Abstract-N-Type calcium channel antagonists may suppress sympathetic activity. The purpose of this study was to assess the effects of amlodipine and cilnidipine on the cardiac sympathetic nervous system and the neurohormonal status of essential hypertension. 123 I-metaiodobenzylguanidine (MIBG) cardiac imaging was performed and blood samples were taken to determine plasma renin activity and plasma norepinephrine concentration before and 3 months after drug administration in 47 patients with mild essential hypertension. Twenty-four of the patients were treated with 5 to 10 mg/d of amlodipine; the other 23 were treated with 10 to 20 mg/d of cilnidipine. For comparison, 12 normotensive subjects were also studied. No significant differences were found in the basal characteristics between the 2 hypertensive groups. In both hypertensive groups, both the systolic and diastolic blood pressures were significantly reduced to similar levels 3 months after drug treatment. Before the drug treatment, the 2 hypertensive groups had a significantly higher washout rate and lower heart-to-mediastinum (H/M) ratio compared with the normotensive subjects. The H/M ratio significantly increased (PϽ0.05) in combination with a decreased washout rate (PϽ0.02) after drug treatment in the cilnidipine group. In the amlodipine group, a significant decrease in washout rate (PϽ0.04) was noted, without an increase in the H/M ratio. However, no significant changes were found in plasma renin activity and plasma norepinephrine concentration in either group. Thus, in patients with essential hypertension, cilnidipine suppressed cardiac sympathetic overactivity and amlodipine had a little suppressive effect. Cilnidipine may provide a new strategy for treatment of cardiovascular diseases with sympathetic overactivity. (Hypertension. 1999;33:1447-1452.) Key Words: calcium channels Ⅲ amlodipine Ⅲ cilnidipine Ⅲ sympathetic nervous system Ⅲ plasma Ⅲ renin Ⅲ imaging C alcium antagonists are now widely used for the treatment of various types of hypertension. Despite their ability to lower the high blood pressure effectively, calcium antagonists do not always protect against cardiovascular complications because the use of short-acting calcium antagonists is associated with increased risk of acute myocardial infarction and mortality 1 and does not reduce the incidence of cardiac events. 2 Doubt about the use of calcium antagonists has arisen from their effects on neurohormonal status of patients, because neurohormonal activation is considered to be an important variable in the unexpected results obtained with short-acting calcium channel blockers. 3 Sympathetic overactivity plays a major role in the pathophysiology of hypertension. 4 -7 To lessen or avoid the further neurohormonal activation caused by short-acting calcium channel blockers, third-generation dihydropyridine-based calcium antagonists have been developed that have potential clinical benefits: gradual onset of action and a long duration of effects. However, a recent report on an increase in cardio...

Endothelial function is impaired in essential hypertension. T-type but not L-type voltage-gated Ca

Abstract-Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. (VSMCs) and may contribute to pathological states associated with atherosclerosis, hypertension, and balloon injury. However, the molecular mechanisms involved in Ang II-induced hypertrophy remain largely unknown. In general, changes in protein synthesis results from alterations at the transcriptional and translational levels. The global nature of trophic stimulation by Ang II suggests that alterations in translation-initiation of preexisting mRNA may be involved.Initiation of mRNA translation is controlled by multiple protein-protein interactions and phosphorylation/dephosphorylation mechanisms. Eukaryotic initiation factor 4E (eIF4E) plays a key role in mRNA translation and its regulation. 1,2 eIF4E binds to the 7-methylguanosine triphosphate ("cap") structure at the 5Ј-end of cytoplasmic mRNA and interacts with eIF4G, a large scaffold protein that binds to other translation factors, including eIF4A and eIF3. This complex of eIF4E, eIF4G, and eIF4A is termed eIF4F, and functions to translocate mRNA to the proper position, thereby promoting translation. 3 Phosphorylation of eIF4E increases its affinity for the 5Ј-cap 4 and facilitates its incorporation into eIF4F complexes. 1 Indeed, stimulators of translation often result in enhanced phosphorylation of eIF4E.A new substrate for extracellular signal-regulated kinase (ERK), called mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), was recently discovered. Mnk1 is a serine/threonine kinase that phosphorylates eIF4E in vitro. 5,6 Studies using dominant-negative or activated Mnk1 mutants demonstrated that TPA-induced activation of Mnk1 resulted in direct modulation of eIF4E phosphorylation. Further, activation of Mnk1 by anisomycin, UV, TNF-␣, or IL-1␤ was mediated by p38 MAPK, whereas TPA-induced Mnk1-activation was mediated via ERK. Interestingly, activation of Mnk1 by serum was mediated by both ERK and p38 MAPK. 7

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These data suggest that, in concert with NF-kappaB, JNK regulates thrombin-induced ICAM-1 expression by a mechanism that is dependent on Galpha(q), Gbetagamma, Ras, Rac1 and the Src kinase family.