PMC

Interplay between channel gating and open channel block. (A) Schematic depicting inhibition of current (black line) by a prototypical open channel blocker. Three agonist applications (green bars) are shown. The first agonist application in the absence of blocker shows the control response. The second agonist application, which follows the application and removal of a blocker (red bar), shows that the blocker cannot access its binding site when the channel is closed. The third agonist application, which is made in the presence of a blocker, shows that the blocker can access its binding site and inhibit agonist-activated current when the channel is in the open state. Entry of a blocker into open channels accelerates the apparent decay of the response and decreases the steady state response. Because the blocker cannot bind until the channel opens, peak current in response to the first agonist application in the presence of the blocker may be unaffected, as shown here. However, if blocker binding is fast relative to current activation kinetics, the peak response may be reduced. (B) Ion channels can transition between open, ion permeable states and closed, impermeable states. k_c is transition rate into closed state and k_o is transition rate into open state. (C–E) The size of channel blocking compounds (red) and depth of the blocking site affects blocker interactions with the channel gate. (C) Small channel blockers, such as inorganic cations, can block open channels without preventing channel closure or affecting gating transitions. k_on is blocker binding rate and k_off is blocker unbinding rate. When the channel is blocked by a blocker that does not interact with the gate, channel closing rate is k′_c and channel opening rate is k′_o. (D) Small-to-intermediate-sized organic channel blockers can block open channels without preventing channel closure, but nevertheless can interact with the channel gate, either accelerating or decelerating gating transitions. When the channel is blocked by a blocker that interacts with the gate, channel closing rate is k″_c and channel opening rate is k″_o. (E) Large, organic, sequential/foot-in-door blockers can block open channels and prevent channel closure. k‴_c is channel closing rate when the channel is blocked by a sequential/foot-in-the-door blocker.

(A) No blocker binding step;(B) 1-minute blocker binding step; (C) 2-minute blocker binding step.

Pharmacological PSNS blockade mortality and ECG. A: Mortality during severe hypoglycemia was 33% in the control (white bar) and 15% in M2 blocker (gray bar) group, with no mortality in the N blocker group. B: Premature ventricular contraction (PVC) frequency was similar between control (0.14 ± 0.3/min) and M2 blocker (0.15 ± 0.3/min). Premature ventricular contractions were significantly reduced with N blocker (0.003 ± 0.007/min). C: First-degree heart block was completely prevented in N blocker vs. controls (0.1 ± 0.2/min), whereas that in M2 blocker (0.006 ± 0.013/min) was similar to that in controls. D: Second-degree heart block was similar between M2 blocker (0.17 ± 0.3/min) and control (1.8 ± 7/min). N Blocker completely prevented second-degree heart block. E: Third-degree heart block was also completely prevented by N blocker compared with control (32%), with no difference in M2 blocker (15%). F: Nonsustained ventricular tachycardia was prevented in both M2 and N blocker groups compared with control (21%), but this difference did not reach significance. *P < 0.05 vs. controls. Data are mean ± SD. N = 13–25/group.

Effects of antihypertensive drugs, calcium channel blocker (CCB), angiotensin type I receptor blocker (ARB), angiotensin-converting enzyme inhibitor (ACEI), β blocker and diuretics on Rho-associated kinase (ROCK) activity in patients with hypertension. A, Western blot analysis for phospho-myosin-binding subunit (p-MBS), total-myosin-binding subunit (t-MBS), and β tublin in calcium channel blocker, ARB, ACEI, β blocker and diuretic groups. B, ROCK activity (p-MBS/t-MBS) in the CCB, ARB, ACEI, β blocker and diuretics groups.