Inhibition of calcium release of diazoxide studied in the isolated rat kidney.

Isolated kidneys of normotensive Wistar rats (NWR) and of genetically hypertensive Kyoto rats (SHR) were perfused. Contraction of intrarenal vascular smooth muscle cells were induced by barium ions (0.1 to 1.0 mmol) as well as by high potassium concentrations (40 mmol). It was shown that barium stimulates intracellular calcium stores to release activator calcium. Repeated stimulation with barium under calcium-free perfusion conditions resulted in depletion of these stores. In kidneys of SHR rats the tension development in response to barium was stronger as compared with NWR rats and the time needed to deplete the stores was prolonged. This suggests that smooth muscle cells of SHR rats contain more sequestered calcium. Diazoxide inhibited the barium contracture rapidly, reversibly and dose dependently. The inhibition was non-competitive. Percentual inhibition was equal in NWR and in SHR rat kidneys. Moreover, diazoxide did not block the calcium influx across the sarcolemma membrane. The magnitude of the potassium contractures depended entirely upon the extracellular calcium concentration. In the range of 0.1 to 1.0 mmol calcium, tension development varied linearly with log calcium concentration. Diazoxide also inhibited the potassium contractures, provided normally filled calcium stores were available. The combined results strongly suggest that diazoxide prevents intracellular calcium stores to release calcium and, furthermore, that this action is the basic mechanism of the vasodilating activity of diazoxide in smooth muscle cells of rat intrarenal vessels.