Depolarization shift response

Flecainide decreases the maximal rate of depolarization in atrial tissue and shifts the membrane responsiveness curve to the right. 

Inhaled anesthetics change heart rate either directly by altering the rate of sinus node depolarization or indirectly by shifting the balance of autonomic nervous system activity. Bradycardia is often seen with halothane, probably through vagal stimulation. In contrast, enflurane, and sevoflurane have little effect, and both desflurane and isoflurane increase heart rate. In the case of desflurane, cardiovascular responses include a transient sympathetic activation that can lead to marked increases in heart rate and blood pressure when high inspired gas concentrations are administered. 

Fig. 8.3 Effects of dietary selenium on p-adrenergic responses in rat heart, (a) L-type Ca2+ currents (I(a i recorded from ventricular myocytes with depolarization from —70mV to OmV, for 200 ms. Mean ( SEM) values of peak amplitudes of IcaL in both experimental and control groups. The cell capacitances of these three groups of cardiomyocytes were similar, (b) Average current-voltage relationships for peak IcaL (measured as the difference between the peak Ca2+ current and the end of 200-ms depolarization). The maximums of IcaL of both experimental groups were shifted to the right with respect to the control, (c) The threshold potentials were significantly more negative and activation potentials were more positive in both experimental groups with respect to the control. (Adapted from Sayar et al. 2000.)...

Dopamine acting via the D2 receptors has complex effects on Na+ currents. An increase in the amplitude of this current has been reported in a minority of cells (Surmeier et al., 1992a). These currents are also reduced in response to a D2 receptor activation by means of a negative shift in voltage dependence of steady-state inactivation (Surmeier et al., 1992a). In cells in which a D2-mediated decrease in Na+ current was measured, the decrease was due to a shift in the voltage dependent inactivation towards more hyperpolarized potentials. This would make no difference at hyperpolarized Down state potentials but a big difference at more depolarized Up state potentials, where the effect would be to reduce the Na+ current in most cells. 

Regulation of cellular activities by cyclic AMP-dependent protein kinase (PKA) is a critical pathway in neuronal responses via the potassium channel A-current (Childers and Deadwyler 1996). In rat hippocampal cells, PKA phosphorylation of the potassium channel produced a negative shift in the voltage-dependence (Deadwyler et al. 1995). CBi receptor stimulation resulted in a decrease in intracellular cyclic AMP, net dephosphorylation of the channels, activation of the A-type potassium currents, and hyperpolarization of the membrane (Deadwyler et al. 1995 Hampson et al. 1995). The significance of cannabinoid-mediated hyperpolarization of the axon terminals is that it can cause a depression in the response to depolarizing stimuli and failure in neurotransmitter release at the synapse (Childers and Deadwyler 1996). 

Phthalide 30 dose-dependently relaxed phenylephrine- and KCl-induced precontractions in aortas isolated from spontaneous hypertensive rats [354]. Neither endothelium removal nor /V°-nitro-L-arginine methyl ester (L-NAME) affected the vasodilatory response of 30 [354], These results were not in line with Xu s observation that 30 stimulated NO release from bovine aortic endothelial cells [342]. Phthalide 30 also non-competitively right-shifted cumulative phenylephrine and high K+-depolarized Ca2+ dose-response curves but did not affect caffeine-induced Ca2+ release from internal stores [354]. The discrepancies among experiments may have been due to the differences in the choice of animals and preparations utilized. 

Ultimately, the motor end-plate membrane gets repolarized inspite of the continued presence of the drug substance by virtue of a shift in receptor conformation. Though the membrane is normally poised for a new lease of depolarization, yet ACH and the motor nerve impulses do not succeed to evoke an appreciable response. Perhaps, this could be due to the fact that the nicotinic receptor is not positioned in its desired configuration. It has also been observed that during this critical phase, the neuromuscular blockade usually occurs specifically on certain characteristic features of competitive blockade and this may even get antagonized partially by the aid of anticholinesterases. 

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