Current Hypertension Reviews - Volume 9, Issue 3, 2013

Voltage-gated calcium (Ca2+) channels are ubiquitous in excitable cells, and intracellular Ca2+ transients, in which the channels play key roles, trigger many physiological events. At this time, 10 members of the voltage-gated Ca2+ channel family in mammals are recognized, and they play diverse roles in the signal transduction system. The CaV1 subfamily (L-type) is involved in contraction, secretion, integration of synaptic input in neurons, regulation of gene expression, and, in specialized sensory cells, synaptic transmission at ribbon synapses. The members of the Cav2 subfamily (P/Q-, N-, and R-types) initiate synaptic transmission at fast synapses. The Cav3 subfamily is important in rhythmically firing cells such as cardiac nodal cells and thalamic neurons. The channels in this family are essential for the cyclic firing of action potentials. This article summarizes the relationships between the molecular and physiological functions of these Ca2+ channel proteins.

It has recently been reported that voltage-dependent Ca channel subtypes, e.g., L-, T-, N-, and P/Q-type, are expressed in renal arterioles and renal tubules, and the inhibition of these channels exerts various effects on renal microcirculation. For example, selective blockade of L-type Ca channels with nifedipine preferentially dilates the afferent arteriole and potentially induces glomerular hypertension. On the other hand, recently developed Ca channel blockers (CCBs) such as mibefradil and efonidipine block both T-type and L-type Ca channels and consequently dilate both afferent and efferent arterioles, leading to lowering of intraglomerular pressure. Interestingly, aldosterone has recently been recognized as a factor exacerbating renal diseases, and its secretion from adrenal gland is mediated by T-type Ca channels. Furthermore, T-type CCBs were shown to ameliorate renal dysfunction by suppressing inflammatory processes and renin secretion. On the basis of histological evaluations, N-type Ca channels are present in peripheral nerve terminals innervating both afferent and efferent arterioles. Further, it was suggested that N-type CCBs such as cilnidipine suppress renal arteriolar constriction induced by enhanced sympathetic nerve activity, thereby lowering intraglomerular pressure. Taken together, various Ca channel subtypes are present in the kidney and blockade of selective channels with distinct CCBs exerts diverse effects on renal microcirculation. Inhibition of T-type and N-type Ca channels with CCBs is anticipated to exert pleiotropic effects that would retard the progression of chronic kidney disease through modulation of renal hemodynamic and non-hemodynamic processes.

Calcium channel blockers are one of the most useful antihypertensive agents because of their definite blood pressure lowering action. Although the antihypertensive effect of calcium channel blockers is attributed predominantly to the blockade of L-type calcium channels, recent studies demonstrate that the blockade of other subtypes of calcium channels, including T-type and N-type calcium channels, offers renal protective action because of their beneficial action on glomerular capillary pressure, renal fibrotic process, sympathetic nerve activity and aldosterone synthesis. It requires more extensive studies to clarify whether the ostensibly beneficial actions of these calcium channel blockers are available in a clinical setting.

Calcium channel blockers are the strongest and most widely used antihypertensive drugs in Japan. Calcium channel blockers dilate both artery and arteriole that increases end-organ perfusion, thus possessing few side effects especially for the elderly hypertensive patients. The safety of calcium channel blockers was well established. In this paper, important clinical evidence supporting the effectiveness of calcium channel blockers and improving cardiovascular endpoints will be reviewed. Calcium channel blockers protect end-organs from hypertensive vascular injury. In addition, calcium channel blockers show non-inferiority to angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics regarding cardiovascular endpoints. Furthermore, calcium channel blockers may have superiority to betablockers. Although cardiovascular protection by calcium channel blockers largely depends on their potent blood pressure lowering ability, including central blood pressure, calcium channel blockers can manifest blood pressure-independent vascular protection. Thus, calcium channel blockers are basic antihypertensive drugs, and constitute the treatment of choice to obtain target blood pressure for most hypertensive patients, especially for high-risk population and those with resistant hypertension. An intense treatment of hypertension with adequate doses of calcium channel blockers is mandatory to improve cardiovascular prognosis.

