Current Hypertension Reviews (v.9, #3)

Voltage-gated calcium (Ca2+) channels are ubiquitous in excitable cells, and intracellular Ca2+ transients, inwhich 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 CaV1subfamily (L-type) is involved in contraction, secretion, integration of synaptic input in neurons, regulation of geneexpression, and, in specialized sensory cells, synaptic transmission at ribbon synapses. The members of the CaV2subfamily (P/Q-, N-, and R-types) initiate synaptic transmission at fast synapses. The CaV3 subfamily is important inrhythmically firing cells such as cardiac nodal cells and thalamic neurons. The channels in this family are essential for thecyclic firing of action potentials. This article summarizes the relationships between the molecular and physiologicalfunctions of these Ca2+ channel proteins.

Renal Microcirculation and Calcium Channel Subtypes by Koichiro Homma, Koichi Hayashi, Shintaro Yamaguchi, Seitaro Fujishima, Shingo Hori, Hiroshi Itoh (182-186).
It has recently been reported that voltage-dependent Ca channel subtypes, e.g., L-, T-, N-, and P/Q-type, areexpressed in renal arterioles and renal tubules, and the inhibition of these channels exerts various effects on renalmicrocirculation. For example, selective blockade of L-type Ca channels with nifedipine preferentially dilates the afferentarteriole 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 bothafferent and efferent arterioles, leading to lowering of intraglomerular pressure. Interestingly, aldosterone has recentlybeen recognized as a factor exacerbating renal diseases, and its secretion from adrenal gland is mediated by T-type Cachannels. Furthermore, T-type CCBs were shown to ameliorate renal dysfunction by suppressing inflammatory processesand renin secretion. On the basis of histological evaluations, N-type Ca channels are present in peripheral nerve terminalsinnervating both afferent and efferent arterioles. Further, it was suggested that N-type CCBs such as cilnidipine suppressrenal 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 distinctCCBs exerts diverse effects on renal microcirculation. Inhibition of T-type and N-type Ca channels with CCBs isanticipated to exert pleiotropic effects that would retard the progression of chronic kidney disease through modulation ofrenal hemodynamic and non-hemodynamic processes.

Mechanistic View of Renal Protective Action of Calcium Channel Blockade by Naoki Sugano, Koichi Hayashi, Tatsuo Hosoya, Takashi Yokoo (187-192).
Calcium channel blockers are one of the most useful antihypertensive agents because of their definite bloodpressure lowering action. Although the antihypertensive effect of calcium channel blockers is attributed predominantly tothe blockade of L-type calcium channels, recent studies demonstrate that the blockade of other subtypes of calciumchannels, including T-type and N-type calcium channels, offers renal protective action because of their beneficial actionon glomerular capillary pressure, renal fibrotic process, sympathetic nerve activity and aldosterone synthesis. It requiresmore extensive studies to clarify whether the ostensibly beneficial actions of these calcium channel blockers are availablein a clinical setting.

Clinical Science of Calcium Channel Blocker to Inhibit Hypertensive Vascular Injury by Tsuneo Takenaka, Yoichi Ohno, Hiromichi Suzuki (193-201).
Calcium channel blockers are the strongest and most widely used antihypertensive drugs in Japan. Calciumchannel blockers dilate both artery and arteriole that increases end-organ perfusion, thus possessing few side effectsespecially 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 cardiovascularendpoints 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 blockersand 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 pressurelowering ability, including central blood pressure, calcium channel blockers can manifest blood pressure-independentvascular protection. Thus, calcium channel blockers are basic antihypertensive drugs, and constitute the treatment ofchoice to obtain target blood pressure for most hypertensive patients, especially for high-risk population and those withresistant hypertension. An intense treatment of hypertension with adequate doses of calcium channel blockers ismandatory to improve cardiovascular prognosis.

T-type Ca Channel Blockers in Patients with Chronic Kidney Disease in Clinical Practice by Masanori Abe, Kazuyoshi Okada, Masayoshi Soma (202-209).
Chronic kidney disease (CKD) progressively increases the risk of cardiovascular disease (CVD) and end-stagerenal disease (ESRD) in line with its severity. Recent studies have revealed that albuminuria and proteinuria in CKD arerisk factors for both ESRD and CVD. Accordingly, reductions in albuminuria and proteinuria are associated with a trendin reduced renal death and cardiovascular events. Renin-angiotensin-aldosterone system inhibitors, including angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers are recommended as first-choice drugs for the treatmentof hypertensive patients with CKD according to several guidelines. However, monotherapy is not sufficient to controlblood pressure, particularly in patients with CKD, highlighting the need for combination drug therapy. Calcium channelblockers (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-typeand T-type calcium channels are located in both efferent and afferent arterioles. Therefore, CCBs that block either T-typeor N-type calcium channels may exert renoprotective effects by dilating the efferent artery and protecting the glomerulusfrom hyperfiltration injury. It has been established that T-type CCBs exert a renal protective action by amelioratingglomerular microcirculation via vasodilatory activity on both afferent and efferent arterioles. Additionally, blockade of theT-type Ca channel suppresses inflammatory processes, renin-angiotensin-aldosterone system, and oxidative stress. Sucheffects of T-type CCBs seem to provide good efficacy in terms of the progression of renal outcome and the prevention ofcardiovascular events in patients with CKD.

The first-line depressor agents for hypertensive patients with chronic kidney disease are the renin-angiotensinsystem inhibitors because of their antiproteinuric and reno-protective effects. However, only one renin-angiotensin systeminhibitor often cannot achieve target blood pressure in patients with injured kidney. Thus, second-line antihypertensivesare required. Calcium channel blockers are frequently added on the renin-angiotensin system inhibitors in hypertensivepatients with chronic kidney disease. However, they do not always show reno-protective effects because of theirglomerular 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 causesglomerular hypertension. The decrease in glomerular pressure due to their systemic hypotesive effect is counteracted bythe glomerular pressure-incresing action. However, L-/N-type calcium channel blockers inhibits norepinephrine releasefrom the sympathetic nerve terminal by blockade of N-type calcium channels, and dilate both afferent and efferentarterioles, which were innervated sympathetically, resulting in decrease in glomerular pressure. Actually, we havedemonstrated that an L-/N-type calcium channel blocker cilnidipine decreased urinary protein more greatly than an L-typecalcium 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 therenin-angiotensin system inhibitor-treated hypertensive patients with proteinuria.

Vasospastic Angina and Ca Channel Blockers by Shinya Minatoguchi (219-223).
Coronary artery spasm is one of the causes of angina pectoris,acute myocardial infarction and ventricularfibrillation-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 whatkinds of Ca channel blockers shows the best prognosis of VSA. We performed a meta-analysis in which 4Ca channelblockers amlodipine, nifedipine, benidipine and diltiazem were used for the treatment of VSA patients and found thatamong 4 Ca channel blockers, benidipine showed a statistically significant better prognostic effect on MACE thanamlodipine, nifedipine or diltiazem.