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Substituted 1,2,3,4-tetrahydroaminonaphthols: antihypertensive agents, calcium channel blockers, and adrenergic receptor blockers with catecholamine-depleting effects.

Substituted 1,2,3,4-tetrahydroaminonaphthols were found to be calcium channel blockers with antihypertensive properties. These compounds also possessed adrenergic beta-receptor blocking activity. From the structure-activity studies, no clear correlation emerged between the in vitro calcium channel blocking activity and the acute anti-hypertensive activity in cannulated spontaneously hypertensive rats. Extensive pharmacological testing of selected compounds indicated that aminonaphthols are antihypertensive agents with many pharmacological properties. The relative contribution of various pharmacological actions toward the observed antihypertensive activity is unclear. Since the clinically useful calcium channel blocker verapamil is structurally related to these compounds, one of the aminonaphthols, trans-3-[(3,3-diphenylpropyl)amino]-1,2,3,4-tetrahydro-6,7 -dimethoxy-2-naphthalenol (12), was compared with verapamil for calcium channel blocking activity, adrenergic blocking activity, and catecholamine-depleting activity. Both compounds were found to be equipotent in these test systems.

Action Potentials↗

Effects of a calcium channel blocker, manidipine, on insulin sensitivity in essential hypertensives.

This study was designed to investigate the effects of the calcium channel blocker manidipine on insulin-dependent glucose uptake (insulin sensitivity) and insulin action to renal sodium handling and pressor systems in essential hypertensive (EHT). Seven EHT were hospitalized and a 2-h euglycemic hyperinsulinemic glucose clamp was performed in a fasting condition before and after 2 weeks administration of manidipine (20 mg/day). Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Manidipine administration decreased mean blood pressure and increased M-value significantly in EHT. Before the manidipine treatment, hyperinsulinemia during the clamp induced a decrease of urinary sodium excretion and increases of plasma norepinephrine and plasma renin activity in EHT. After manidipine treatment, however, hyperinsulinemia induced natriuresis and did not augment the pressor systems activity. Thus, the calcium channel blocker improved insulin resistance as assessed by glucose clamp technique in EHT. Suppression of augmented renal sodium reabsorption and pressor system activities of insulin may be connected with the hypotensive mechanisms and the natriuresis caused by calcium channel blockers.

Blood Glucose↗

Calcium channel blockers: do they have pleiotropic effects on atherosclerosis?

Since 1980, calcium channel blockers (CCBs) have been used effectively to lower high blood pressure (HBP). Flekestein proposed that CCBs could be used to avoid calcium deposition on the arterial wall, one of the main components of atherosclerosis. This is also called ectopic calcium. This review briefly looks over the current role of CCBs in atherosclerosis and the future based on human trials still in progress.

Animals↗

Arterial pressure and heart rate responses to calcium channel blockers administered in the brainstem in rats.

The study examined the possibility that organic calcium channel blockers alter autonomic nervous system function by acting on brainstem neurons. Intracisternal administration of diltiazem or verapamil produced dose-related decreases in arterial pressure and heart rate. Diltiazem administered by drop on the dorsal surface of the brainstem at the obex or microinjected directly into the nucleus tractus solitarius also decreased arterial pressure and heart rate. The responses were absent or markedly attenuated in rats previously treated with 6-hydroxydopamine or with bilateral electrolytic lesions of the nucleus tractus solitarius but were preserved in rats treated with atropine or with sham nucleus tractus solitarius lesions. Nifedipine or ethylene glycol-bis-(beta-aminoethyl ether)N,N'-tetraacetic acid administered on the dorsal surface of the brainstem at the obex decreased arterial pressure and heart rate. Vehicle, acid saline, or sucrose solution failed to alter arterial pressure or heart rate. These results suggest that organic calcium channel blockers produce excitation of the nucleus tractus solitarius neurons, directly or indirectly, which results in the withdrawal of sympathetic nervous activity and in the decrease in arterial pressure and heart rate. The results suggest that calcium ion plays an important role in maintaining integral function of neurons in the brainstem, particularly in the nucleus tractus solitarius.

Animals↗

[Calcium channel blockers and atherosclerosis].

As changes in the calcium transport mechanisms contribute to cellular changes in atherosclerosis, it has been proposed that calcium channel blocker (CCB) may be effective in slowing the progression of coronary artery disease. CCBs possess anti-oxidative properties and protective effects on vascular cells. Randomized clinical trials including PREVENT and ELSA may establish a potentially new therapeutic role for third-generation dihydropyridinoline CCBs in the treatment of atherosclerosis.

Animals↗

Effect of calcium channel blockers on proteoglycan synthesis by vascular smooth muscle cells and low density lipoprotein--proteoglycan interaction.

