1,4-Dihydropyridine calcium channel ligands: Selectivity of action. The roles of pharmacokinetics, state-dependent interactions, channel isoforms, and other factors

The selectivity of action of the clinically available calcium channel antagonists depends on a number of factors: 1) Mode of calcium mobilization - intracellular and extracellular sources. 2) Class and subclass of calcium channel involved. 3) Pharmacokinetic considerations, including distribution and interactions with cell membranes. 4) State-dependent interactions - voltage- and frequency-dependent interactions. 5) Pathologic state of tissue and channel regulation. These factors will be illustrated with particular reference to the 1,4-dihydropyridine series of ligands. The Ca²⁺ channel antagonists may be placed in several classes according to their rates of onset and offset of action, and the overall cardiovascular activity of an agent can profoundly alter its hemodynamic response. Additionally, third-generation agents such as lacidipine and lercenadipine partition extensively into plasma membranes according to membrane composition. Calcium mobilization through the L-type channel is the dominant target of the available antagonists: hence, systems that rely dominantly or exclusively on other mobilization processes are insensitive. Renal afferent and efferent arterioles that regulate glomerular flow and resistance are sensitive to the powerful vasoconstrictive effects of angiotensin II; however, only the processes in the afferent arteriole are sensitive to the Ca²⁺ channel antagonists. An important and subtle process for conferring tissue selectivity of action is derived from state-dependent interactions between channel and drug, whereby, according to the modulated-receptor hypothesis, drugs may exhibit preferential affinity for or access to different states of the channel - resting, open, or inactivated. Transitions between these states are determined by membrane potential and biochemical factors, including channel phosphorylation. The 1,4-dihydropyridine series exhibit significant and structure-dependent voltage-dependent interactions, which reflect a preferential interaction with open and/or inactivated channel states. The differential pharmacology of the L-type Ca²⁺ channel is a further determinant of tissue selectivity. The cardiovascular system expresses three different α₁ subunits - Ca_v1.2_A-C - and although a detailed pharmacological comparison is not yet available, there is sufficient evidence to indicate important differences. Thus, the 1,4-dihydropyridine nisoldipine interacts differentially with recombinant channels derived from cardiac and vascular smooth muscle. A number of disease states, both clinical and experimental, have been associated with changes in Ca²⁺ channel expression and function, although the causal relationship is often not established. Thus, in cardiac hypertrophy and failure the majority of studies reveal a reduction in L-type channel number or function.