Hajime Takamatsu

Effect of inhibition of Na+-K+ ATPase on the prostacyclin generation of cultured human vascular endothelial cells.

Prostacyclin (PGI2) generation of cultured human vascular endothelial cells (VEC) was observed coincidentally with the increase of 45Ca net influx. Ca ionophore A23187 enhanced not only PGI2 generation and 45Ca net influx but also 45Ca efflux. PGI2 generation was completely abolished by the pretreatment with Ca++ immobilizer, TMB-8. A Na+-K+ ATPase inhibitor, ouabain increased 45Ca net influx, but decreased 45Ca efflux, and enhanced PGI2 generation. These observation indicate that PGI2 generation of VEC may be regulated by not only Ca++ but also Na+, and it was suggested that enhanced PGI2 generation by ouabain might be derived from the increased cytosolic Ca++concentration by the decreased Ca++ efflux, and it was considered to be originated from the suppression of Na+-Ca++ exchange systems by the increased intracellular Na+ concentration via inhibition of Na+-K+ ATPase activity by ouabain. Enhancement of PGI2 generation of VEC by the increased ouabain like substances (OLS) in hypertension is suspected to be beneficial on the maintenance of vascular homeostasis.

Modulation of prostacyclin generation in cultured human vascular endothelial cells and the effects of human α-natriuretic polypeptide

Vascular endothelial cells have been known to possess not only a barrier function but also other biologically important functions maintaining vascular homeostasis. Among these, the generation of prostacyclin is one of the most conspicuous functions, and the modulation of its synthesis and liberation has been of interest with reference to the interaction with several vasoactive substances, including human atrial alpha-natriuretic polypeptide. This paper investigates the regulatory mechanism of prostacyclin generation using cultured human vascular endothelial cells as far as Ca2+ flux, (Na+ + K+)-ATPase activity, and Na+-Ca2+ exchange systems are concerned. Through these experimental studies the following results were obtained. Prostacyclin generation was triggered by an increase of Ca2+ influx, and an increase in intracellular Na+ also enhanced it, and this was accompanied by a decreased Ca2+ efflux arising from suppression of Na+-Ca2+ exchange systems. (Na+ + K+)-ATPase activity as well as prostacyclin generation was also enhanced by the increase of intracellular Na+. These results indicate a possible link between the mechanism which generates prostacyclin in the human vascular endothelial cells and the mobilization of electrolytes; however, in this aspect human atrial alpha-natriuretic polypeptide had no effect on the endothelial cells.

REGULATION OF PROSTACYCLIN GENERATION BY ANGIOTENSIN CONVERTING ENZYME RELATED SUBSTANCES IN CULTURED HUMAN VASCULAR ENDOTHELIAL CELLS.

The regulation of prostacyclin (PGI2) generation by angiotensin I-converting enzyme (ACE) related substances was investigated using cultured human vascular endothelial cells. Angiotensin I (AI) or bradykinin (BK) increased PGI2 generation and ACE activity, while the ACE inhibitor, captopril decreased both of them, and angiotensin II (AII) did not show any effect. The increasing rate of PGI2 generation induced by AI or BK was not affected by the pretreatment with captopril. These results suggest that the accumulation of AI or BK via the inhibition of ACE by captopril did not cause the enhancement of PGI2 generation. Rather, it was proposed that the enhanced PGI2 generation by AI or BK might be regulated by ACE activation derived from these substances, as an autoregulation mechanism.