The Institutional Ethical Committee approved this open label randomized parallel group study protocol conducted during period 2012-2013. Informed consent was obtained from study participants. All the participants who were receiving Amlodepine in the age group between 20 to 60 years with sitting systolic blood pressure between 140-160 mm Hg and diastolic blood pressure between 90-100 Hg. Patients were excluded, if the hypertension was secondary to hepatic, renal, cardiac or endocrine disorders, pregnant or lactating. In the present study, 84 patients were screened and after meeting the inclusion and exclusion criteria, a total of 60 patients were enrolled in the study. Thirty patients received either Amlodipine 5 mg OD or Cilnidipine 10 mg OD for duration of eight weeks. Blood Pressure (BP), Heart Rate (HR), carotid-femoral Pulse Wave Velocity (cf PWV), Augmentation Index (AIx) and Aortic augmentation pressure (AoAP) were measured at baseline and at the end of eight weeks. Demographic, clinical and laboratory records of the enrolled patients were also recorded. After the completion of the study, the patients were instructed to consult their physician for further management; however, none of the patients were deprived of antihypertensive medication.

The Carotid Femoral (CF) PWV was measured using a Volume-plethysmographic apparatus. (Periscope, M/s Genesis Medical Systems, Hyderabad India). This instrument also records blood pressure and electrocardiogram. The subjects were examined in the spine position after a 10 minutes rest, with electrodes connected to all the four limbs and cuffs wrapped on both the brachia and ankles. The plethysmographic sensor and the oscillometric pressure sensors positioned in these cuffs records volume waveforms and blood pressure respectively. Initially the brachial ankle pulse wave velocities (baPWV) of the right and left were obtained from the stored wave forms. Subsequently, cf PWV was calculated automatically from the mathematical equation. cf PWV= 0.833* average baPWV-233.3 [13–15]. Augmentation index (AIx) was calculated as the increment in pressure from the first shoulder in the ascending aortic pressure wave to the peak of this wave, expressed as a percentage of the peak ascending aortic pressure wave. AIx=100*ΔP/PP. where ΔP is Augmentation pressure [16].

The statistical analysis was carried using Graph pad prism software (Version-5, USA) continuous data was presented as Mean±SD and Categorical as actual numbers and percentages. For normally distributed data, with-in group analysis was performed by using paired t-test and between group analyses by unpaired t-test. Non-normally distributed data was analysed by using non-parametric “Mann-Whitney U test”. Categorical variables were analysed with “Fischer’s exact test”. All the efficacy parameters were presented as absolute change from baseline. A negative sign indicates decrease and vice versa. For statistical significance, a two tailed probability value of less than 0.05 was considered. A sample of 25 patients per group was required to demonstrate an estimated change in primary efficacy variable cf PWV of 1 m/s from baseline in both groups, with 80% power to detect the difference and two sided alpha error of 0.05 [17]. Additionally 5 patients were added to pay off for drop outs.

In the present comparative study, there were 21 males and 9 females in the Amlodipine group and 24 males and 6 females in the Cilnidipine group. There was no statistically significant difference in demographic, anthropometric and clinical characteristics of Amlodipine and Cilnidipine groups. Additionally, baseline haemodynamic and vascular indices parameters were also similar between the two groups as shown in [Table/Fig-1]. After eight weeks of treatment with Amlodipine and Cilnidipine, it was found that [Table/Fig-2] there was a significant change in the haemodynamic and vascular indices from baseline in each group. [Table/Fig-3,4,5 and 6]. When we evaluated the absolute change from baseline to eight weeks in the peripheral haemodynamic parameters between Amlodipine and Cilnidipine groups [Table/Fig-7], it became apparent that there was no statistically significant difference between the two groups. However, we found a statistically significant change in the central haemodynamic and vascular indices in the Cilnidipine group as compared to Amlodipine. All the subjects who participated in the study showed good compliance and none of them developed side effects.

