Calcium Channel Blocker Nicardipine Research Articles

Nicardipine hydrochloride suppresses DNA synthesis in human mesangial cells stimulated with recombinant human (rh) platelet-derived growth factor AA, rh interleukin-1 alpha, or rh tumor necrosis factor-alpha.

In order to define the role of cytokines in mesangial cell pathophysiology, we measured the mitogenic activity of recombinant human platelet-derived growth factor AA (rhPDGF-AA), rh interleukin-1 alpha (rhIL-1 alpha) and rh tumor necrosis factor-alpha (rhTNF-alpha) in cultured human mesangial cells, and investigated the effect of the calcium channel blocker nicardipine hydrochloride on their cell mitogenic activity. DNA synthesis in mesangial cells, stimulated by rhPDGF-AA, rhIL-1 alpha or rhTNF-alpha, was measured using [3H]TdR up take and similar investigations, with nicardipine hydrochloride added to the above, were conducted. The results showed DNA synthesis in cultured human mesangial cells were stimulated by rhPDGF-AA, rhIL-1 alpha and rhTNF-alpha, and this effect was reduced by the addition of nicardipine hydrochloride. Since rhPDGF-AA, rhIL-1 alpha and rhTNF-alpha are released by the inflammatory cells which infiltrate glomeruli, these cytokines may be involved in the mechanisms of mesangial cell proliferation observed in immune-mediated mesangial proliferative glomerulonephritis. Nicardipine hydrochloride reduced DNA synthesis in cultured human mesangial cells in response to these cytokines, suggesting possible application in medical therapy for immune-mediated mesangial proliferative glomerulonephritis.

Assessment of blood pressure during naproxen therapy in hypertensive patients treated with nicardipine

Nonsteroidal antiinflammatory drugs (NSAIDs) are known to attenuate the antihypertensive effects of a variety of antihypertensive agents including diuretics, beta-blockers, and vasodilators. Because of their unique mechanisms of actions, calcium channel blockers may not be subject to this interaction. This multicenter, double-blind, randomized, placebo-controlled study was designed to assess the effect of NSAID therapy on blood pressure control in stable hypertensive patients treated with a calcium channel blocker. One hundred patients with stable blood pressure control on 30 mg nicardipine three times a day were treated with 375 mg naproxen twice a day or placebo for 4 weeks. The mean diastolic blood pressures and estimated mean arterial pressures in both groups changed < 1 mm Hg during the 4 weeks of study drug treatment. None of the changes was significantly different from baseline and the two treatment groups were not significantly different from each other. Body weight in the placebo-treated patients did not change significantly whereas body weight in the naproxen-treated patients increased significantly, from 90.3 +/- 3.2 kg to 91.0 +/- 3.2 kg (mean = 0.7, P = .0003). At 4 weeks there was a mean loss of 0.1 kg in the placebo group and a mean gain of 0.4 kg in the naproxen group compared to baseline weights, neither of which was statistically significant (P = .60 and P = .071, respectively). These results indicate that despite a significant increase in body weight, the antihypertensive action of the calcium channel blocker nicardipine is not significantly affected by cotreatment with naproxen.

Endogenous vasoactive systems and the pressor effect of acute N omega-nitro-L-arginine methyl ester administration.

The contribution of the renin-angiotensin system (RAS) and various endogenous vasoconstrictors on the pressor response to acute N omega-nitro-L-arginine methyl ester (L-NAME) administration (200 micrograms/kg/min) was assessed in anesthetized Wistar rats. Activity of the endogenous RAS was suppressed either by chronic treatment by a nonpeptide angiotensin II (AII) receptor antagonist (losartan) or an angiotensin-converting enzyme inhibitor (ACEI: enalapril), DOCA-salt pretreatment (without previous uninephrectomy), and binephrectomy (36-40 hours before experiments). We also studied the influence of chronic dietary sodium restriction. The role of alpha 1-adrenoceptor activity, endothelin (ET), and eicosanoids was evaluated in rats pretreated by prazosin, phosphoramidon (a nonspecific blocker of the conversion of big ET to ET), indomethacin, and the thromboxane A2 (TXA2) prostaglandin H2 (PGH2)-receptor antagonist SQ 29548, respectively. Finally, we tested the influence of the calcium channel blocker nicardipine on the vasopressor effect of L-NAME. In nonpretreated animals, L-NAME infusion induced an increase in mean arterial pressure (MAP) of 38 +/- 4 mm Hg. Chronic suppression of the RAS by losartan, enalapril, or DOCA did not alter the response to L-NAME, but the effect of L-NAME was moderately blunted in binephrectomized rats. Moderate attenuation (approximately 25%) and to a similar extent of the pressor effect of L-NAME was afforded by the low-sodium diet, phosphoramidon, SQ 29548, and indomethacin, whereas nicardipine markedly blunted by 74% the effect of L-NAME. We conclude that the acute pressor effect of L-NAME is mediated (at least in part) by cyclooxygenase-dependent products (mainly TXA2) and ET, but not by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects and interaction of nicardipine and volatile anesthetics in the rat heart-lung preparation.

