Regulation of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban in the failing and nonfailing heart.
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Animals↗
Biomedical subjects
D Dobrev
Publications and source records attributed to D Dobrev.
N-desethylamiodarone modulates intracellular calcium concentration in endothelial cells.
The main in-vivo metabolite of amiodarone, N-desethylamiodarone (DEAM), possesses clinically relevant class-II antiarrhythmic and vasodilator activities. Vasodilation by DEAM is endothelium dependent and involves a sustained and biphasic increase in cytosolic free Ca2+ concentration ([Ca2+]i). The aims of this study were to explore the mechanisms mediating the DEAM-induced increase in [Ca2+]i in endothelial cells and to determine whether this increase in [Ca2+]i was associated with altered cell proliferation. Cultured bovine aortic endothelial cells were loaded with the Ca2+-sensitive fluorescent dye Fura-2/AM, and [Ca2+]i measured spectrofluorimetrically. DEAM increased [Ca2+]i concentration dependently (EC50 approximately 6 microM) both in the presence and absence of extracellular Ca2+. In the presence of extracellular Ca2+, the response of [Ca2+]i to DEAM (10 microM) consisted of an initial rise to a plateau followed by a second increase to micromolar levels. The initial plateau was reduced by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (200 nM) and by the antioxidant ascorbic acid (100 microM). The initial rate of rise in [Ca2+]i was decreased by blocking mitochondrial Ca2+ release with cyclosporine A (1 microM). Under Ca2+-free conditions, the response of [Ca2+]i to DEAM (10 microM) was also biphasic, consisting of an initial transient peak and a second slow increase. When extracellular Ca2+ was restored, [Ca2+]i rose to micromolar concentrations. The initial peak was abolished by thapsigargin, but not altered by ascorbic acid or cyclosporine A. Both the second [Ca2+]i increase and that due to restoring extracellular Ca2+ were reduced by ascorbic acid but not affected by thapsigargin or cyclosporine A. The DEAM-induced generation of free radicals and sustained increase in [Ca2+]i might alter cell proliferation and endothelial cell proliferation was indeed concentration-dependently inhibited by DEAM (IC50 approximately 2.5 microM). In conclusion, the DEAM-induced [Ca2+]i increase in endothelial cells is due to Ca2+ influx from the extracellular space and to Ca2+ release from endoplasmic reticulum and mitochondria and involves enhanced generation of free radicals.
Amiodarone↗
Local venous response to N-desethylamiodarone in humans.
OBJECTIVE: Amiodarone, a class III antiarrhythmic agent, is a potent vasodilator in vivo. Its main metabolite, N-desethylamiodarone, contributes to the antiarrhythmic action of amiodarone after long-term treatment. It is unknown whether N-desethylamiodarone has acute vascular effects. The aim of this study was to explore the mechanism of action of N-desethylamiodarone in human hand veins. METHODS: The dorsal hand vein compliance technique was applied in 36 healthy male volunteers. In hand veins preconstricted with the alpha1-adrenergic receptor agonist phenylephrine or prostaglandin F2alpha, N-desethylamiodarone and an inhibitor of nitric oxide formation (N(G)-monomethyl-L-arginine, L-NMMA) were infused in the presence or absence of a cyclooxygenase inhibitor (acetylsalicylic acid), and the venodilator effect was measured. Furthermore, N-desethylamiodarone was infused after oral treatment with hydrocortisone or coinfused with alpha-tocopherol. Additional experiments were carried out in bovine aortic endothelial cells to explore the effects of N-desethylamiodarone on the intracellular Ca2+ concentration ([Ca2+]i). RESULTS: N-Desethylamiodarone produced dose-dependent venodilation (47% +/- 4% maximum). In vitro, 10 micromol/L N-desethylamiodarone caused a sustained increase of the endothelial [Ca2+]i. Pretreatment of the volunteers with acetylsalicylic acid reduced the maximum N-desethylamiodarone-induced venodilation to 22% +/- 8%; L-NMMA reduced the maximum N-desethylamiodarone-induced venodilation to 18% +/- 11%. Pretreatment with acetylsalicylic acid and coinfusion of N-desethylamiodarone and L-NMMA abolished the venodilation, whereas hydrocortisone had no effect. Coinfusion of alpha-tocopherol and N-desethylamiodarone reduced the maximum N-desethylamiodarone-induced venodilation to 11% +/- 4%. CONCLUSIONS: In concentrations estimated to be in the therapeutic range, N-desethylamiodarone dilates preconstricted human hand veins in vivo and increases endothelial [Ca2+]i in vitro. Subsequently the cyclooxygenase (COX-1) and the endothelial nitric oxide synthase pathways are activated. The resulting venodilation does not involve inflammatory cytokines, inducible nitric oxide synthase, or inducible cyclooxygenase (COX-2).
