Down-Regulation Of Ca(V)1.2 Channels During Hypertension: How Fewer Ca(V)1.2 Channels Allow More Ca2+ Into Hypertensive Arterial Smooth Muscle

Hypertension is a clinical syndrome characterized by increased arterial tone. Although the mechanisms are varied, the generally accepted view is that increased Ca(V)1.2 channel function is a common feature of this pathological condition. Here, we investigated the mechanisms underlying vascular dysfunction in a mouse model of genetic hypertension. Contrary to expectation, we found that whole-cell Ca(V)1.2 currents (I-Ca) were lower in hypertensive (BPH line) than normotensive (BPN line) myocytes. However, local Ca(V)1.2 sparklet activity was higher in BPH cells, suggesting that the relatively low I-Ca in these cells was produced by a few hyperactive Ca(V)1.2 channels. Furthermore, our data suggest that while the lower expression of the pore-forming (1c) subunit of Ca(V)1.2 currents underlies the lower I-Ca in BPH myocytes, the increased sparklet activity was due to a different composition in the auxiliary subunits of the Ca(V)1.2 complexes. I-Ca currents in BPN cells were produced by channels composed of (1c)/(2)/(3) subunits, while in BPH myocytes currents were probably generated by the opening of channels formed by (1c)/(2)/(2) subunits. In addition, Ca2+ sparks evoked large conductance, Ca2+-activated K+ (BK) currents of lower magnitude in BPH than in BPN myocytes, because BK channels were less sensitive to Ca2+. Our data are consistent with a model in which a decrease in the global number of Ca(V)1.2 currents coexist with the existence of a subpopulation of highly active channels that dominate the resting Ca2+ influx. The decrease in BK channel activity makes the hyperpolarizing brake ineffective and leads BPH myocytes to a more contracted resting state.