A two-for-one bargain: using cilnidipine to treat hypertension and its comorbidities.

Hypertension is a leading cause of morbidity and mortality, and even small reductions in blood pressure (BP) can significantly reduce the associated cardiovascular complications and end-organ damage1,2. Calcium channel blockers (CCBs) are among the most commonly used antihypertensive medications currently on the market, and the use of CCBs is especially effective for the treatment of hypertension in the elderly who frequently have large vessel stiffness3. CCBs inhibit voltage-gated calcium channels in the myocardium and vasculature to reduce cardiac and smooth muscle contractility and decrease cardiac output and total peripheral resistance (Figure 1)3. In the current issue, Kazuomi and colleagues examined the ability of cilnidipine, a unique CCB that blocks both N- and L-type calcium channels, to lower BP4. Cilnidipine blocks N-type channels to inhibit the release of norepinephrine at the sympathetic nerve endings and also blocks the L-type calcium channels to stimulate vessel dilation3. The novelty of this CCB lies in the fact that it reduces BP using a two directional approach rather than acting on a single cause of hypertension. The current study also highlights a new aspect in hypertension therapy: blocking the N-type channel to inhibit sympathetic nerve activation may also help in treating comorbidities of hypertension. Figure 1 Overview of the hemodynamic effects of cilnidipine. Cilnidipine is a highly vasoselective calcium channel blocker that inhibits both L and N voltage dependent calcium channels. Kazuomi and colleagues evaluated 615 Japanese patients over 12 weeks of cilnidipine treatment, using ambulatory BP monitoring (ABPM). This observational clinical trial was named the Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N-Channel Blocker Cilnidipine (ACHIEVE – ONE) trial, and the primary endpoint evaluated was nocturnal BP dipping. Patients were stratified before treatment according to nocturnal dipping status: extreme dippers, dippers, non-dippers, or risers. The differences in dipping status reflect altered circadian rhythms, as risers or extreme dippers have been shown to have abnormal diurnal patterns. Following cilnidpine treatment, all four groups had lower 24 h blood pressure levels. Interestingly, the four groups showed differences in nocturnal systolic blood pressure (SBP) and diastolic blood pressure (DBP) after treatment, indicating that cilnidipine efficacy depended on dipping status. Cilnidipine treatment improved the nocturnal dipping status in the group of extreme dippers and risers. Cilnidipine had previously been shown to be an effective drug for patients displaying higher blood pressure and pulse rates in the morning and was shown to be more effective than amlodipine, another CCB5. The major implications of this study were that cilnidipine is effective in lowering BP through a direct effect on sympathetic nerve activation and vessel stiffness and through indirect effects on circadian rhythms. This study highlights that evaluating circadian patterns may serve as an additional marker to measure treatment efficacy. Abnormal circadian variation is a comorbidity associated with hypertension. A lack in nocturnal dipping has also been related to increased risk of cardiovascular events. Moreover, circadian rhythm has been shown to dramatically regulate the sympathetic nervous system. Cilnidipine treatment yielded variable results depending upon the circadian variation of the patient. Cilnidipine reduced nighttime blood pressure to a greater extent than daytime blood pressure in the risers group compared with the other groups. In the dippers, the daytime blood pressure decrease was greatly than seen in the nighttime. Even though similar doses of cilnidipine were administered, the effect of the drug on the patient varied depending on the extent of circadian abnormality. One beneficial side effect of cilnidipine was that it partially restored normal circadian rhythms. Subjects in the riser group had increased incidence of chronic kidney disease, whereas subjects in the extreme dipper group had increased risk of cerebral or cardiac ischemia. Although the trial did not study the effect of cilnidipine on these comorbidities, additional studies are warranted to determine if cilnidipine can reduce these risks. A possible advantage of cilnidipine could be the ability to individualize and optimize the use of this CCB depending on the presence of comorbidities such as circadian variations, renal dysfunction, and organ damage due to ischemia in hypertensive patients. Cilnidipine is considered unique for its ability to block both L-type and N-type calcium channels3. N-type calcium channels regulate sympathetic nerve