|ISSN No. 1606-7754 Vol.13 No.2 August 2005|
The mechanism of action of calcium channel blockers in the treatment of diabetic nephropathy
Wael M Yousef1, Adel H Omar1, Mohamed D Morsy2, Moshira M. Abd El-Wahed3, Naglaa M Ghanayem4
Departments of Clinical Pharmacology1, Physiology2, Pathology3, Biochemistry4, Faculty of Medicine, Menoufiya University, Egypt
Three types of calcium channels have been identified voltage-sensitive, receptor operated (cardiac muscle and vascular smooth muscle) and stretch operated (in some blood vessels) channels. Using electrophysiological and pharmacological techniques, three different types of voltage-gated calcium channels have been identified, namely, L-type (for long lasting, large channels), T–type (for transient, tiny channels) and N–type (for neuronal, neither L nor T). Many compounds are known to have a calcium channel inhibitory effect. Calcium antagonists, based on the specificity of inhibition of the slow calcium current, can be classified into three groups: Group A: for 90 to 100 percent inhibition of calcium influx without change in the sodium current (verapamil, diltiazem and the dihydropyridines); Group B: for 50 to 70 percent inhibition of calcium influx current without change in the sodium current (bepridil, cinnarizine and prenylamine) and Group C: for agents exhibiting some inhibition of calcium influx (phenytoin, indomethacin and propranolol). There is now increasing evidence that, certain calcium channel blockers especially the dihydropyridines are more strongly associated with vasodilation of afferent arterioles than of efferent arterioles and also with increase intraglomerular pressure and albuminuria. Thus they have a beneficial effect in terms of reducing proteinuria and slowing the progression of diabetic renal failure.
Keywords: Amlodipine, calcium channel blockers, diabetic nephropathy, diabetes mellitus, diltiazem, ischaemia
By the year 2000, it is estimated that 85,000 individuals will enter into ESRD annually, incurring yearly medical expenditures of approximately US$50,000 per individual. ESRD patients are estimated to consume more than 10 times the health care resources of the average US citizen. Many studies have been performed to clarify the potential benefits of reducing DNP and ESRD in diabetic patients and have confirmed the cost-effectiveness of nephroprotective strategies in the diabetic population primarily through a reduction in ESRD related case costs.1,2
Calcium Channel Blockers
Calcium ions are vital in many biologic processes including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, haemostasis and the metabolism of bone. Calcium antagonists are drugs whose pharmacologic actions are derived primarily from the blockage of calcium influx through calcium channels in excitable membranes. They affect the entry of calcium rather than its intracellular actions and are referred to by some authors as “Calcium Entry Blockers” to make their actions clearer. Since extracellular calcium concentration is approximately 10,000 times greater than its intracellular concentration in a resting smooth muscle, it is clear that small changes in the permeability of calcium across the plasma membrane could have a significant effect on cellular function. The calcium ion is an almost ubiquitous intracellular second messenger. This indicates the multiplicity of the effects associated with drug actions aimed at interfering with calcium ions. In view of the widespread involvement of intracellular calcium as a regulator of cell function, calcium antagonists have been shown to affect many different physiological processes, including secretion of hormones, muscle contraction, platelet function and neurotransmitter release. However, when given to man or experimental animals, their major effects are related to the heart and vascular smooth muscle and their other actions are relatively unimportant. This tissue specificity is critically important in practice. One important factor of this specificity is heterogenicity of calcium channels. Another factor that leads to physiological selectivity is the characteristic of many calcium antagonists that show properties of “use-dependence” i.e. blocking more effectively in those cells in which the calcium channels are most active. Many investigators also show “voltage dependent” blocking actions i.e., blocking more strongly when the membrane is depolarized; this may be partially responsible for the marked selectivity that some drugs show between different kinds of smooth muscles.3
Types of Calcium Channels
