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To elucidate the roles of endogenous angiotensin II (AII) and renal sympathetic nerve activity (RSNA) in modulation of renal blood flow (RBF), we recorded RBF and RSNA in conscious two-kidney, one-clip (2K1C) hypertensive rabbits with blood pressure (BP) reduced to a similar extent by captopril (5 mg/kg) and nicardipine (4.3 micrograms/kg/min). We measured plasma concentrations of AII, arginine vasopressin (AVP), and norepinephrine (NE). Despite comparable depressor effects, changes in RBF showed different profiles with the two drugs in renal hypertensive rabbits. After captopril injection, RBF was consistently increased to 143 +/- 7%. In contrast, with nicardipine infusion, RBF was initially increased to 114 +/- 5% and then significantly decreased to 86 +/- 4%. The increase in RSNA was greater with captopril than with nicardipine. Plasma concentration of AII was decreased with captopril but significantly increased with nicardipine. In sham-clipped normotensive rabbits in which plasma AII was not increased, RBF was not reduced with nicardipine. Thus, vasoconstrictor actions of RSNA and increased AII may have overcome the vasodilatory effect of nicardipine in conscious renal hypertensive rabbits. Because the increase in RSNA was smaller with nicardipine, we speculate that the vasoconstriction induced by AII, as well as background BP level, played a substantial role in determining RBF.

This randomized, double-blind, crossover study was aimed at detecting efficacy differences in blood pressure control and peripheral circulation in cerebral aortic and femoral districts of slow-release nicardipine, 40 mg, and captopril, 50 mg, given twice daily to 20 primary hypertensive patients (9 male, 11 female; age range 33-60 years) for a period of 4 weeks for each treatment. Blood flow velocities in the aorta, common carotid artery, internal carotid artery, middle cerebral artery, and common femoral artery were noninvasively measured using a 2.0- or 5-MHz Doppler probe. Systolic blood pressure fall was similar with nicardipine (from 156 +/- 12 to 139 +/- 8 mm Hg, p less than 0.001) and captopril (from 158 +/- 13 to 146 +/- 13 mm Hg, p less than 0.001) while significant efficacy difference (p less than 0.005) in diastolic pressure control was detected (from 104 +/- 6 to 91 +/- 8 mm Hg, p less than 0.001 with nicardipine and from 102 +/- 6 to 98 +/- 7 mm Hg with captopril). Regarding regional hemodynamics, nicardipine increased (from 119 +/- 24 to 133 +/- 27 cm/s), and captopril did not affect systolic velocity in the aorta (difference between final data, p less than 0.03). In the common carotid artery systolic velocity was increased solely by nicardipine. No significant changes were detected in the other vessels explored.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to measure the efficacy and side effects of oral nicardipine in the treatment of Raynaud's phenomenon (RP). The study consisted of a 3-week baseline period followed by a double-blind, randomized, two-period placebo-controlled, balanced crossover design. Both treatment periods of 3 weeks with either oral nicardipine (3 x 30 mg) or matching placebo were interrupted by a 2-week washout period. Twenty-five patients with either primary (n = 16) or secondary (n = 9) RP participated. Twelve of them had taken part in a previous study on the acute effects of i.v. nicardipine to find out whether long-term efficacy could be predicted by the acute circulatory effects. No statistically significant differences were found between nicardipine and placebo for number, duration, or severity of vasospastic attacks or for any of the microcirculatory parameters (finger skin temperature and laser Doppler flux) measured during a finger cooling test. In patients with primary RP, heart rate significantly increased during nicardipine treatment (mean +/- SD: 9 +/- 6 beats/min; p less than 0.05). The long-term effects could not be predicted by the outcome of the i.v. study. Plasma nicardipine concentrations varied considerably, but in general were on the low side (17.4 +/- 3.7 ng/ml; range, 0-55.4 ng/ml). The adverse effects reported with nicardipine were similar to those with placebo, and required withdrawal of two patients on nicardipine and one on placebo. In conclusion, the results show that oral nicardipine does not significantly alter the course of RP.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared the abilities of verapamil and nicardipine to protect the porcine myocardium from the consequences of ischaemia-reperfusion in vivo. Infusion of verapamil (50 micrograms/kg) into the left anterior descending coronary artery LAD (i.c.a.), in 15 min immediately before ligation depressed regional contractile function, reduced infarct size by 80%, and enabled contractile function to recover partially during reperfusion. Verapamil (10 micrograms/kg i.c.a.) did not depress contractile function before ligation or permit its recovery during reperfusion, despite reducing infarct size by 80%. Lower doses of verapamil were not cardioprotective. Nicardipine (10 and 30 micrograms/kg i.c.a.) depressed contractile function before ligation but did not permit its recovery during reperfusion. Nicardipine did not reduce infarct size development. Thus, drug-induced negative inotropic activity (which presumably reflects myocardial calcium channel blockade) and cardioprotection are not linked. Verapamil can markedly reduce infarct size development at a dose that exerts no detectable negative inotropic activity. This cardioprotective effect of verapamil was greatly reduced by intravenous (i.v) pretreatment with aspirin (30 mg/kg), which alone did not alter infarct size development. Thus, the cardioprotective effect of verapamil (10 micrograms/kg i.c.a.) appears to be mediated by a cyclooxygenase product, possibly prostacyclin.