Calcium channel blockers are known to retard atherosclerosis. In this study, we tested the hypothesis that one mechanism by which calcium channel blockers retard atherosclerosis is through the modulation of proteoglycan metabolism by vascular smooth muscle cells. We investigated the effect of amlodipine and nifedipine on proteoglycan synthesis by human aortic smooth muscle cells and the ability of the newly synthesized proteoglycans to bind low density lipoprotein (LDL). Confluent smooth muscle cells were incubated with [(35)S]sulfate alone or [(35)S]sulfate and [(3)H]leucine in the presence and absence of different concentrations of amlodipine and nifedipine (0.1--20 microg/ml) for 24 h, and newly synthesized proteoglycans were analyzed. Both amlodipine and nifedipine inhibited proteoglycan synthesis by smooth muscle cells in a dose-dependent manner; however, amlodipine was significantly more potent than nifedipine in this regard. In the presence of 20 microg/ml amlodipine, media and cellular proteoglycans decreased by 56%. This was due to inhibition of de novo proteoglycan synthesis by amlodipine. Compared with the proteoglycans synthesized by control smooth muscle cells, those synthesized by cells exposed to amlodipine were smaller and less sulfated, and contained fewer glycosaminoglycan chains. In addition, proteoglycans synthesized by cells treated with amlodipine bound LDL with low affinity. These results suggest that amlodipine may protect against atherosclerosis through a proteoglycan-mediated mechanism.

Amlodipine↗

Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management.

In 2003, U.S. poison control centers were consulted after 9650 ingestions of calcium channel blockers (CCBs), including 57 deaths. This represents more than one-third of the deaths reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System database that were associated with cardiovascular drugs and emphasizes the importance of developing a guideline for the out-of-hospital management of calcium channel blocker poisoning. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of calcium channel blockers. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of calcium channel blockers alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. The panel's recommendations follow. The grade of recommendation is in parentheses. 1) All patients with stated or suspected self-harm or the recipient of a potentially malicious administration of a CCB should be referred to an emergency department immediately regardless of the amount ingested (Grade D). 2) Asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. These patients do not need referral or prolonged observation (Grade D). 3) Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose, whichever is lower (see Table 5), would warrant consideration of referral to an emergency department (Grade D). 4) Do not induce emesis (Grade D). 5) Consider the administration of activated charcoal orally if available and no contraindications are present. However, do not delay transportation in order to administer charcoal (Grade D). 6) For patients who merit evaluation in an emergency department, ambulance transportation is recommended because of the potential for life-threatening complications. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension. Consider use of intravenous calcium, glucagon, and epinephrine for severe hypotension during transport, if available (Grade D). 7) Depending on the specific circumstances, follow-up calls should be made to determine outcome at appropriate intervals based on the clinical judgment of the poison center staff (Grade D).

Adult↗

Contraction-induced muscle damage in humans following calcium channel blocker administration.

Following contraction-induced damage of skeletal muscle there is a loss of calcium homeostasis. Attenuating the damage-induced rise in myocellular calcium concentration may reduce proteolytic activation and attenuate other indices of damage; calcium channel blockers have been shown to be effective in this regard. The effect of administration of a calcium channel blocker (CCB), amlodipine, on indices of muscle damage following a unilateral 'damage protocol', during which subjects performed 300 maximal isokinetic (0.52 rad s(-1)) eccentric contractions with the knee extensors was investigated. The design was a randomized, double-blind crossover. On one occasion, prior to the damage protocol, subjects consumed CCB for 7 days prior to and for 7 days following the damage protocol. Biopsies were taken from the vastus lateralis prior to (baseline) and following the damage protocol at 4 h and 24 h post-damage. Isometric peak knee extensor torque was reduced (P < 0.05) immediately post-, 24 h post- and 48 h post-damage protocol compared to pre-exercise values with no effect of treatment. Desmin disruption was attenuated (P < 0.05) with CCB versus placebo at 4 h post-damage. Z-band streaming was significantly (P < 0.05) elevated compared to baseline at both times post-damage, but was lower with CCB at 4 h (P < 0.05). Damage resulted in increased inflammatory cell (macrophage) infiltration into skeletal muscle at both 4 h and 24 h post-damage, with no effect of CCB. Neutrophil number was elevated by the damage protocol, but was higher at 24 h post-damage in the CCB condition (P < 0.05). Creatine kinase (CK) activity was higher (P < 0.05) at 24 h and 48 h following the damage protocol compared to baseline, with no effect of treatment. In conclusion, the reduction in desmin disruption and Z-band streaming indicates that CCB attenuated, or delayed, the contraction-induced damage to sarcomeric proteins.

