Abstract
IntroductionComorbidities such as diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are often associated with altered coronary microvascular function. However, the specific mechanisms affected by the various comorbidities have not been investigated in detail. Here we studied endothelium‐dependent and ‐independent vasodilation of isolated small coronary arteries, as well as vasoconstrictor responses to endothelin‐1 and their specific mechanisms of action in swine with multiple comorbidities.Methods and ResultsDM (streptozotocin, 150mg/kg i.v.) and hypercholesterolemia (high fat diet) were induced in 10 female swine, which were followed for 6 months (DM+HC). In a separate group of 9 female swine, CKD (by renal artery embolization) was added on top of the two risk factors and animals were followed for 6 months (DM+HC+CKD). 12 female healthy swine on normal pig‐chow served as controls. At sacrifice, coronary small arteries were isolated and vasomotor control was studied in vitro. Both DM+HC and DM+HC+CKD groups showed impaired endothelium‐dependent vasodilation to bradykinin, mainly via loss of EDHF‐dependent mechanism. No changes were seen in the response to the exogenous NO‐donor, SNAP, indicating preserved smooth muscle cell function. Coronary arteries from swine with DM+HC exhibited a blunted vasoconstriction to endothelin‐1, (ET‐1), due to increased ETB‐mediated vasodilation. In contrast, adding CKD to DM+HC resulted in enhanced ET‐1 vasoconstriction.ConclusionDiabetic metabolic dysregulation and chronic kidney disease induce comorbidityspecific perturbations in coronary microvascular function in swine.Support or Funding InformationSupported by grants from the European Commission FP7‐Health‐2010 grant MEDIA‐261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014‐11(RECONNECT)] and The Academy of Finland 251272.
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