Voltagedependent Ca2 Channels VDCCs

VDCCs are expressed in all vascular SMCs and are important players in the maintenance of vascular tone (33). Although two principal types of VDCCs, dihydropyridine-sensitive high-voltage-activated L-type and low-voltage-activated, rapidly-inactivating T-type, VDCCs have been characterised in vascular SMCs (33), electrophysiological evidence currently suggests that only L-type VDCCs are expressed in PASMCs (13, 22).

Despite the fact that L-type VDCC inhibitors are widely used to treat PPH, surprisingly little is known about the electrophysiological properties and regulation of L-type VDCCs in PASMCs. Clapp and Gurney (13) characterized nifedipine-sensitive Ca2+-andBa2+-permeable VDCC currents in rabbit PASMCs (13). The amplitude of VDCC was reduced by ~45% by the vasosodilator sodium nitroprusside (SNP), suggesting that SNP can cause vasodilatation partly via inhibition of VDCC (13). Recently, an analysis of the current density of L-type VDCCs has revealed that it is greater in conduit than in resistance artery rabbit PASMCs (22). Intriguingly, acute hypoxia causes an increase in Ca2+

currents (using Ba2+ as the permeating ion) and shifts the voltage-conductance dependence to the right along the voltage axes in resistance PASMCs; in conduit PASMCs, the current amplitude is decreased and the activation dependence is shifted in the opposite direction (22). The molecular mechanism of these effects has not been investigated. Similar upregulation of L-type VDCC currents also occurs in rat resistance PASMCs during CH (Fig. 2), suggesting that an increased expression of L-type VDCCs, together with simultaneous inhibition of Kv channels, contributes to membrane depolarisation and CH-induced pulmonary hypertension. Increased Ca2+ influx through L-type VDCC could also contribute to vascular remodelling in pulmonary arteries.

Figure 2. Up-regulation of the L-type VDCC currents by chronic hypoxia in rat resistance PASMCs. Mean current-voltage relationships (4-9 cells) for IBa recorded in the presence of 10 raM BaJ+ (circles), and 1 (iM Bay K 8644 (triangles) or 10 fiM nifedipine (squares), an activator and inhibitor of L-VDCCs, respectively, in control (A) and CH (3-4 weeks, B) animals. Inserts show IBa at 0 mV in representative cells in the absence and presence of Bay K 8644 and nifedipine as indicated by symbols. Currents were recorded using Cs+-based, 10 mM EGTA-containing pipette solutions. Holding potential was -80 mV.

Figure 2. Up-regulation of the L-type VDCC currents by chronic hypoxia in rat resistance PASMCs. Mean current-voltage relationships (4-9 cells) for IBa recorded in the presence of 10 raM BaJ+ (circles), and 1 (iM Bay K 8644 (triangles) or 10 fiM nifedipine (squares), an activator and inhibitor of L-VDCCs, respectively, in control (A) and CH (3-4 weeks, B) animals. Inserts show IBa at 0 mV in representative cells in the absence and presence of Bay K 8644 and nifedipine as indicated by symbols. Currents were recorded using Cs+-based, 10 mM EGTA-containing pipette solutions. Holding potential was -80 mV.

Another important class of calcium selective channels is transient receptors potential channels (TRPCs), which form the molecular basis of the store-operated or capacitative Ca2+ entry channels and agonist-activated nonselective cation channels in variety of tissues including Vascular SMCs. The role of TRPCs in the control of excitation and contraction of PASMCs has only recently been described and will be discussed in detail in a later chapter.

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