Adult↗
Evidence for Edg-3 receptor-mediated activation of I(K.ACh) by sphingosine-1-phosphate in human atrial cardiomyocytes.
Sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) have been reported to activate muscarinic receptor-activated inward rectifier K(+) current (I(K.ACh)) in cultured guinea pig atrial myocytes with similar nanomolar potency. Members of the endothelial differentiation gene (Edg) receptor family were recently identified as receptors for SPP; however, these receptors respond only to micromolar concentrations of SPPC. Here we investigated the sphingolipid-induced activation of I(K.ACh) in freshly isolated guinea pig, mouse, and human atrial myocytes. SPP activated I(K.ACh) in atrial myocytes from all three species with a similar nanomolar potency (EC(50) values: 4-8 nM). At these low concentrations, SPPC also activated I(K.ACh) in guinea pig myocytes. In contrast, SPPC was almost ineffective in mouse and human myocytes, thus resembling the pharmacology of the Edg receptors. Transcripts of Edg-1, Edg-3, and Edg-5 were detected in human atrial cells. Moreover, activation of I(K.ACh) by SPP was blocked by the Edg-3-selective antagonist suramin, which did not affect basal or carbachol-stimulated K(+) currents. In conclusion, these data indicate that I(K.ACh) activation by SPP and SPPC exhibits large species differences. Furthermore, they suggest that SPP-induced I(K.ACh) activation in human atrial myocytes is mediated by the Edg-3 subtype of SPP receptors.
Analysis of Variance↗
The effects of verapamil and diltiazem on N-, P- and Q-type calcium channels mediating dopamine release in rat striatum.
1. The putative inhibitory effects of verapamil and diltiazem on neuronal non-L-type Ca2+ channels were studied by investigating their effects on either K+- or veratridine-evoked [3H]-dopamine ([3H]-DA) release in rat striatal slices. Involvement of N-, P- and Q-type channels was identified by sensitivity of [3H]-DA release to omega-conotoxin GVIA (omega-CTx-GVIA), omega-agatoxin IVA (omega-Aga-IVA) and omega-conotoxin MVIIC (omega-CTx-MVIIC), respectively. 2. KCl (50 mM)-evoked [3H]-DA release was abolished in the absence of Ca2+, and was insensitive to dihydropyridines (up to 30 microM). It was significantly blocked by omega-CTx-GVIA (1 microM), omega-Aga-IVA (30 nM) and was confirmed to be abolished by omega-CTx-MVIIC (3 microM), indicating involvement of N-, P- and Q-type channel subtypes. 3. Verapamil and diltiazem inhibited K+-evoked [3H]-DA release in a concentration-dependent manner. The inhibitory effects of verapamil or diltiazem (each 30 microM) were fully additive to the effect of omega-CTx-GVIA (1 microM), whereas co-application with omega-Aga-IVA (30 nM) produced similar effects to those of omega-Aga-IVA alone. 4. As shown previously, veratridine-evoked [3H]-DA release in Ca2+ containing medium exclusively involves Q-type Ca2+ channels. Here, diltiazem (30 microM) did not inhibit veratridine-evoked [3H]-DA release, whereas verapamil (30 microM) partially inhibited it, indicating possible involvement of Q-type channels in verapamil-induced inhibition. However, verapamil (30 microM) inhibited this release even in the absence of extracellular Ca2+, suggesting that Na+ rather than Q-type Ca2+ channels are involved. 5. Taken together, our results suggest that verapamil can block P- and at higher concentrations possibly N- and Q-type Ca2+ channels linked to [3H]-DA release, whereas diltiazem appears to block P-type Ca2+ channels only.
