Although the role of endothelin in the vascular system has been investigated extensively, its involvement in cardiac physiology and pathology is still largely equivocal. Recently, I have provided the first measurements of interstitial endothelin levels in rat hearts (see references 44 and 48 of list of publications) which showed that cardiac tissue levels of endothelin are much lower both in normoxia and after ischemia/reperfusion than has hitherto been assumed. These measurements indicate that endogenous endothelin may be beneficial in mammalian hearts, both in normoxia and in ischemia/reperfusion rather than detrimental, as has been assumed using high concentrations of exogenous endothelin. Additional aspects relevant to endothelin action in ischemia/re perfusion relate to secondary mediators such as prostanoids, nitric oxide and platelet activating factor, whose release is in part governed by endothelin. Their role in ischemia/reperfusion is being studied using endothelin measurements, receptor antagonists, and novel, more specific endothelin converting enzyme inhibitors provided by Parke Davis Pharmaceutical Research, USA.
A direct consequence of tissue endothelin measurements was the observation that endothelin receptor antagonists "mobilize" endogenous endothelin, which results in a time-dependent increase in endothelin efflux from the heart (see ref. 47). It was reported recently that endothelin-A/B antagonists increased plasma levels several to manyfold in rats and humans. These unexpected observations are likely explained by interference of endothelin-A/B receptor antagonists with endothelin-B receptor-mediated endocytosis (ref. 53). On the other hand, endothelin-A receptors seem to mediate all deleterious effects of endothelin in several species, including the rat heart (ref. 57). These questions have been investigated successfully using antagonists also provided by Parke-Davis, and are pursued further with respect to the roles played by receptor-mediated clearance versus enzymatic degradation through neutral endopeptidase 24.11.
A major recent finding concerns the involvement of endothelin in reperfusion arrhythmias (ref. 51). Comprehensive evidence was presented which showed that angiotensin converting enzyme inhibitors are anti-arrhythmic in a rat heart model by suppressing endothelin secretion and action. This important finding is the basis for further studies probing the involvement of endothelin in the anti-arrhythmic effect of ischemic preconditioning (see below). Another topic presently studied is the role of endothelin in congestive heart failure. Presently, there is some evidence for an involvement of endothelin in this condition, however, it is not clear to what extent changes in endothelin production and action are causal to and/or epiphenomena in the sequelae observed in different models of this disease. In particular the role of increased big endothelin levels observed in plasma of patients with congestive heart failure and in experimental models of this condition are not clear and are being investigated.
Before embarking on the roles played by endothelin in cardiac physiology, I have provided evidence that the synthesis and release of endothelin by cultured endothelial cells is regulated by intracellular Ca2+ (ref. 42 and 43). These investigations showed that this ion plays a dual role, i. e., increases endothelin release up to a concentration of ~400 nM, but inhibits endothelin production at higher levels. These data are of relevance to ischemia/reperfusion-related topics and are being followed up using a customer-made apparatus designed to measure cardiac Ca2+ levels on a beat-to-beat basis will become available.
A prominent feature of post-ischemic endothelial cell dysfunction is a decrease in endothelium-dependent vasodilation, and studies into its mechanism have implicated the nitric oxide/cyclic GMP pathway. However, both nitric oxide donors and inhibitors of nitric oxide synthesis mitigate ischemic injury. It is likely that the discrepancy relates to differences between the models. Recently, I have studied the role of the nitric oxide/cyclic GMP pathway in a rat model of ischemia/reperfusion dysfunction (ref. 54 and 55). It was shown that under normoxic conditions, basal nitric oxide release results in tonic inhibition of endothelin production, while the ischemic insult triggers the synthesis and release of endothelin which leads to receptor-mediated damage of endothelial and myocyte cell membranes, which ultimately results in substantial impairment of nitric oxide synthesis and loss of vasodilator tone.
Depending on man-power, it is hoped that these studies can be continued in the near future. Further details need closer scrutiny, e. g. the role of reactive oxygen species and secondary mediators dependent on endothelin such as platelet activating factor and prostanoids.
Here, the pathogenesis and etiology of human primary varicosis is a major focus. In view of the many different mediators produced by the vascular endothelium and vascular smooth muscle as well as the multiple interactions between them (nitric oxide/endothelin; endothelin/prostanoids; endothelin/atrial natriuretic peptide; endothelin/angiotensin II) it was hypothesized that varicosis may originate in an imbalance between endothelial mediators and smooth muscle function. We have shown recently (see ref. 56) that cultured human endothelial cells derived from varicose veins synthesize smaller amounts of vasoconstrictor factors which may predispose to reduced active wall tension due to weak smooth muscle contraction. Presently, further aspects of endothelial dysfunction in varicosity are being studied, including cytosolic calcium ion transients in cultured smooth muscle cells derived from varicose veins and in vivo-measurements of saphenous vein reactivity in the presence of endogenous and exogenous endothelial mediators and pharmacological agents.