Adult↗

Sustained reduction of intraocular pressure in humans with the calcium channel blocker verapamil.

We investigated the effect of the calcium channel blocker verapamil on intraocular pressure in human volunteers. In the initial trial, 15 subjects with untreated ocular hypertension were tested. After a baseline measurement was obtained with applanation tonometry, a 40-microliter drop of verapamil, 1.25 mg/ml, was instilled in one eye. After 30 minutes, a second reading was taken. In a subsequent trial of 12 untreated ocular hypertensive subjects, the duration of action was determined using the same dose and method of delivery. Results showed that verapamil elicited a mean +/- S.E.M. change in intraocular pressure of -3.8 +/- 0.900 mm Hg in the treated eye, and -1.6 +/- 0.400 mm Hg in the untreated eye. This reduction was statistically different in both eyes (treated eye, P = .0007; untreated eye, P = .005). This decrease in intraocular pressure remained statistically significant when compared to predrug baseline values for up to ten hours.

Administration, Topical↗

Depletion of cardiac noradrenaline stores by the calcium-channel blocker D-600.

The actions of the calcium-channel blocker D-600 on cardiac noradrenaline stores were investigated by giving rats the drug systemically and then using a high-performance liquid chromatograph equipped with an electrochemical detector to determine the noradrenaline content of their hearts. A single 5-mg/kg dose of D-600 caused a significant depletion of noradrenaline content of the ventricles (approximately 31%) but not of the auricles. However, when multiple doses of D-600 were given at 12-h intervals, the depletion of cardiac noradrenaline content was more marked and both the auricular and ventricular contents were significantly decreased. Depletion of noradrenaline content was maximal 4 h after administration of D-600. A partial recovery of noradrenaline content occurred 16 h after administration of D-600, indicating that this effect of D-600 is reversible. In in vitro studies, D-600 (10(-7) to 10(-3) M) evoked a dose-related increase in the basal outflow of tritium from the rat isolated atria preloaded with [3H]noradrenaline ([3H]NA), indicating that depletion of cardiac noradrenaline stores by D-600 may be due to a direct action on sympathetic nerves rather than to increased reflex sympathetic activity secondary to profound vasodilation caused by the drug. The metabolic profile of tissue 3H content and of D-600-evoked 3H overflow was also examined. Whereas greater than 90% of tissue 3H content consisted of unchanged [3H]NA, 60-70% of the D-600-evoked overflow consisted of [3,4-3H]dihydroxyphenylglycol, and approximately 5% was unchanged NA, thus indicating that D-600 causes release of [3H]NA intraneuronally.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effect of calcium channel blocker nifedipine on uterine artery flow velocity waveforms.

Calcium channel blockers have been used successfully in the treatment of pregnancy hypertension and premature labor. Only limited information related to their effect on uterine blood flow during pregnancy is available. In this study we measured the ratio between peak systolic to end-diastolic flow velocity (S/D ratio) in the ascending branch of the uterine artery in nine pregnant patients prior to and following a 10-mg dose of sublingual nifedipine. Another group of seven matched patients who received a placebo served as a control group. All studies were performed between 17 and 22 weeks gestation. The S/D ratio decreased shortly after sublingual nifedipine, but the change was not significant. It increased gradually afterward so that by 60 minutes it returned to the control value. The mean systolic blood pressure decreased by 8.6% to its lowest value after 25 minutes (P less than 0.01). The mean diastolic blood pressure decreased by 15.7% to its lowest value after 35 minutes (P less than 0.002). Maternal heart rate did not change significantly. No significant changes were observed in any of the measured variables in the placebo group. In conclusion, nifedipine does not induce significant changes in uterine arterial resistance in midtrimester and may be considered during pregnancy, providing that large fluctuations in maternal blood pressure are avoided.

Arteries↗

Evaluation of nitrendipine--a new calcium channel blocker.

Nitrendipine (Baypress; Bayer-Miles), a new calcium channel blocker, was administered to 38 hypertensive patients in an oral dose of 20 mg once or twice daily. Both systolic and diastolic blood pressures were reduced to a clinically relevant extent within 2 hours of taking the medication. There was no loss of effect during the 57 days of the trial. No significant changes in heart rate were noted. On the whole, side-effects were mild and transient and consisted mainly of dizziness, headache, joint pains and oedema.

Adult↗

The effects of calcium channel blockers on isoproterenol induced cyclic adenosine 3',5'-monophosphate generation in intact human lymphocytes.