The effects of the calcium channel blocker nicardipine (N) and the volatile anesthetics halothane (H), enflurane (E), isoflurane (I), and sevoflurane (S) on myocardial metabolism after postischemic reperfusion were assessed in the isolated rat heart-lung preparation. Wistar-ST rats were randomly divided into six groups (each groupn=9) as follows: control (C) group, no drugs; N group, N (100 ng·ml-1); H group, 1% H and N; E group, 2.2% E and N; I group, 1.5% I and N; and the S group, 3.3% S and N. In the presence of the volatile anesthetics, the preparations were perfused for 10 min, made globally ischemic for 8 min, and then reperfused for 10 min. N 100 ng·ml-1 was administered 5 min before ischemia except in the C group. Three hearts in the C and H groups (eachn=9) and one heart in the E group (n=9) failed to recover from ischemia. The recovery times in the N, I and S groups were significantly shorter than controls. Although there was no significant difference in myocardial lactate concentrations among the groups, ATP content in the N, H, E, I and S groups was significantly higher than in controls. Glycogen content in the N, E, I and S groups was also significantly higher than in controls. These results suggest that N improves myocardial recovery from ischemia; however, in the presence of H or E it may cause significant myocardial depression.

Different types of calcium channels mediate central synaptic transmission.

Synaptic transmission is mediated by calcium entry through voltage-dependent calcium channels in presynaptic nerve terminals. Various types of calcium channel have been characterized in neuronal somata, but it is not clear which subtypes induce transmitter release at central synapses. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTx) suppresses the excitatory postsynaptic responses only partially, whereas potassium-induced release of glutamate from brain synaptosomes can be blocked by omega-Aga-VIA (ref. 9), a blocker of P-type calcium channels and possibly of other types of calcium channels. Here we test type-specific calcium-channel blockers on postsynaptic currents recorded from neurons in thin slices of rat central nervous system. Inhibitory postsynaptic currents in cerebellar and spinal neurons and excitatory postsynaptic currents in hippocampal neurons are markedly suppressed by omega-Aga-IVA and reduced to a lesser extent by omega-CgTx. The L-type calcium channel blocker nicardipine had no effect. Our results indicate that at least two types of calcium channel mediate synaptic transmission in the mammalian central nervous system.

Calcium mediates gastrin-induced gastric histamine release in the rat

This study examined the second messenger system responsible for gastrin-induced histamine release from the rat stomach. We examined the effect of different concentrations of ionized calcium, the calcium-channel blockers verapamil and nicardipine, and the intracellular calcium-chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) on gastrin-stimulated histamine release in the totally isolated vascularly perfused rat stomach. Moreover, the effect on baseline histamine release of caffeine as well as of forskolin and 3-isobutyl-1-methylxanthine (IBMX) was tested. Gastrin induced an immediate 10- to 15-fold increase in venous histamine. Perfusate ionized calcium in the 0.25-1.25 mM range did not affect histamine release; histamine release was attenuated by the 0.00 and 1.75 mM calcium concentrations. Verapamil, nicardipine, and BAPTA/AM inhibited gastrin-stimulated histamine release. Caffeine stimulated the release, whereas forskolin and IBMX had no effect. We conclude that gastrin-induced histamine release from the rat stomach is mediated by calcium, probably both from the intracellular pool and by transmembrane flux from the extracellular space.

Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes.