Chronic kidney disease (CKD) progressively increases the risk of cardiovascular disease (CVD) and end-stage renal disease (ESRD) in line with its severity. Recent studies have revealed that albuminuria and proteinuria in CKD are risk factors for both ESRD and CVD. Accordingly, reductions in albuminuria and proteinuria are associated with a trend in reduced renal death and cardiovascular events. Renin-angiotensin-aldosterone system inhibitors, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers are recommended as first-choice drugs for the treatment of hypertensive patients with CKD according to several guidelines. However, monotherapy is not sufficient to control blood pressure, particularly in patients with CKD, highlighting the need for combination drug therapy. Calcium channel blockers (CCBs) reduce blood pressure and are useful antihypertensive drugs. Three types of CCBs––the L-, T-, and Ntypes–– are in clinical use. In renal tissue, L-type calcium channels are present only in the afferent arterioles, while N-type and T-type calcium channels are located in both efferent and afferent arterioles. Therefore, CCBs that block either T-type or N-type calcium channels may exert renoprotective effects by dilating the efferent artery and protecting the glomerulus from hyperfiltration injury. It has been established that T-type CCBs exert a renal protective action by ameliorating glomerular microcirculation via vasodilatory activity on both afferent and efferent arterioles. Additionally, blockade of the T-type Ca channel suppresses inflammatory processes, renin-angiotensin-aldosterone system, and oxidative stress. Such effects of T-type CCBs seem to provide good efficacy in terms of the progression of renal outcome and the prevention of cardiovascular events in patients with CKD.

The first-line depressor agents for hypertensive patients with chronic kidney disease are the renin-angiotensin system inhibitors because of their antiproteinuric and reno-protective effects. However, only one renin-angiotensin system inhibitor often cannot achieve target blood pressure in patients with injured kidney. Thus, second-line antihypertensives are required. Calcium channel blockers are frequently added on the renin-angiotensin system inhibitors in hypertensive patients with chronic kidney disease. However, they do not always show reno-protective effects because of their glomerular pressure-increasing action; Antihypetensive calcium channel blockers suppress L-type calcium channels, which exist in glomerular afferent but not efferent arterioles, and their afferent arteriole-specific vasodilation causes glomerular hypertension. The decrease in glomerular pressure due to their systemic hypotesive effect is counteracted by the glomerular pressure-incresing action. However, L-/N-type calcium channel blockers inhibits norepinephrine release from the sympathetic nerve terminal by blockade of N-type calcium channels, and dilate both afferent and efferent arterioles, which were innervated sympathetically, resulting in decrease in glomerular pressure. Actually, we have demonstrated that an L-/N-type calcium channel blocker cilnidipine decreased urinary protein more greatly than an L-type calcium channel blocker amlodipine in the renin-angiotensin system inhibitor-treated patients with chronic kidney disease. Thus, L-/N-type calcium channel blockers are one of suitable candidates for the second-line antihypertensives in the renin-angiotensin system inhibitor-treated hypertensive patients with proteinuria.

Coronary artery spasm is one of the causes of angina pectoris,acute myocardial infarction and ventricular fibrillation-related sudden death. It has been established that Ca channel blockers are protective against vasospastic angina (VSA) and treatment with Ca channel blockers provides a better prognosis of VSA. However, it is not still clarified what kinds of Ca channel blockers shows the best prognosis of VSA. We performed a meta-analysis in which 4Ca channel blockers amlodipine, nifedipine, benidipine and diltiazem were used for the treatment of VSA patients and found that among 4 Ca channel blockers, benidipine showed a statistically significant better prognostic effect on MACE than amlodipine, nifedipine or diltiazem.