulation of myocardial contractility, namely through the release of neurohumoral agents, such as NO and endothelin-1, among others, is well documented (3,20). Furthermore, previous immunocytochemical studies demonstrate that these cells express the CL/RAMP receptor system responsible for IMD biological action, although IMD expression is restricted to cardiomyocytes in rats and humans (31).…”

“…The lower muscular end was fixed in a phosphorbronze clip, and the upper tendinous end was attached to an electromagnetic length-tension transducer (University of Antwerp, Antwerp, Belgium; Ref. 20). Preload was initially set between 3 and 4 mN according to muscle dimensions.…”

Negative inotropic effect of selective AT2 receptor stimulation and its modulation by the endocardial endothelium

“…This is in contrast to what happens with other vasodilating and negative inotropic pathways, like endothelin ET B receptor stimulation. In fact, in the same animal species, the endothelium dependent ET B -mediated negative inotropic effect is mediated by nitric oxide and prostaglandins (Leite-Moreira and Bras-Silva, 2004). …”

Acute neurohumoral modulation of diastolic function

“…We demonstrated that selective ET B1 receptor stimulation slowed myocardial relaxation (decreased dT/dt min ) through the release of NO and prostaglandins, whereas there was a faster relaxation upon preferential ET B2 receptor stimulation [32]. More recently, we demonstrated that the lusitropic effect of selective ET B receptor stimulation is dependent in the integrity of the endocardial endothelium, being negative when it is intact and positive when it is damaged [32].…”

“…ET A receptor activation evokes vasoconstriction [41], mitogenesis [46] and increased inotropism [22,25] whereas ET B receptor stimulation is associated with vasodilatation and growth inhibitory effects [40] associated with apoptosis [47]. The latter was further subdivided in ET B1 and ET B2 receptor subtypes: the ET B1 receptor is predominantly expressed in the vascular and endocardial endothelium and its stimulation elicits vasodilatation [12] and a negative inotropic effect [32] and the ET B2 receptor is located on vascular smooth muscle and myocardial cells, mediating vasoconstriction [59] and positive inotropism [32]. The ET B receptor is also responsible for the pulmonary clearance [15] and endothelial reuptake [48] of circulating ET-1.…”