AT 1 -RECEPTOR RESPONSE TO NON-SATURATING ANG-II CONCENTRATIONS ISAMPLIFIED BY CALCIUM CHANNEL BLOCKERS: Calcium influx regulate AT 1 R signaling
2017 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261Article in journal, Editorial material (Refereed) Accepted
Background: Blockers of angiotensin II type 1 receptor (AT 1 R) and the voltage gated calcium channel 1.2 (Ca V 1.2) are commonly used for treatment of hypertension. Yet there is little information about the effect of physiological concentrations of angiotensin II (AngII) on AT 1 R signaling and whether there is a reciprocal regulation of AT 1 R signaling by Ca V 1.2.
Methods: To elucidate these questions, we have studied the Ca 2+ signaling response to physiological and pharmacological AngII doses in HEK293a cells, vascular smooth muscle cells and cardiomyocytes using a Ca 2+ sensitive dye as the principal sensor. Intra-cellular calcium recordings were performed in presence and absence of Ca V 1.2 blockers. Semi- quantitative imaging methods were used to assess the plasma membrane expression of AT 1 R and G-protein activation.
Results: Repeated exposure to pharmacological (100 nM) concentrations of AngII caused, as expected, a down-regulation of the Ca 2+ response. In contrast, repeated exposure to physiological (1 nM) AngII concentration resulted in an enhancement of the Ca 2+ response. The up-regulation of the Ca 2+ response to repeated 1 nM AngII doses and the down- egulation of the Ca 2+ response to repeated 100 nM Angll doses were not accompanied by a parallel change of the AT 1 R plasma membrane expression. The Ca 2+ response to 1 nM of AngII was amplified in the presence of therapeutic concentrations of the Ca V 1.2 blockers, nifedipine and verapamil, in vascular smooth muscle cells, cardiomyocytes and HEK293a cells. Amplification of the AT 1 R response was also observed following inhibition of the calcium permeable transient receptor potential cation channels, suggesting that the activity of AT 1 R is sensitive to calcium influx.
Conclusions: Our findings have implications for the understanding of hyperactivity of the angiotensin system and for use of Ca 2+ channel blockers as mono-therapy in hypertension.
Place, publisher, year, edition, pages
Stockholm: BioMed Central, 2017.
Calcium, AT1R, Cell imaging, VGCC, hypertension
Medical and Health Sciences
Research subject Medical Technology
IdentifiersURN: urn:nbn:se:kth:diva-203989OAI: oai:DiVA.org:kth-203989DiVA: diva2:1083618
QC 201703282017-03-212017-03-212017-04-12Bibliographically approved