It has been suggested that angiotensin II (AngII) via AT1 receptors (AT1R) can regulate the activity of L-type Ca
2+-channel (VGCC). Little is known of any reciprocal regulation. To study if VGCC play a role in AngII induced AT
1R dependent calcium signaling we performed [Ca
2+]
i studies in conditions where VGCC are blocked, by Nifedipine, or down regulated, by a PKC inhibitor.
We recorded the [Ca2+]i to repeated doses of physiological (1 nM) AngII in AT1R expressing HEK293a cells at (three time points) 0 min, following a five and following additional 30 min recovery. The 1st dose of physiological AngII gave a robust calcium peak, no significant desensitization was observed to the 2nd dose, and the response to the 3rd dose was 2-fold enhanced. In the presence of Nifedipine the 1st dose gave a seven times higher response compared to control, followed by a gradual desensitization to the 2nd and 3rd dose. The same pattern was found in the presence of BIMII a PKC inhibitor, a boosted response to the 1st dose followed by a gradual desensitization.
The experimental set up was repeated in primary culture of rat ventricular myocytes. We found that the results were consistent with the HEK293a model, blockage of VGCC drastically up-regulate the AT1R dependent [Ca2+]i response to a physiological AngII dose.
This enhanced response could not be explained by increased recruitment of AT1R to the plasma membrane or an increase in G-protein recruitment.
We conclude that reduced L-type Ca
2+-channel activity can up-regulate AT
1R signaling and that this regulation is not due to an up-regulation of receptor number or G-protein activity. These findings should be considered prior to hypertension treatment with calcium channel blockers.