activity, and aberrant sympathetic nerve stimulation is a major cause of hypertension2. Abnormal sympathetic activity has also been associated with many complications of hypertension, including stroke, heart failure, and renal failure3. The additional reduction in abnormal sympathetic activity has the potential to reduce cardiovascular events indirectly by regulating cellular growth and directly by reducing BP through stimulating vasodilation. Several studies have shown that cilnidipine blocks N-type channels more potently than other CCBs by inhibiting the release of norepinephrine at the nerve endings and displays 10 times more potent coronary vasodilator action compared to other CCBs2,3,6–9. Noguchi et al studied open chest dogs using acute heart failure model and compared nicardipine at equilhypotensive doses to cilnidipine10. They reported similar reductions in aortic pressure, LV end diastolic pressure, right atrial pressure, and coronary vascular resistance10. However, nicardipine increased heart rate and cardiac contractility, which was not seen with cilnidipine. Cilnidipine appeared to have moderate reflex-induced sympathetic stimulation10. These results with cilnidipine may be related to a potent inhibitory action on the N-type calcium channels by blunting the reflex induced sympathetic stimulation11. In the Candesartan and Candesartan/Hydrochlorothiazide in the Treatment of Patients with Essential Hypertension and a Concomitant Disease Left Ventricular Hypertrophy (CANDLE) trial, Chung and associates studied 72 patients with uncomplicated essential hypertension. Patient received cilnidipine or atenolol for 36 weeks. The cilnidipine-treated arm showed a reduced left atrial volume, while the atenolol-treated arm showed increased left arial volume (−5.1% versus 7.3%, p=0.035). The fact that cilnidipine reduces left atrial size indicates it may prove beneficial in the management of essential hypertension with LV diastolic dysfunction12,13. In the Dahl salt sensitive hypertensive rat model, cilnidipine attenuated cardiac fibrosis and diastolic dysfunction to a greater extent than amlodipine14. In hypertensive patients, cilnidipine decreased urine albumin, 8-hydroxy-20-deoxyguanosine, and liver-type fatty-acid-binding protein excretion to a greater extent than amlodipine, indicating that cilnidipine exerts renoprotective effects15. Cilnidipine also improved glucose tolerance and insulin sensitivity without effecting body weight or adiposity in hypertensive patients. Cilnidipine, therefore, may be a therapeutic tool for the metabolic syndrome16. All the above mentioned protective actions of cilnidipine suggest that the drug may have the capability of treating patient comorbidities along with hypertension. Also, since the drug shows different protective actions in different groups of hypertensive patients, it probably also has the potential to be optimized based on these additional disorders. Cilnidipine has also emerged as a good candidate for combotherapy. Cilnidipine in combination with valsartan showed a powerful ability to reduce oxidative stress and angiotensin II levels, indicating that the combination strategy may provide more benefit on vascular function17. In hypertensive and type I diabetic rats, cilnidipine had additive anti-hypertensive and proteinuria-lowering effects when administered in combination with an angiotensin II receptor blocker whereas amlodipine did not provide any additional benefits14. While the study by Kazuomi and colleagues describes an exciting new aspect in dual N- and L-type calcium channel blockade, there were some limitations worth mentioning. Two major limitations were the lack of a control group and the relatively small sample size, which decreased with study power when the patients were classified into sub-groups. The other caveat is that the patients in the extreme dipper group received diuretics, which can potentially complicate the interpretation that cilnidipine treatment improved the nocturnal dipping status especially in the group of extreme dippers. Also, the study speculates but does not examine the direct effect of the drug on comorbidities such as chronic kidney diseases. Future studies that further divide by medication use may provide a better evaluation of the overall efficacy of cilnidipine. In particular, trials evaluating the combination treatment of cilnidipine with renoprotective or cardioprotective agents are warranted, particularly for elderly patients. In conclusion, treatments that normalize circadian rhythm potentially could have beneficial effects on cardiovascular events in the setting of hypertension. Cilnidipine, has the interesting potential to be optimized in hypertensive patients depending on the presence of comorbidities and circadian variations.