Contributions of cardiac “funny” (f) channels and sarcoplasmic reticulum Ca²⁺in regulating beating rate of mouse and guinea pig sinoatrial node

Abstract

The aim of this study was to investigate the effects on spontaneous beating rate of mouse atrial preparations following selective block of cardiac “funny” (f) channels, I(f), and/or suppression of sarcoplasmic reticulum (SR) function in the absence and presence of β‐adrenoceptor stimulation. ZD7288 [to block I(f)] caused a substantial reduction (222 ± 13 bpm) in beating rate from 431 ± 14 to 209 ± 14 bpm, ryanodine alone (to block SR Ca2+ release) reduced beating rate by 105 ± 11 bpm, with subsequent addition of ZD7288 further reducing rate by 57 ± 9 bpm. Cyclopiazonic acid (CPA) alone (to inhibit Ca2+ reuptake by the SR) reduced beating rate by 148 ± 13 bpm with subsequent addition of ZD7288 further reducing rate by 79 ± 12 bpm. In additional experiments measuring Ca2+ transients in the SA node region using Rhod‐2, effects of ivabradine and ZD7288 on rate were again substantially reduced after CPA. Effects of CPA alone on rate developed much more slowly than effects on Ca2+ transient amplitude. ZD7288, ivabradine, and CPA reduced the slope and maximum response of the log(concentration)–response curves for effects of isoprenaline on beating rate. Very little response to isoprenaline remained after treatment with CPA followed by ZD7288. Similar changes in isoprenaline log(concentration)–response curves were seen in guinea pig preparations. These observations are consistent with a role for Ca2+ released from the SR in regulating I(f) and therefore beating rate of SA node preparations; there appear to be additional contributions of SR‐derived Ca2+ to effects of β‐adrenoceptor stimulation on beating rate that are independent of I(f).

Protein Kinase 2β Is Expressed in Neural Crest-Derived Urinary Pacemaker Cells and Required for Pyeloureteric Contraction

“…[3][4][5] Although the physiologic mechanisms by which utPMCs function are poorly studied, Ca 2+ signaling and an internal Ca 2+ clock are thought to regulate their activity in a manner similar to that of heart and gut PMCs. [7][8][9][10][11][12][13][14][15][16][17] Disruption of coordinated ureteric contraction causes nonobstructive hydronephrosis, defined as dilatation of the renal pelvis and ureter without physical obstruction to urinary flow. Previously, we demonstrated that decreased Hedgehog signaling during mouse kidney development results in nonobstructive hydronephrosis.…”

“…48 Ca 2+ signaling has been described as a major signaling pathway in PMC in the heart, gut, and the urinary tract. 8,11,12,[14][15][16][17] PTK2b has also been shown to interact with SRC kinase, a known regulator of HCN channels. [49][50][51] Our results indicate that pharmacologic inhibition of PTK2b in pyeloureteric explant tissue significantly reduces ureteric contraction frequency, suggesting that PTK2b controls PMC function.…”

Positive Feedback Mechanisms among Local Ca Releases, NCX, and ICaL Ignite Pacemaker Action Potentials

“…Recent theoretical and experimental studies (10,20,25) have shown that a selective perturbation of only one clock (either M-clock or Ca-clock), namely by ivabradine, a direct I f inhibitor, or by cyclopiazonic acid, a direct SERCA (SR Ca pump) inhibitor, affects the other clock indirectly. If the timing of the ignition phase onset is a universal timing mechanism of the coupled-clock system, an increase in steady-state APCL in response to either ivabradine or cyclopiazonic acid should be similarly linked to a change in the onset of the ignition phase.…”

Ivabradine inhibits carbachol-induced contractions of isolated rat urinary bladder

“…This is plausible, considering the role of Ca 2+ released from the SR in regulating If in SA node preparations. 21 In bladder overactivity, developed in a rat model following partial bladder outlet obstruction, it was shown that the physiological functioning of ICCs changes and the expression of the HCN channels in bladder ICCs significantly increases. [22][23][24] These findings suggest that the HCN channels and ICCs might play an important role in the pathogenesis of detrusor overactivity.…”