Myocardial contractile actions of endothelin-1 in rat and rabbit papillary muscles. Role of endocardial endothelium.

Abstract

The actions of endothelin on the contractile and twitch configuration characteristics of rat and rabbit papillary muscles were evaluated before and after endocardial endothelium removal. In rabbit papillary muscles, endothelin produced a dose-dependent (10(-11) to 10(-7) M) increase in tension (T) (from 2.7 +/- 0.2 to 8.9 +/- 0.7 g/mm2, p less than 0.01), dT/dt, and Vmax (from 1.14 +/- 0.03 to 3.0 +/- 0.13 Lmax/sec, p less than 0.01), a decrease in time to peak tension (from 251 +/- 9 to 216 +/- 7 msec, p less than 0.05), and an increase in time to half relaxation (from 168 +/- 9 to 293 +/- 14 msec, p less than 0.01). Increasing calcium concentration in the bath from 1.25 to 15 mM greatly attenuated these changes. In the presence of propranolol (10(-5) M), endothelin increased all indexes of contractility but to a lesser extent (T = 2.6 +/- 0.3 to 6.5 +/- 0.2 g/mm2, p less than 0.01; Vmax = 1.16 +/- 0.10 to 2.06 +/- 0.10 Lmax/sec, p less than 0.01). Myocardial catecholamine depletion with reserpine had effects similar to those of propranolol. The myocardial contractile and twitch configuration characteristics of endothelin were similar to those of phenylephrine (10(-4) M), a strong stimulator of the phosphatidylinositol pathway and a moderate beta-adrenergic stimulator. The effects of phenylephrine and endothelin were modified in a similar manner by propranolol (10(-5) M). The presence of nicardipine (3 X 10(-7) M) decreased the absolute increase in contractility caused by endothelin but did not alter the percent change or shift the dose-response curve of endothelin. The actions of endothelin in rat papillary muscles studied at physiological calcium concentrations (Ca2+ = 1.25 mM) were less marked than those of rabbit studied at physiological calcium (Ca2+ = 1.25 mM) but similar to those of rabbit studied at high calcium concentrations (Ca2+ = 15 mM). Removing the endocardial endothelial layer of rabbit papillary muscles did not alter the absolute changes in contractility caused by endothelin but shifted the dose-response curve to the left and markedly altered the effects of endothelin on twitch configuration characteristics. Thus, it would appear that endothelin increases contractility and modifies twitch configuration. It does so more at lower rather than higher extracellular calcium concentrations and in a species, such as rabbit, that responds more to interventions that increase intracellular calcium.(ABSTRACT TRUNCATED AT 400 WORDS)

Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium

“…Direct positive inotropic effects of ET-1 have been described in rat, rabbit, and ferret [3][4][5][6][7] but not in guinea pig 8 or dog 6 myocardium. Recently, a direct inotropic effect of ET-1 has been reported for human atrial myocardium, 26 and a single concentration of ET-1 showed inotropic responses in muscle strips 18 and isolated myocytes 17 from failing human hearts.…”

“…1 In addition, ET-1 acts as a growth factor inducing hypertrophy. 2 Furthermore, ET-1 exerts positive inotropic effects in rat, 3,4 rabbit, 5,6 and ferret 7 but not in guinea pig 8 or dog 6 myocardium. Recently, a local ET production in the heart has been demonstrated; it is secreted from the endocardium, the myocardium, and the coronary endothelium, 9,10 thereby acting in a paracrine and autocrine fashion on myocytes.…”

Cell-cell signaling between adult rat ventricular myocytes and cardiac microvascular endothelial cells in heterotypic primary culture.

“…( 15,17,(22)(23)(24)(25) in which a number of well-documented phenotypic changes occur during adaptation to primary culture. Importantly, by [7][8][9][10] (26,27), emphasizing the importance of using tissue-specific endothelium for in vitro models where appropriate.…”

“…Vascular and endocardial endothelial cells are a potential source ofthese and other peptide cytokines, as well as a number of additional compounds ofdisparate biological activity that maydirectly or indirectly affect the function of adjacent cardiac muscle cells (4,5). Since the initial reports by Brutsaert and co-workers (6,7), several groups have now confirmed that endocardial endothelium can regulate the inotropic response ofsubjacent myofibrils (8,9) and that the function of contractile proteins within ventricular muscle may be regulated by factors released from the microvasculature (10,11).…”

Acute neurohumoral modulation of diastolic function

“…In isolated muscle preparations, ET-1 elicits a dose-dependent (0.1, 1 and 10 nM) acceleration of the rate of tension decline (increased dT/dt min ) [33,38]. To understand the physiologic mechanisms of this positive lusitropic effect, studies were performed in isolated rabbit papillary muscles.…”