The extent to which posture altered the haemodynamic response to slow calcium channel blocker nicardipine was evaluated in 22 male patients with angiographically confirmed coronary artery disease. Patients were randomly allocated to supine or upright posture and an otherwise identical protocol performed in each group. At rest, following a control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0, and 10.0 mg) were administered by i.v. infusion over a total period of 40 min; haemodynamic indices were recorded during the 3-5 min following each 5 min infusion. The exercise effects of the drug, in each posture, were determined by comparison of a control predrug exercise with observations at the same workload following the maximal cumulative dose. Nicardipine reduced resting mean blood pressure (MBP) and systemic vascular resistance index (SVRI) in both postures, the decrease being more pronounced when upright (MBP, -12%, -18%; p less than 0.01: SVRI, -30%, -46%; p less than 0.01). The increases in cardiac index (CI) and stroke volume index (SVI) were higher when upright (29 and 54% vs. 10 and 27%; p less than 0.01). Pulmonary artery occluded pressure (PAOP) increased by 29% when upright, without change when supine. On exercise, the effects for HR, MBP, CI, SI, and SVRI responses were independent of posture; however, a qualitative difference was apparent for PAOP (-17% vs. +14%; p less than 0.05). Thus, although the actions of nicardipine were qualitatively similar, quantitative differences related to posture were confirmed. These differences appeared to relate to posture-related baseline haemodynamic differences between the groups but with similar postnicardipine absolute values.

Left ventricular dysfunction in systemic sclerosis may be due in part to myocardial ischemia caused by a disturbance in coronary microcirculation. We evaluated the pharmacodynamic effect of the calcium channel blocker nicardipine on left ventricular function assessed by radionuclide ventriculography in 20 patients with systemic sclerosis. Resting gated, blood-pool images were obtained at baseline and 90 min after 40 mg of oral nicardipine. The mean (+/- SEM) left ventricular ejection fraction significantly increased from 65.4 +/- 2.3% at baseline to 71.3 +/- 2.3% after nicardipine (p less than 0.005). The mean global defect score significantly decreased from 2.90 +/- 0.73 without nicardipine to 1.50 +/- 0.52 with nicardipine (p less than 0.01). The mean number of left ventricular sectors with severe hypokinesis significantly decreased from 0.80 +/- 0.24 at baseline to 0.20 +/- 0.09 after nicardipine (p less than 0.05). No significant side effects were observed with nicardipine. These results demonstrate short-term improvement in left ventricular function with nicardipine in patients with systemic sclerosis.

The effects of two chemically unrelated calcium channel blockers--nicardipine and verapamil--on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 microgram/100 ml forearm tissue/min dilated the forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 microgram/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 micrograms/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipine.

