flunarizine and Hypertension

Topics: Calcium Channel Blockers; Clinical Trials as Topic; Double-Blind Method; Flunarizine; Humans; Hypertension; Parkinson Disease, Secondary

Episodic spontaneous hypothermia is an infrequent disorder, with unknown pathogenic mechanisms. A systemic cause or underlying brain lesion has not been found for the disease. We report four new patients, 3-9 years old, with episodic hypothermia lower than 35 degrees C, marked facial pallor, and absent shivering. The episodes could last a few hours or four days, and recurred once a week or every 2-3 months. Two patients also demonstrated bradycardia, mild hypertension, and somnolence during the events; in one of them, profuse sweating was also a feature, and all four presented with either headache, a periodic childhood syndrome, or both (recurrent abdominal pain, cyclic vomiting, or vertigo). Three patients reported a family history of migraine. Neurologic examination, endocrine function, and imaging studies were normal. Migraine prophylactic therapy was of moderate efficacy. Spontaneous resolution was observed in one patient. The clinical characteristics of the syndrome allow for its inclusion as a childhood periodic syndrome related to migraine.

Topics: Abdominal Pain; Body Temperature; Bradycardia; Child; Child, Preschool; Consciousness Disorders; Cyproheptadine; Diagnosis, Differential; Female; Flunarizine; Genetic Predisposition to Disease; Humans; Hyperhidrosis; Hypertension; Hypothermia; Infant; Male; Migraine Disorders; Neurologic Examination; Periodicity; Reference Values; Remission, Spontaneous; Syndrome

A series of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds were synthesized as calcium-channel blockers and antihypertensive agents. Compounds were evaluated for calcium-channel-blocking activity by determining their ability to antagonize calcium-induced contractions of isolated rabbit aortic strips. The most potent compounds were those with fluoro substituents in the 3- and/or 4-positions of both rings of the diphenylmethyl group. Bis(4-fluorophenyl)acetonitrile analogue 79 was similar in potency to bis(4-fluorophenyl)methyl compound 1. The methylene analogue of 1 (78) and derivatives of 1 that contained a hydroxyl (76), carbamoyl (80), amino (81), or acetamido (82) substituent on the methyl group were less potent. In most cases, substituents on the phenoxy ring, changes in the distance between the aryloxy group and the piperidine nitrogen, and the substitution of S, N(CH3), or CH2 for the oxygen atom of the aryloxy group had only a small to moderate effect on the potency. The best compounds in this series were more potent than verapamil, diltiazem, flunarizine, and lidoflazine, but were less potent than nifedipine. Compounds were evaluated for antihypertensive activity in spontaneously hypertensive rats (SHR) at an oral dose of 30 mg/kg. Of the 55 compounds tested, only nine produced a statistically significant (p less than 0.05) reduction in blood pressure greater than 20%; all of these compounds had fluoro substituents in both rings of the diphenylmethyl group. One of the most active compounds in the SHR at 30 mg/kg was 1-[4-[3-[4-[bis(3,4-difluorophenyl)methyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (63), which produced a 35% reduction in blood pressure and was similar in activity to nifedipine. At lower doses, however, 4-[bis(4-fluorophenyl)methyl]-1-[3-(4-chlorophenoxy)propyl]piperidine (93) was one of the most effective antihypertensive agents, producing reductions in blood pressure of 17 and 11% at oral doses of 10 and 3 mg/kg, respectively; 63 was inactive at 10 mg/kg.

Topics: Animals; Antihypertensive Agents; Aorta; Calcium; Calcium Channel Blockers; Hypertension; Male; Molecular Structure; Muscle Contraction; Piperidines; Rabbits; Rats; Rats, Inbred SHR; Structure-Activity Relationship

Increased cerebrovascular permeability to protein is a well-documented finding in acute and chronic hypertension. In this study, we examined the effect of pretreatment with a calcium entry blocker, flunarizine, on the increased cerebrovascular permeability to protein that develops in norepinephrine-induced acute hypertension.. Protein transfer was assessed qualitatively with Evans blue dye and quantitatively with iodine-125-labeled serum albumin.. Brains of hypertensive rats showed increased permeability to both tracers. The number and size of the areas of Evans blue extravasation were smaller in the hypertensive groups pretreated with flunarizine intravenously. This was supported by the quantitative studies, which demonstrated a significant decrease in protein transfer in total brain of hypertensive rats pretreated with intravenous flunarizine, 1 mg/kg (p less than 0.005) and 2.5 mg/kg (p less than 0.001). Data from individual brain regions showed that pretreatment with flunarizine resulted in significant reduction of protein transfer in most brain regions.. These data support the hypothesis that calcium plays a role in increased cerebral endothelial permeability in hypertension.

Topics: Animals; Blood Pressure; Blood-Brain Barrier; Calcium; Capillary Permeability; Endothelium, Vascular; Evans Blue; Flunarizine; Hypertension; Iodine Radioisotopes; Male; Norepinephrine; Rats; Rats, Inbred WF; Serum Albumin

The pattern of Evans blue extravasation in the brain in norepinephrine-induced acute hypertension is similar to our previous observations using horseradish peroxidase as a tracer. Pretreatment with flunarizine IV resulted in significant reduction of RISA leakage in all regions of the brains of acutely hypertensive rats. The reduction in RISA leakage in the drug-treated hypertensive group is not attributable to differences in the blood pressure elevations which were not significantly different in both groups. These studies suggest a role for calcium in the increased endothelial permeability occurring in cerebral vessels in acute hypertension. Further morphological studies are required to determine whether flunarizine reduces permeability by decreasing pinocytosis.

