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Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index SI; i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 ± 10 and 13 ± 6 mm Hg, n = 49) and E (15 ± 10 and 13 ± 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced ≤85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 ± 11 and 8 ± 10 mm Hg; diastolic, 5 ± 8 and 5 ± 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 ± 1.2 for SBP and 0.6 ± 0.9 for DBP; E, 0.6 ± 0.8 for SBP and 0.5 ± 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.

In this study on 91 subjects we tested the hypothesis of an enhanced sympathetic activity in uncomplicated essential hypertension employing spectral analysis of heart rate variability. With this technique the tonic sympathetic and vagal activities and their changes are respectively assessed by the power of ~0.1 Hz (low frequency, LF) and ~0.25 Hz (respiratory linked, high frequency, HF) components of the spectrum of the beat by beat variability of RR interval. When comparing the 40 subjects with diastolic blood pressure consistently >95 mmHg (hypertensives, Ht), with 35 age-matched controls (diastolic arterial pressure <90 mmHg, Nt), we observed that LF was greater and HF smaller in Ht as compared to Nt, thus suggesting an enhanced sympathetic activity and a reduced vagal activity in Ht. Additionally, passive tilt, which in Nt enhances LF Δ26 ± 2 normalized units (nu) and reduces HF (Δ– 22 2, nu), produced smaller (P<0.05) changes in Ht (ΔLF6.3 ± 2.7 and ΔHF-7.5 ± 2.3 nu). Furthermore, the values of LF at rest and the altered effects of tilt on LF and HF were significantly correlated with the degree of the hypertensive state. Chronic ß-adrenergic blockade (atenolol 100 mg once daily for 2 weeks, n13) reduced heart rate and blood pressure (from 162/103 to 136/88 mmHg) together with a significant diminution of LF and an increase of HF. Thus, spectral analysis of RR variability appears to be a convenient non-invasive technique to follow the progressive alterations in sympatho-vagal balance present in essential hypertension.