Hypertension becomes more prevalent with advancing age, and the hemodynamic pattern differs from that in younger patients. In the elderly, elevated blood pressure is primarily due to reduced compliance of large vessels, resulting in an increase in total peripheral resistance, but in younger subjects it mainly reflects an increase in cardiac output. Vasodilator drugs, such as calcium antagonists, might therefore be expected to be particularly effective in lowering blood pressure in the elderly. Clinical experience has confirmed the safety and antihypertensive efficacy of these drugs, with some workers suggesting that calcium antagonists are particularly effective in the elderly. A 6-month multicenter study involving 2,184 patients has shown a direct correlation between pretreatment blood pressure and the degree of blood pressure reduction observed during nicardipine treatment with or without other antihypertensive drugs. Isolated systolic hypertension was significantly reduced but diastolic blood pressure was not affected. The incidence of side effects among elderly hypertensive patients, both with and without concomitant disease, was slightly lower than in younger patients.

Blood pressure and clinical status of 1,736 patients with cerebrovascular disease were observed during 12 months of treatment with nicardipine. The most common diagnoses were chronic cerebral ischemia (53.2%), transient ischemic attacks (TIA; 25.1%), and cerebral infarct (8.7%); 50.1% of patients were classed as hypertensive [systolic blood pressure (SBP) > or = 160 mm Hg or diastolic blood pressure (DBP) > or = 90 mm Hg]. Most patients (91.2%) received a daily dose of 60 mg nicardipine. Additional treatments included diuretics (37%), beta-blockers (11.5%), other antihypertensive drugs (15.8%), platelet antiaggregants (25.1%), and cardiotonic drugs (15.1%). A total of 282 patients (16.2%) were lost to follow-up, 21 (1.2%) patients withdrew due to side effects, 32 (1.8%) died, and 9 (0.5%) patients had treatment interrupted due to concomitant illness. In the hypertensive subgroup, blood pressure (SBP/DBP) was reduced from a mean baseline value of 175 +/- 22/97 +/- 14 mm Hg to 152 +/- 17/85 +/- 11 mm Hg at 3 months and 149 +/- 23/81 +/- 11 mm Hg after 12 months of treatment. The incidence of TIA or stroke among these patients was reduced from 29 cases (3.5%) during the first 3 months to 11 cases (1.54%) during months 4-12 (p < 0.01). In normotensive patients there were 18 (2.15%) cases during months 1-3 and 13 (1.55%) cases during months 4-12 (difference not significant). In the 280 patients treated with nicardipine alone, the most frequent side effects during the first month were facial flushing (6.8%), gastrointestinal problems (5%), dizziness (3.2%), headache (3.2%), drowsiness (3.2%), and hypotension (1.1%). Most of these side effects were transient.(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic effects of nicardipine were studied in 10 normotensive patients (nine men, one woman; age 43-70 years, mean 56 years) and five patients with mild to moderate hypertension (four men, one woman; age 46-72 years, mean 62.8 years); in all patients coronary heart disease was confirmed by angiography. Hemodynamic parameters were determined before and after intravenous administration of nicardipine in cumulative doses of 2.5, 7.5, and 12.5 mg for 10 min each. Nicardipine significantly reduced systolic aortic pressure, diastolic aortic pressure, and mean aortic pressure in normotensive patients [139 +/- 8.7 vs. 114 +/- 9.2 mm Hg (p < 0.001), 73 +/- 9.1 vs. 56 +/- 7.9 mm Hg (p < 0.001), 97 +/- 7.8 vs. 7.8 +/- 7.9 mm Hg (p < 0.001), respectively] and in hypertensive patients [166 +/- 7.4 vs. 128 +/- 8.6 mm Hg (p < 0.001), 83 +/- 9.4 vs. 56 +/- 10.9 mm Hg (p < 0.001), 110 +/- 15.5 vs. 78 +/- 12.0 mm Hg (p < 0.001), respectively]. Systemic vascular resistance was decreased significantly in hypertensive patients [1,363 +/- 188 vs. 707 +/- 137.7 dyn sec cm-5 (p < 0.001)] and in normotensive patients [1,110 +/- 225.3 vs. 682 +/- 92.4 dyn sec cm-5 (p < 0.001)]. Heart rate increased from 68 +/- 6.8 to 83 +/- 11.4 beats/min (p < 0.001) in normotensive patients but the increase from 72 +/- 14.7 to 80 +/- 14.2 beats/min in hypertensive patients was not significant. Mean pulmonary artery pressure did not change significantly in hypertensive patients and increased slightly in normotensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, placebo-controlled study was carried out over 120 days to assess the metabolic tolerance and patient acceptability of nicardipine in 20 patients with Type 2 diabetes mellitus and slight hypertension. Following a 21-day washout period during which all patients received placebo, 13 men and 7 women (mean age 45 years, systolic blood pressure 150-165 mm Hg or diastolic blood pressure 85-100 mm Hg) were randomly assigned to treatment with oral nicardipine 60-90 mg/day (n = 9) or placebo (n = 11). No significant differences were observed between the nicardipine- and placebo-treated groups in terms of fasting and postprandial blood glucose concentrations, fasting plasma insulin levels, or glycosylated hemoglobin A1c after 60 and 120 days' treatment. There was also no change in the plasma levels of total cholesterol, HDL-cholesterol, triglycerides, and apolipoproteins. Side effects were minor and did not differ significantly between groups. All patients who had received nicardipine for 120 days wished to pursue treatment. Nicardipine, which was well tolerated, appears to be an interesting alternative for the treatment of mild essential hypertension in Type 2 diabetic patients, although further studies are required to establish its effects on renal function in this population.