To determine whether endothelin-1 (ET-1) induces hypertrophy of cardiomyocytes, the effects of ET-1 on the expression of muscle-specific genes and a proto-oncogene, c-fos, in cultured neonatal rat cardiomyocytes were examined by Northern blot analysis. ET-1 (10(-7) M) induced about twofold to fourfold increases in the gene expression of myosin light chain 2, alpha-actin, and troponin I after 6 hours, which continued up to 24 hours. The ET-1-induced increases in mRNA levels for these muscle-specific genes were dose dependent (10(-9) to 10(-7) M). Run-on transcriptional assay showed that the changes in mRNA level for three muscle-specific genes were regulated, at least in part, at the transcriptional level. 12-O-Tetradecanoylphorbol 13-acetate (TPA), a potent protein kinase C activator, and the Ca2+ ionophore ionomycin also increased mRNA levels of three muscle-specific genes. ET-1, TPA, and ionomycin similarly induced the expression of c-fos after 30 minutes, which returned to an undetectable level after 6 hours. ET-1 remarkably and dose-dependently stimulated accumulation of total inositol phosphates in cardiomyocytes. Morphometrical evaluation showed that ET-1 significantly increased surface area of cardiomyocytes without cell proliferation. ET-1 also dose-dependently stimulated the synthesis of protein and DNA, which was unaffected by the L-type calcium channel blocker nicardipine. These data suggest that ET-1 induces hypertrophy of cardiomyocytes associated with the induction of muscle-specific gene transcripts through the possible involvement of protein kinase C activation or intracellular Ca2+ mobilization.

Combined Use of Nifedipine and Diltiazem for the Treatment of Severe Hypertension

Calcium channel blockers are a heterogeneous group of drugs that have enhanced our ability to concurrently control blood pressure, treat coronary artery disease, and avoid many of the side effects of previously available antihypertensive agents. Patients with severe hypertension may require multiple agents for adequate control of blood pressure because of either poor control with one agent or side effects from high doses of a single agent. Laboratory investigations have shown a synergistic effect on receptor binding, as well as increased drug levels with the concurrent use of diltiazem and a dihydropyridine calcium channel blocker (nifedipine or nicardipine). It is as yet unknown whether these effects on receptor binding and increased drug levels translate into greater clinical efficacy in blood pressure control. We have reported what we believe to be the first case in which this interaction was used successfully to control previously poorly controlled hypertension, while minimizing side effects.

Central Hypotensive Effects of Nicardipine in Conscious Freely Moving Spontaneously Hypertensive Rat

The central cardiovascular effects of the calcium channel blocker nicardipine was studied in conscious freely moving normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Nicardipine was administered in a 1.5 microliters volume into the lateral ventricle of the brain (i.c.v.) or intravenously (i.v.). The injection of vehicle alone did not significantly change mean arterial pressure (MAP) or heart rate (HR). Nicardipine (10, 30, 100 and 300 micrograms/kg) intravenously administered, dose-dependently decreased MAP and increased HR in WKY and SHR. However, when administered i.c.v., nicardipine (10 micrograms/kg) increased MAP and HR in WKY and decreased MAP without any significant change in HR in SHR. These results are consistent with previous work reporting an exaggerated hypotensive response to i.c.v. administration of dihydropyridine calcium channel blockers in anesthetized SHR as compared to WKY. They suggest that a 1,4-dihydropyridine-sensitive pressor system is present in the SHR but not in the WKY.

Effect of oral nicardipine on anorectal function in normal human volunteers and patients with irritable bowel syndrome

Paired controlled studies were performed in 10 normal volunteers and 32 patients with irritable bowel syndrome to investigate the effect of the calcium channel blocker nicardipine, on the responses of the anorectum to rectal distension and a meal. Nicardipine was administered orally in standard (20 mg) and sustained-release (30 mg twice a day) formulations. In normal volunteers standard nicardipine had no significant effect on the rectal responses to distension but did significantly reduce the postprandial motility index (P less than 0.05). In the patients with irritable bowel syndrome, standard nicardipine caused a significant reduction in distension-induced rectal motor activity (P less than 0.05) and increased the rectal sensory thresholds for desire to defecate and discomfort (P less than 0.02). Slow-release nicardipine caused a significant reduction in distension-induced activity (P less than 0.05) but did not alter rectal sensory thresholds. Both formulations of nicardipine significantly reduced the postprandial motility index (P less than 0.05) and symptoms (P less than 0.05). In conclusion, this study confirms that calcium channel blockers may be useful in the management of irritable bowel syndrome.

How Does Posture Influence the Haemodynamic Assessment of a Cardiovascular Drug? Experience with Nicardipine

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.