Three types of calcium channels have been identified- voltage-sensitive, receptor operated (cardiac muscle & vascular smooth muscle) and stretch operated (in some blood vessels) channels. The regulation of calcium ions depends on both the entry and exit of calcium across the plasma membrane and on the sequestration and release of calcium within the cell. At the membrane level, calcium entry into the cell occurs partly through voltage gated calcium channels (VGCCs) which open when the cell membrane is depolarized. VGCCs belong to a family of homologous proteins that also includes channels for sodium and potassium. In addition, there are believed to be receptor-operated calcium channels (ROCCs), which are coupled to excitatory receptors either directly or via G-proteins and open in response to receptor ligands, such as noradrenaline acting on alpha1-adrenoceptor. In general, calcium channels are membrane-spanning, funnel-shaped glycoproteins that function like ion selective valves. They form a water-filled pore that open and close to permit calcium ions to move in the direction of its electrochemical concentration gradient. Each channel has outer and inner gates: the outer gates are specifically blocked by tetrodotoxin in fast channels and by calcium channel blockers in slow channels. The inner gates, particularly in slow channels, appear to be dependant on the phosphorylation state of the membrane. The position of a channel gate, which is a portion at or near the inner side of the gate, indicates whether the channel is in the closed or opened state. Verapamil and diltiazem block slow channel conduction at the inner gate and possess some fast channel blocking activity as well.4
When conformational changes in the channel macromolecule occur, the activation and inactivation gates move into and out of an occluding position. This determines opening and closing of the channel pore. Calcium binding sites present in the pore ensure ion selectivity of the channels. Phosphorylation sites as well as drug and toxin binding sites of the channel macromolecule play important roles in the regulation of the channel. It should be emphasized that the exact macrostructure of the channel proteins, putative gates and other regulatory sites is unknown at this time.5
Though the direct evidence for ROCCs appears to be strong, they have so far eluded identification experimentally and some even doubt their existence. ROCCs do not appear to be targets for any of the known types of calcium antagonists which act only on VGCCs.6
Types of VGCCs
Using electrophysiological and pharmacological techniques, Tsien et al4 identified three different types of VGCCs which they called L-type (for long lasting, large channels), T–type (for transient, tiny channels) and N–type (for neuronal, neither L nor T). They are classified according to their activation and inactivation kinetics, their conductances, their ion specificity and their sensitivity to drug and toxin. Subsequently, high threshold VGCCs were found to exist in some neurons and were termed P-type channels (for purkinje cells).
There are several endogenous and exogenous modulators that inhibit calcium channels, including dependence of the tissue on external calcium ions, existence of calcium channel subtypes, voltage dependence of drug binding and effects, and frequency dependence of drug effects. All excitable tissues contain voltage dependent calcium channels and high affinity, reversible and stereospecific binding sites for calcium channel-inhibiting drugs. However, calcium antagonists do not affect every tissue equally.7
These are widely distributed in many tissues particularly in heart, smooth and skeletal muscles. They are highly sensitive to the dihydropyridines e.g. nifedipine, phenylalkylamines e.g. diltiazem. There appear to be diverse forms of the L-type channels (L1,2,3,4 isoforms) allowing tissue selectivity and diversity of function.8,9
Thses N-type channels generally seemed to be sensitive to W-contoxins and in certain instance may be coupled to transmitter release whereas selective antagonists of L-type channels do not normally modify neurotransmitter release. Like T but unlike L, N- channels, contribute to phasic currents and require strongly negative holding potentials for complete removal of inactivation. Like L but unlike T, N –current requires strong depolarization for activation and is relatively sensitive to the inorganic blockers cadmium.11
These were proposed by Llinas et al12 on the basis that, dihydropyridine and contoxin resistant currents present in cerebellar Purkinje and granule cells. The most selective toxin is funnel web spider venom. They may form a larger proportion of calcium channels in the brain. Although several calcium ion channels are known, all presently available CCBs act preferentially or solely on one of them, the L-channel.