Endothelial cell storage and release of endothelin as a cardioregulatory mechanism.

Abstract

Coronary vascular endothelial cells release substances into the coronary circulation that modify the contractile system of cardiac myocytes, and cardiac myocytes may release factors that modulate the secretion of cardioregulatory substances by endothelial cells. This regulatory loop is sensitive to the rate of coronary flow and tissue oxygen tension. In the present study, coronary venous effluent from isolated perfused hearts and the contents of the coronary vascular endothelial cells have been collected, the latter by disrupting the cells with coronary perfusion at high pressure. The relative amounts of upregulating and downregulating factors in both collections have been estimated by assaying their effects on the contractility of isolated cardiac trabeculas. The amount of upregulating factor stored in the endothelial cells is sensitive to the rate of coronary flow just before disruption of the cells. The quantity of endothelin in the coronary venous effluent and in the vascular endothelial cell contents was measured by radioimmunoassay and compared with the degree of upregulation of contractility produced by the two types of solutions. Upregulation was never produced in the absence of endothelin. The extent of the increase in contractility that was observed with endothelial cell contents correlated with the concentration of endothelin and was approximately the same as the increase in contractility from similar concentrations of endothelin added to standard Krebs' solution. The amount of the increase in contractility from coronary effluent could be accounted for by the concentration of endothelin in the effluent with the additional presence of some downregulating factor as well. The endothelin antagonist BQ123 inhibited the upregulation from coronary perfusate. It appears that endothelin alone can account for all of the upregulation of contractility produced by the vascular endothelial cells. Coronary flow, probably through shear forces, seems to regulate the production of endothelin possibly from an inactive precursor. Tissue oxygen tension appears to modulate the rate of release of the endothelin from endothelial cells though substances released by cardiac myocytes or other cells in the tissue. The downregulating factor is stored to a much smaller extent.

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

“…In the normal heart, ET-1 mRNA is expressed in EE (372), and ET-1 release has been demonstrated ] from EE cell culture (372) and from EE in isolated cardiac muscle (107, 146). ET-1 is also expressed in coronary vascular endothelium and in MyoCapE, and its release has been demonstrated in the venous effluent of isolated beating hearts (366). ET-1 is not normally expressed in normal, postnatal cardiomyocytes (306,415).…”

“…ET is one of the most potent positive inotropic agents known (326,366,372). Its inotropic action resembled the characteristic positive inotropic effect induced by the cardiac endothelium (372,459,611) and has been partly explained by a similarly enhanced affinity of the contractile proteins to calcium (613), secondary to changes resulting from activation of the sarcolemmal Na ϩ /H ϩ exchanger (286).…”

“…Similar autocrine interactions of ET may also exist with endothelium-derived PGI 2 (116) and ANG II (105). McClellan et al (366) proposed ET storage and release from cardiac endothelial cells as a supportive cardioregulatory mechanism. Low ET concentrations may have important protective activities in the normal heart.…”

“…Modulation of the contractile state of subjacent cardiomyocytes by endocardial endothelial cells was subsequently extended to include the contribution of the endothelium in the myocardial capillaries (323,366,414,470). Further observations both in vitro and in vivo on aspects of the effects of cardiac endothelium and of related autocrine and paracrine factors and cytokines on cardiac function were made by many investigators in various animal species, including in humans (24, 48, 67, 81-83, 104, 146, 205, 206, 326, 372, 442, 446, 447, 511, 539, 543, 611) (Fig.…”

Autonomic Contribution to Endothelin-1 Increase during Laboratory Anger-Recall Stress in Patients with Coronary Artery Disease

“…Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that can be released rapidly by activated macrophages (1) and the vascular endothelium (2-4) in response to stimuli of short duration (5), thereby contributing to coronary plaque rupture (6,7) and triggered cardiac events (8,9), including those triggered by emotional stress (10). The multifactorial regulation of ET-1 includes stimulated release by cytokines (11)(12)(13)(14) and autonomic factors.…”