Abstract 37: Loss Of BK Ca - IP3R Functional Coupling Underlies Vascular Hypercontractility In Spontaneously Hypertensive Rats

The cellular mechanisms underlying enhanced vascular contractility in hypertension are still not fully clear. Recent studies have demonstrated that functional coupling between the large-conductance Ca 2+ -activated K + (BK Ca ) channel in the cell membrane and inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum is involved in the regulation of intracellular Ca 2+ in vascular smooth muscle cells (VSMC) and vascular contractility. Here, we examined the role of BK Ca -IP3R coupling in vascular hypercontractility in Spontaneously Hypertensive Rats (SHR), as compared with Sprague Dawley (SD) rats. In pressurized mesenteric arteries, paxilline (1μM), a selective BK Ca channel blocker, significantly increased norepinephrine (1μM)-induced vasoconstriction in both SHR (% initial diameter: 71.6±6.8% [95.9±13 of 132.8±6.2 μm] and 65.0±4.8% [80.6±7.7 of 123.6±3.9 μm] in arteries treated with vehicle and paxilline respectively, n=4, PCa channels are involved in hypercontractility in SHR. In inside-out patch-clamp, BK Ca channels in VSMCs isolated from mesenteric arteries of SHR and SD rats displayed identical calcium and voltage sensitivity. We next examined the effect of the selective IP3R-agonist, Adenophostin A, on BK Ca current density in VSMCs, using patch-clamp whole-cell mode. The results demonstrated that Adenophostin A (5μM) significantly increased BK Ca current density in VSMCs from both SHR (from 41.9± 5.7 to 61.5±9.1 pA/pF; n=6 cells, pCa current density was significantly diminished in VSMCs of SHR as compared with SD rats. In conclusion, the results indicate that loss of functional coupling between BKca and IP3R is involved in vascular hypercontractility in SHR arteries.