Direct effects of endothelin in the rat kidney

In the present study, we tested the direct effects of endothelin (ET) on rat kidney in vivo. ET was infused into the left renal artery of anesthetized rats at a rate of 0.5, 5, 20, or 40 pmol/h. ET reduced ipsilateral urine volume (V), clearance of inulin (CIN), and clearance of p-aminohippuric acid (CPAH) in a dose-dependent manner. Thus ET at 20 pmol/h did not change V but decreased renal plasma flow (RPF) and glomerular filtration rate (GFR) by 27.6 +/- 14.3 and 30.8 +/- 10.4%, respectively, in the ipsilateral kidney. ET at 0.5 pmol/h was without effect and at 5 pmol/h had only minor effects on CIN and CPAH of ipsilateral kidney. At 40 pmol/h, ET reduced ipsilateral V, GFR, and RPF by 52.3 +/- 21.4, 58.4 +/- 14.5, and 72.5 +/- 10.6%, respectively. Filtration fraction and fractional excretion of Na remained unchanged during ET infusion. ET, 40 pmol/h, infused into the renal artery together with atrial natriuretic peptide (ANP) at a rate of 12 pmol/h reduced the ipsilateral V, GFR, and RPF by 33.2 +/- 6.3, 26.1 +/- 6.0, and 27.2 +/- 7.1%, respectively, decrements less than those with ET alone. When a calcium-channel blocker nicardipine was infused at a rate of 2.5 micrograms/h into the renal artery together with ET, 20 pmol/h, there was little change in the ipsilateral V, RPF, and GFR; ET, 40 pmol/h, with nicardipine did not change V and decreased GFR and RPF by 25.9 +/- 5.6 and 23.1 +/- 10.8%, respectively, decrements less than those without nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic Effect of Nicardipine on Left Ventricular Function in Systemic Sclerosis

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.

Interaction between isoproterenol and dihydropyridines in heart cells

The negative inotropic potencies (IC 50) of the calcium channel blockers nicardipine (12 ± 2 nM) and nifedipine (9 ± 2 nM) measured in cultured chick embryo ventricular cells were not significantly different. Exposure of the cells to isoproterenol potentiated the negative inotropic effect of low concentrations of nicardipine (10 −9-10 −8 M) and decreased the effect of higher concentrations (10 −7 M). In contrast, isoproterenol shifted the entire dose-response curve for nifedipine to the right. These results provide evidence that activation of β-adrenoceptors modulates the negative inotropic effect of nifedipine and nicardipine differently.

Nicardipine after spinal cord compression in the lamb

To study the effects of the calcium channel blocker nicardipine on spinal cord blood flow and spinal evoked potentials, the following study was undertaken. After cord compression, which was productive of paraparesis, nicardipine was administered intravenously in 10 anesthetized lambs. Ten control animals were subjected to compression but received saline instead. Nicardipine produced a significant decrease in mean arterial pressure when compared to the control group. Thirty minutes after compression, spinal cord blood flow also was lower in the nicardipine group compared with controls. Spinal evoked potentials did not recover after compression in either group.

Nicardipine reduces calcium accumulation and electrolyte derangements in regional cerebral ischemia in rats.

We studied the effects of the calcium channel blocker nicardipine on regional tissue Ca2+, Na+, K+, and water shifts in the brains of seven Sprague-Dawley rats after permanent occlusions of the middle cerebral artery. We also assessed the entry of [14C]nicardipine into the brains of five rats; the highest concentrations of [14C]nicardipine were in the infarcted area. Nicardipine treatment significantly reduced Ca2+ accumulation in the middle cerebral artery territory by 60% compared with six untreated rats 6 hours after arterial occlusion. Eight 125-micrograms/kg boluses of nicardipine given every 30 minutes starting 5 minutes after arterial occlusion also significantly reduced the Na+ and K+ shifts in the middle cerebral artery territory by 40% and 50%, respectively, 6 hours after arterial occlusion. Nicardipine appears to reduce Ca2+ accumulation more than it reduces Na+ and water accumulation and K+ loss. Our results suggest that a calcium channel blocker can protect brain tissues in a model of focal cerebral infarction by directly reducing Ca2+ entry into ischemic cells.

The Effect of a New Calcium Channel Blocker Nicardipine on 24-hour Ambulatory Blood Pressure and the Pressor Response to Isometric and Dynamic Exercise

We have assessed the potential antihypertensive effect of a new slow channel blocker, nicardipine, in a group of patients with essential hypertension. Fourteen patients completed a study using the 'Oxford' system for recording blood pressure during free ambulation and physiological testing. An initial 24-h recording was performed on no treatment and repeated following chronic therapy with 40 mg b.d. of nicardipine. During each recording, the patients performed isometric and dynamic exercise according to a standardized protocol. Within-patient comparisons of consecutive mean hourly systolic and diastolic blood pressures showed a reduction throughout the 24 h during nicardipine therapy. The reduction in blood pressure was also maintained at the peaks of isometric and dynamic exercise. Side-effects were encountered frequently and led to four patient withdrawals. Nicardipine appears to be effective in reducing blood pressure although the frequency of encountered side-effects may limit its usefulness as a first-line antihypertensive agent.