The Metabolic Barrier of the Coronary Endothelium as a Determinant of Flow Responses

Summary

Numerous vasoactive substances are extensively degraded during coronary passage in the isolated heart of the guinea pig, largely because of enzymes located on or in the vascular endothelial cells. Examples of such substances are adenosine, adenine nucleotides (ATP, ADP, AMP, α,β- and β,γ-methylene ATP), bradykinin, and acetylcholine. Consequently, the endothelium modulates the effective concentrations of these agonists at the cell membrane receptors mediating coronary dilatation. This can be readily evidenced for bradykinin by adding converting enzyme (kininase II) inhibitors, such as ramiprilat, and for adenosine in the presence of cell uptake blockers, e. g., dipyridamole. At least in the case of adenosine, the metabolic capacity of the endothelium for adenosine phosphorylation or degradation is so great that, at submicromolar concentrations, adenosine practically cannot pass from the intra- to the extravascular space, or vice versa. As shown in experiments with selectively prelabeled endothelial adenine nucleotides, even adenosine escaping from endothelial cells is taken up and degraded downstream, still within the coronary system. This finding supports the proposed role of the endothelium in maintaining the homeostasis of adenosine. Due to endothelial catabolism, it appears that coronary dilatation by many infused agonists must be indirect, necessitating mediation by the endothelium itself. Moreover, the enhanced dilatory efficacies of infused adenosine, acetylcholine, and bradykinin in hearts where vascular permeability has been increased by pretreatment with hydroxyl radicals presumably reflect facilitated access to membrane receptors situated abluminally on the endothelial cells and/or on the vascular smooth muscle cells (adenosine).

The coronary endothelium poses a powerful metabolic barrier, restricting the passage of many vasoactive substances and determining the respective flow responses. However, this barrier is not invariant, but can be modified by drugs or by enhanced vascular permeability, such as under inflammatory conditions and in post-hypoxic myocardium.