We have investigated the effects of clinically available calcium channel blockers (nifedipine, verapamil and diltiazem) on isoproterenol stimulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) generation in intact human lymphocytes. After preincubation of various calcium antagonists with intact lymphocytes at 37 degrees C for 15 minutes, 10 microM nifedipine or verapamil partially inhibited isoproterenol induced cyclic AMP generation in the presence of cyclic AMP phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) while they alone had no effect on cyclic AMP level at a concentration of up to 100 microM. In contrast, 10 nM-1.0 microM nifedipine, verapamil or diltiazem potentiated cyclic AMP generation induced by isoproterenol in a dose dependent manner. Similar results were observed in the time course studies of cyclic AMP generation. These effects are somewhat similar to the effect of phenothiazine, a calmodulin inhibitor, which, at 10 microM (close to IC50), also potentiated the effects of isoproterenol. In contrast, lanthanum chloride (LaCl3), an extracellular inorganic calcium antagonist, at 1.0 mM, inhibited isoproterenol induced cyclic AMP generation. The biochemical mechanisms underlying these potentiating effects are unknown. It may be partly related to the effect of calcium channel blockers (at least for nifedipine) on preventing beta 2 adrenergic receptor desensitization. This may provide a potential mechanism for the synergistic effect between calcium channel blockers and beta 2 adrenoceptor agonists on bronchial dilatation.

1-Methyl-3-isobutylxanthine↗

Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room.

Calcium channel blockers and beta-blockers intoxications account for up to 65% of deaths for cardiovascular drugs, causing severe clinical symptoms refractory to standard medications. The most serious poisonings are those resulting from verapamil and propanolol ingestion. Both support and antidotic therapy are necessary for these potentially unstable patients. Supportive measures and the use of digoxin-specific antibody fragments are first line treatment for digitalis glycoside poisoning.

Adrenergic beta-Antagonists↗

Neuroprotective properties of calcium-channel blockers.

Increases in intraneuronal Ca2+ concentration, which accompany cerebral ischemia and traumatic brain injury, initiate a cascade of biochemical events that can eventually result in cell lysis and death. Calcium-channel blockers, in certain experimental models of focal and global ischemia, attenuate the increase in intracellular Ca2+ concentration and thereby ameliorate neurologic damage. Clinical efficacy varies among disease states. After nontraumatic subarachnoid hemorrhage, nimodipine has become a standard of care. Calcium-channel blockers improve outcome, whether given before or after onset of vasospasm. Although the precise mechanism of their beneficial effect remains unclear (vasodilation vs. attenuation of increases in intracellular Ca2+ concentrations), numerous studies have demonstrated decreased neurologic morbidity. Although there also is suggestive evidence of benefit in human stroke, these results have not been sufficiently impressive to result in the widespread use of these drugs as neuroprotectants. In clinical trials after cardiac arrest, calcium-channel blockers have been ineffective. In clinical traumatic brain injury, data suggest moderate efficacy in younger patients and those with post-traumatic subarachnoid hemorrhage, although overall outcome is not changed. The future role of calcium-channel blockers as neuroprotectants appears bright. Newer classes of compounds, with greater specificity and fewer side effects, may provide greater clinical benefit.

Animals↗

Antioxidant and cytoprotective activities of the calcium channel blocker mibefradil.

Mibefradil is a new calcium channel antagonist (CCA) that acts on both L- and T-type channels, with 10-fold selectivity for T-type channels. In this study, the structural interactions of mibefradil with cardiac membrane lipid bilayers were directly examined with small-angle x-ray diffraction approaches and correlated with lipid peroxidation and bovine aortic endothelial cell viability assays. Electron density profiles (A vs electrons/A3) calculated from the diffraction data (37 degrees C) demonstrated that mibefradil had an equilibrium location in the hydrocarbon core/headgroup region of the cardiac bilayer, 12-27 A from the center of the membrane. Mibefradil also effected a pronounced reduction in electron density 0-11 A from the center of the cardiac membrane concomitant with a 7.5% (3 A) decrease in membrane hydrocarbon core thickness; these changes in membrane structure were not observed with the phenylalkylamine verapamil, a CCA with some structural similarity to mibefradil. As a result of membrane physico-chemical interactions, mibefradil inhibited (10-500 nM) lipid peroxide formation in liposomes enriched in polyunsaturated fatty acids. In aortic endothelial cells, mibefradil also inhibited loss of cell viability (IC50 of 2 microM) following acute oxy-radical generation by dihydroxyfumarate and Fe-ADP; the order of potency was mibefradil > verapamil > diltiazem. These findings indicate that the chemical structure of mibefradil contributes to biophysical interactions with the cell membrane that underlie antioxidant and cytoprotective activities in models of oxidative stress.

Animals↗

Understanding the calcium channel blockers.

The widespread use of the calcium channel blocking agents provides a significant challenge to the critical care nurse. A thorough understanding of their mechanism of action and the implications of therapy is necessary to provide patients with safe nursing care.

Action Potentials↗