Topics: Acute Disease; Animals; Capillary Permeability; Cerebrovascular Circulation; Evans Blue; Flunarizine; Hypertension; Iodine Radioisotopes; Rats; Rats, Inbred WF; Serum Albumin; Serum Albumin, Radio-Iodinated

Following Skelton's procedure with unilateral adrenonephrectomy, contralateral adrenal enucleation and application of 1% NaCl with drinking fluid, normal rats develop hypertension and generalized severe arteriosclerosis within 7 weeks, experimental group I. Thereby the mean systolic blood pressure increased from 108 +/- 10 to 223 +/- 12 mm Hg, and 90 arteriosclerotic blood vessels could be counted in 100 histological sections (10 from each animal) of the hearts. Following Skelton's procedure and admixture of flunarizine with the food (40 mg flunarizine per kg for 8 weeks, started 1 week before the operation; mean plasma flunarizine value: 336 +/- 136 ng/ml at the end of the experiment), experimental group II, all rats developed hypertension too, whereby the mean systolic blood pressure increased from 109 +/- 10 to 214 +/- 16 mm Hg, but in contrast to experimental group I, only one artery with sclerosis could be observed in 100 comparable histological sections of the hearts. The untreated control rats, experimental group III, remained normotensive, and no arteriosclerotic blood vessels could be observed. The findings presented show that the calcium-antagonist flunarizine with the dosage used does not reduce hypertension, but almost completely suppresses hypertension-induced arteriosclerosis of the myocardial blood vessels without lowering the high blood pressure.

Topics: Animals; Blood Pressure; Cardiomegaly; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Fibrin; Flunarizine; Hypertension; Male; Muscle, Smooth, Vascular; Organ Size; Rats; Rats, Inbred Strains

Topics: Animals; Arteriosclerosis; Blood Pressure; Coronary Artery Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Flunarizine; Hypertension; Intracranial Arteriosclerosis; Kidney Diseases; Male; Rats

Cerebral blood flow (CBF) was measured and cerebrovascular resistance (CVR) was calculated in anesthetized spontaneously hypertensive rats (SHR) and normotensive rats (NR) following the administration of incremental dosages of i.v. flunarizine or papaverine. CBF and CVR changes following papaverine were the same in both groups of rats irrespective of the dose of the drug. The effect of flunarizine was much more pronounced in SHR than in NR. The results point out the greater dependency of basal cerebrovascular tone in SHR upon Ca2+ influx into vascular smooth muscle cells.

Topics: Animals; Blood Pressure; Calcium; Cerebrovascular Circulation; Flunarizine; Hypertension; Papaverine; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Vascular Resistance

Forty-one patients (21 males and 20 females) suffering from arterial hypertension associated with peripheral and cerebral vascular distress were treated for a period of 60 days with an extempore combination of labetalol (an antihypertensive drug with an alpha- and beta-blocking action) and flunarizine (a calcium-antagonist). Changes in supine and standing arterial blood pressure and in supine heart rate were evaluated periodically. Haematological and urinary controls of a number of biomedical indices were performed in basal conditions and after 60 days. The combination was found to show a rapid efficacy in the entire patient group: both supine and standing systolic and diastolic blood were significantly reduced as early as the tenth day of treatment. No significant changes in heart rate were observed. The combination revealed neither orthostatic hypotensive effects nor side-effects of such a degree of severity as to require reduction of the dose or discontinuation of the treatment.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Aged; Blood Pressure; Calcium Channel Blockers; Cinnarizine; Drug Therapy, Combination; Ethanolamines; Female; Flunarizine; Heart Rate; Humans; Hypertension; Labetalol; Male; Middle Aged; Piperazines; Vascular Diseases

In 48 cases with well-documented retinal vasculopathy, the therapeutic effect of cinnarizine and flunarizine over a period of several months to 3 years has been clinically evaluated. Objective measurements comprised determination of visual field and acuity, funduscopy, three-mirror funduscopy, and fluorangiography with determination of capillary leakage and circulation time. The most prominent features were disappearance of cotton wool nodules, improvement of visual function and capillary perfusion, inhibition of capillary leakage, and a positive hemokinetic effect in arteriolar, capillary, and venous beds. Degeneration of post-ganglionic fibers was partly restored. In some patients with glaucoma, the aspect of the optic disc was normalized. It is concluded that selective calcium-entry-blockers clearly improve tissue perfusion in ischemic areas.

Topics: Adult; Arterioles; Autonomic Fibers, Postganglionic; Calcium Channel Blockers; Capillaries; Cinnarizine; Diabetic Retinopathy; Female; Flunarizine; Fluorescein Angiography; Humans; Hypertension; Ischemia; Male; Middle Aged; Optic Disk; Retinal Artery; Retinal Vein; Venules