| Regulation of cardiac responses to increased load: Role of endothelin-1, angiotensin II and collagen XV | ||
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The present work underlines the importance of autocrine/paracrine ET-1 in regulation cardiac function. In detail, the findings of the present study are summarized as follows:
Myocardial overexpression of PMCA attenuated early induction of hypertrophic response to ET-1 but not to increased load, while baseline cardiac function remained intact. The results suggest that PMCA plays a role in regulation of myocardial function.
Coronary vasoconstriction response to ET-1 was augmented by pharmacological inhibition of endogenous NO formation and the enhanced constrictor effect was substantially reversed by AM. ET-1 also induced AM synthesis and release. These findings are consistent with the hypothesis that AM may play a compensatory role against excessive coronary vasoconstriction induced by ET-1.
ET-1 contributed significantly to the Frank-Starling response in hypertrophic dTG rat hearts. In contrast, AT1 receptor antagonists did not seem to interfere with the Frank-Starling response, underlining the significance of endothelin system as a regulator of cardiac function in hypertrophic transgenic rat hearts with human renin and angiotensinogen genes.
In mice hearts, ET-1 had a dual role in contractile responses during loading with Gregg effect; ETA receptor activation increased contractility while ETB activation decreased it. AT1 receptor antagonist had no effect on contractile performance, suggesting that ET-1 plays a role in regulation of contractility during load independently of Ang II.
Type XV collagen deficiency caused mild cardiac dysfunction, first detectable as a diminished inotropic response to isoproterenol. It is possible that the heart phenotype is due to impaired perfusion as a result of the capillary endothelial damage. Furthermore, the present findings support the idea that type XV is a structural component of the extracellular matrix needed to stabilize capillaries and muscle fibres, and is essential for the proper functioning of the heart.