Distribution Of L-type Ca2 Research Articles

Combined L-/T-Type Calcium Channel Blockers

Opening of the voltage-dependent Ca2+ channels permits influx of Ca2+ across the plasma membrane, triggering diverse physiological processes. These channels are widely distributed in the cardiovascular system, constituting the main route for Ca2+ entry essential for excitation and contraction. Ten unique α1 subunits, grouped in 3 families (CaV1, CaV2, and CaV3), that encode the low-voltage–activated T-type and the high-voltage–activated L-, N-, P/Q- and R-type Ca2+ channels, have been identified.1,2 L-type Ca2+ channels are predominantly expressed in the hearts and peripheral vasculature and serve as the preferred molecular target of the initial Ca2+ channel antagonists in the treatment of hypertension.3 Recently, a growing body of evidence has accumulated depicting important roles of T-type Ca2+ channels in the regulation of cardiovascular function, such as generation of pacemaker potential and regulation of arterial resistance.3,4 T-type Ca2+ channels are found in various cell types, including neurons, cardiomyocytes, vascular smooth muscle cells, and endocrine cells, where they participate in a variety of physiological processes, such as low-threshold Ca2+ spike generation, action potential firing, pacemaking, impulse conduction, maintenance of myogenic tone, cell proliferation, and hormone secretion.1 In addition to their predominant role in the regulation of vascular function, T-type Ca2+ channels are also involved in cardiomyocyte growth and survival.3 T-type Ca2+ channel blockers are capable of interrupting certain pathological hypertrophic signaling pathways, including calcineurin-mediated nuclear factor of activated T cells–3 activation.1 The importance of voltage-dependent Ca2+ channels is demonstrated by the clinical efficacy of Ca2+ channels blockers in certain disease conditions, as well as the widespread distribution and function of these channels.1 Three classes of chemically distinct L-type Ca2+ channel blockers have been widely used clinically depending on their biophysical and conformation-dependent interactions …

Ca 2+ Channel Subtypes and Pharmacology in the Kidney

A large body of evidence has accrued indicating that voltage-gated Ca(2+) channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca(2+) channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca(2+) channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca(2+) channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca(2+) channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca(2+) channels and elicit vasodilation of afferent and efferent arterioles, which suggests the presence of T-type Ca(2+) channels in both arterioles and the distinct impact on intraglomerular pressure. Recently, aldosterone has been established as an aggravating factor in kidney disease, and T-type Ca(2+) channels mediate aldosterone release as well as its effect on renal efferent arteriolar tone. Furthermore, T-type CCBs are reported to exert inhibitory action on inflammatory process and renin secretion. Similarly, N-type Ca(2+) channels are present in nerve terminals, and the inhibition of neurotransmitter release by N-type CCBs (eg, cilnidipine) elicits dilation of afferent and efferent arterioles and reduces glomerular pressure. Collectively, the kidney is endowed with a variety of Ca(2+) channel subtypes, and the inhibition of these channels by their specific CCBs leads to variable impact on renal microcirculation. Furthermore, multifaceted activity of CCBs on T- and N-type Ca(2+) channels may offer additive benefits through nonhemodynamic mechanisms in the progression of chronic kidney disease.

Pharmacology of N-type Ca2+ channels distributed in cardiovascular system (Review).

Irregular functions in Ca2+ channels are intimately involved in many aspects of cardiovascular diseases. We can obtain a wide variety of L-type Ca2+ channel antagonists to treat hypertension and angina pectoris. Dihydropyridines (DHPs) have, first of all, been extensively developed due to their high selectivity for L-type Ca2+ channel and safety in pharmacological aspects. In contrast, many lines of evidence suggest that clinical efficacy of those DHPs are limited and undesirable effects are sometimes observed because of the specific distribution of L-type Ca2+ channels. As well as the L-type, peripherally distributed N-type Ca2+ channel plays a key role in cardiovascular regulation through autonomic nervous system. Recently, we developed a unique DHP derivative, cilnidipine (FRC8653) which has a dual antagonistic action on both L-type and N-type Ca2+ channels. Our recent studies with this DHP have made it clear that the N-type Ca2+ channel is also a new therapeutic target in cardiovascular diseases. We review the recent advances in pharmacology of the N-type Ca2+ channel and therapeutic implications of their antagonists.

Voltage-gated calcium channels inPleurodelesoocytes: classification, modulation and functional roles

In unfertilised Pleurodeles oocytes, two distinct types of high voltage-activated Ca2+ channels are expressed: a slowly inactivating Ca2+ channel and a transient one. The first is dihydropyridine-sensitive and is referred to as the L-type Ca2+ channel. The transient channel is highly sensitive to Ni2+. Phosphorylation through protein kinases G and A facilitates and inhibits the L-type Ca2+ channel respectively. The transient type channel is insensitive to stimulation by protein kinases (A and G). The functional expression of L-type and transient Ca2+ channels is modulated by the two maturation seasons. The transient Ca2+ currents are only observed during the resting season, while the L-type current is observed either alone during the breeding season or in association with the transient current during the resting season. Moreover, the current density of the L-type Ca2+ channel is much greater during the breeding season than the resting season. Thus, the wide distribution of L-type Ca2+ channels in Pleurodeles oocytes during the two seasons suggests that the roles of these channels may be important in the regulation of the maturation process.

Longitudinal distribution of Na+ and Ca2+ channels and beta-adrenoceptors on the sarcolemmal membrane of frog cardiomyocytes.

1. The distribution of L-type Ca2+ and tetrodotoxin-sensitive Na+ channels and of beta-adrenergic receptors was examined in frog ventricular myocytes using the whole-cell patch-clamp technique and a double capillary for extracellular microperfusion. 2. Rod-shaped cells (250-300 microns long) were sealed at both ends to two patch-clamp pipettes and positioned transversally at different positions between the mouths of two microcapillaries separated by a thin wall. A combination of nifedipine (1 microM) and tetrodotoxin (0.3 microM) (blocking solution) was added to one capillary in order to inhibit macroscopic Ca2+ and Na+ currents (Ica and INa, respectively) in the part of the cell exposed to this capillary. 3. Moving the cell in 10-20 microns steps from the control capillary to the capillary containing the blocking solution induced step decreases in Ica and INa amplitudes. Complete block of both currents occurred when the entire cell was exposed to the blocking solution. 4. Each step decrease in current was due to the loss of activity of the functional Ca2+ and Na+ channels present in the slice of sarcolemmal membrane newly exposed to the blocking solution. These step current changes allowed longitudinal mapping of current density for Ca2+ and Na+ channels on the sarcolemmal membrane. 5. Addition of a submaximal concentration of isoprenaline (10 nM) to the control capillary induced a local increase in Ica which enabled examination of the distribution of functional beta-adrenergic receptors as well. 6. Our results demonstrate that Ca2+ and Na+ channels and beta-adrenergic receptors are equally and essentially uniformly distributed on the sarcolemmal of frog ventricular myocytes.