[Table/Fig-3]:

Showing comparison of Systemic blood pressure before and after Amlodipine and Cilnidipine treatment

[Table/Fig-4]:

Showing comparison of aortic blood pressure before and after Amlodipine and Cilnidipine treatment

[Table/Fig-5]:

Showing comparison of cf-PWV before and after Amlodipine and Cilnidipine treatment

[Table/Fig-6]:

Showing comparison of AIx @ HR 75 before and after Amlodipine and Cilnidipine treatment

Hypertension is a major cardiovascular risk factor, which affects both large and small arteries. Population based studies have reported that large artery stiffness is an important determinant of cardiovascular events and mortality in general population and in patients with hypertension [9]. Calcium channel blockers (CCB) are frequently used drugs to treat hypertensive patients in our hospital setup. The mechanism of action in hypertension is due to its inhibition of calcium influx into vascular smooth muscle cells (VMC) that causes relaxation of VMC, decreased after load and systemic blood pressure. It is also evident from the reports that dihydropyridine calcium antagonists improve arterial wall stiffness [18,19].

We studied the haemodynamic and vascular effects of Amlodipine and Cilnidipine and found that there was a statistically significant decrease in peripheral blood pressure when compared to baseline in both the groups after eight weeks but not in Heart rate. Satoshi Morimoto et al., also reported that Amlodipine at 5 mg daily dosage and Cilnidipine at a daily dose of 10 mg per day are equally effective in reducing the blood pressure in patients with mild to moderate hypertension [20]. Additionally, they also improved central blood pressure as well as indices of arterial stiffness (cf PWV & AIx). On comparison between the medications; the decrease in peripheral blood pressure between two groups was not statistically significant. For a similar reduction in peripheral blood pressures, we observed that Cilnidipine showed significantly higher improvement in aortic blood pressure and AoAP as well as markers of arterial stiffness (cf-PWV & AIx) than with Amlodipine.

The proposed mechanisms for such an improvement in cf PWV and AIx by CCBs are acute changes in the functional properties such as vascular smooth muscle relaxation, reduction in wave reflections, improvement in endothelial dysfunction or regulation of sympathetic nervous system. It is unlikely that the structural changes would occur after 8 weeks of therapy, the likely mechanism for the improvement in arterial compliance in present study may be due to improved vascular smooth muscle relaxation possibly by increased bioavailability of NO.

Studies have reported that CCBs also have an anti-inflammatory and anti-oxidative effect independent of their effect on lowering BP [21]. Amlodipine has been reported to increase endothelial nitric oxide synthase (eNOS) activity [22] and to improve endothelial functions [23] in experimental models. Hok Sum Leung et al., showed that Cilnidipine also increases release or bioavailability of NO, due to elevated endothelial Ca²⁺ ions in arteries [24]. Chandra et al., in his study confirmed Cilnidipine significantly induced eNOS activity, as well as increased eNOS concentration in rats when compared with Amlodipine. Also, Cilnidipine is both an L/N-type CCB, has an inhibitory effect on cardiovascular sympathetic neurotransmission in contrast to L type CCB like Amlodipine [25]. One or all of such mechanisms could be the possible explanations for such an improvement over Amlodipine. This makes it useful in the treatment of cardiovascular diseases associated with diminished NO release, such as atherosclerosis. Moreover, this mechanism is independent of its effect on L/N-type receptors [26].

In the present study, we have used non-invasive method, which simultaneously records blood pressure, pressure waves and also calculates the parameters of velocity at different points from these recordings. Although the present equipment data is well validated, however, the accuracy cannot be comparable to the invasive haemodynamic monitoring. Due to ethical reasons, invasive monitoring was not attempted. Cilnidipine showed a better improvement in arterial stiffness than Amlodipine without much difference in blood pressure reduction. However, such an interpretation needs carefulness because the time at which they took the medication before each study day, concomitant medications, co-morbid conditions and wider confidence intervals in electrophysiological parameters could have been confounding factors. Larger-scale studies are required to confirm above stated results.

This study showed that the L/N-type calcium channel antagonist cilnidipine has a similar antihypertensive action to the L-type calcium channel antagonist amlodipine, but is superior in terms of improving arterial stiffness and central aortic pressures. Cilnidipine can be recommended as the treatment of choice for patients with essential hypertension. However Larger-scale studies are required to confirm above stated results.