The effect on blood pressure of the dihydropyridine derivative nicardipine was studied in 87 essential hypertensive patients aged 25-77 years. A total cumulative dose of 8.75 mg nicardipine was administered over a 30-min period by continuous intravenous infusion. The dose was doubled every 10 min from 1.25 to 5.0 mg. The mean blood pressure fall and the heart rate rise were both dose-related. At 30 min, mean blood pressure fell by 18.9 +/- 7.5% vs. baseline values (p less than 0.001), heart rate increased by 28.0 +/- 11.8% (p less than 0.001), and the renin level by 20.7 +/- 32.5% (p less than 0.001). The blood pressure fall was correlated positively with age (r = 0.521; p less than 0.001) and negatively with the rise in heart rate (r = -0.308; p less than 0.01) and renin level (r = -0.205; p = 0.05). After eliminating the linear effects of age by the partial correlation method, blood pressure fall and the initial renin level were no longer correlated (r = -0.046, NS), whereas the positive correlation between age and blood pressure fall persisted after eliminating the effect of renin (r = 0.464; p less than 0.001). The slope of the regression line for the heart rate rise vs. the blood pressure fall was taken to reflect the baroreflex sensitivity. This sensitivity was negatively correlated to age (r = -0.515; n = 51; p less than 0.001) in the 51 of the 87 patients for whom it could be calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic effects of intravenously administered nicardipine (5 mg/h during 85 min) were investigated in 12 Raynaud patients and in 12 healthy volunteers in a double-blind placebo-controlled cross-over study. In both groups we found no change in systolic blood pressure, but a significant fall in diastolic blood pressure of 7 mm Hg (p less than 0.001). Heart rate increased 14 beats/min (p less than 0.001) and forearm blood flow increased 1.0 ml/100 ml/min (p less than 0.01) with a concomitant decrease of 10 arbitrary units (AU) in forearm vascular resistance (p less than 0.001). In healthy volunteers the recovery of the finger skin temperature after cold challenge improved significantly (p less than 0.05). In patients with primary Raynaud's phenomenon we observed a significant (p less than 0.001) increase in skin temperature of 4.6 degrees C before cooling, together with a better recovery after cold induced vasospasm (p less than 0.001). In secondary Raynaud's patients, nicardipine caused no vasodilatation within the skin vessels. There were no significant correlations between the plasma nicardipine concentration and any of the observed pharmacological effects.