Adenosine Receptors at the Coronary Endothelium: Functional Implications

Summary

Cultured coronary endothelial cells (CEC) are characterized by an active metabolism of adenosine (AR) and adenine nucleotides (AN). Extracellularly applied AN (AMP, ADP or, ATP) are rapidly dephosphorylated by a cascade of nucleotidases at the cell surface. AR, formed by these processes or directly added into the incubation medium, is avidly taken up: small amounts are preferentially phosphorylated, larger amounts are degraded mainly to uric acid. With a specially developed dual-chamber perfusion system the ability of AR and AN to penetrate across confluent endothelial layers was determined. Regardless whether these vasoactive compounds were applied at the apical or basal side of the cell layer, at concentrations <10⁻⁶ M only vasoinactive degradatives were detected at the contralateral side.

These in vitro findings can be extended to the in situ coronary endothelium. For example, autoradiographic studies on isolated perfused guinea pig hearts directly demonstrated that this tissue functions as a metabolic barrier which prevents passage of AR from the intravascular to the interstitial space.

Intra-arterially applied AMP, ADP, ATP, or high molecular weight polyadenylic acid, though confined to the intracoronary space, induce coronary flow increases just as promptly as AR. Thus, the smooth muscle relaxing effects of all these vasoactive compounds must be elicited by an endothelium-mediated process involving surface receptors.

AR, NECA, and R-PIA stimulate the formation of cyclic AMP in CEC, a slow process protracted over 15 min. The adenosine agonist effects on endothelial adenylate cyclase (AC) could be blocked by various alkylxanthines. Adenine nucleotides did not influence AC activity. On the other hand, AR as well as its nucleotide derivatives induced a rapid activation of phospholipase C within 15 s.

Obviously two different types of adenosine receptors are present at the surface of CEC:

• a) Adenosine receptors of type A₂, which stimulate endothelial AC in the same way as β-adrenergic compounds;

• b) purinoceptors of a mixed type (designated P¹⁺²), which are activated by AR and its nucleotide derivatives. This receptor uses phospholipase C as a promptly responding signalling system. In contrast to the A₂ receptor, which perhaps participates in the regulation of capillary permeability, the endothelial P₁₊₂ receptor may be involved in the regulation of coronary flow.

According to our results, the microvascular coronary endothelium is not only a morphologie but also metabolic barrier between the interstitial and the intravascular space. The individual cells of this tissue are able to respond to chemical signals via receptors at their luminal and very probably also abluminal surface. Endothelial cells of capillaries and arterioles possibly communicate with each other and via myoendothelial junctions also with the smooth muscle cells of the resistance vessels. This concept could open up new aspects of the metabolic regulation of coronary flow.