Animals↗
Amiodarone causes endothelium-dependent vasodilation in human hand veins in vivo.
OBJECTIVE: Amiodarone, a class III antiarrhythmic agent, is a potent coronary vasodilator. However, direct evidence for its vasodilatory effects in human vasculature in vivo is not available. The aim of the study was to investigate the short-term effects of amiodarone in preconstricted human hand veins and to explore the underlying mechanisms. METHODS: Thirty-one healthy male volunteers were studied with the use of the dorsal hand vein compliance technique. The hand veins of the subjects were preconstricted with the alpha 1-adrenergic receptor agonist phenylephrine, and amiodarone, inhibitors of nitric oxide formation (NG-monomethyl-L-arginine, L-NMMA), and adenosine triphosphate-dependent potassium channels (glyburide [INN, glibenclamide]) were infused in the presence or absence of a cyclooxygenase inhibitor (acetylsalicylic acid), and the venodilator effect was measured. Furthermore, amiodarone was infused in prostaglandin F2 alpha (dinoprost)-preconstricted hand veins. RESULTS: Amiodarone produced dose-dependent venodilation (51% +/- 3% maximum). Maximum amiodarone-induced venodilation was lower in dinoprost compared with phenylephrine-preconstricted veins. Pretreatment with acetylsalicylic acid reduced the amiodarone-induced venodilation by 40% +/- 6%. L-NMMA reduced the amiodarone-induced venodilation after pretreatment with acetylsalicylic acid by 72% +/- 3%. Glyburide decreased the venodilatory response of amiodarone by 31% +/- 11%, whereas only a slight but not statistically significant additional reduction in venodilation was detected after pretreatment with acetylsalicylic acid. Infusion of the solvents of commercially available amiodarone (polysorbate 80 and benzyl alcohol) did not cause vasodilation in phenylephrine-preconstricted veins. CONCLUSIONS: Amiodarone dilates preconstricted human hand veins in vivo and acts as a venodilator through the cyclooxygenase pathway, activation of nitric oxide synthase, and blockade of alpha adrenergic mechanisms.
Adult↗
Voltage-activated calcium channels involved in veratridine-evoked [3H]dopamine release in rat striatal slices.
The present study explored the role of different sub-types of voltage-activated Ca2+ channels (VACCs) in mediating veratridine-evoked [3H]dopamine (DA) release from rat striatal slices. The release of [3H]DA evoked by veratridine (25 microM) decreased by 50.6+/-2.9% (n=8) in the absence of calcium and was completely abolished by 1 microM tetrodotoxin. The L-type Ca2+ channel blockers nifedipine (10 microM), nitrendipine (10 microM), diltiazem (10 microM) and verapamil (10 microM) did not modulate this release. Similarly, [3H]DA release was affected neither by the N-type VACC blocker omega-conotoxin-GVIA (1 microM) nor by the selective P-type channel blockers omega-agatoxin-IVA and omega-agatoxin-TK at low nM concentrations (30 nM), indicating no involvement of N- and P-type Ca2+ channels. In contrast, higher concentrations of omega-agatoxin-IVA that would also inhibit Q-type VACCs, blocked the release of [3H]DA by 27.9+/-8.1% (n=5) and 37.5+/-13.6% (n=3) at 0.3 and 1 microM, respectively. In addition, application of the Q-type Ca2+ channel blocker omega-conotoxin-MVIIC (0.01-3 degrees M) reduced [3H]DA release in a concentration-dependent manner, with maximum inhibition of 35.3+/-4.1% at 3 microM (n=5). On the basis of these results, it is concluded that the Ca2+ channels that participate in veratridine-evoked [3H]DA release are Q-type Ca2+ channels.
Animals↗
Two-electrode telemetric instrument for infant heart rate and apnea monitoring.
Infants may be at risk of life threatening episodes caused by still unknown factors. The Sudden Infant Death Syndrome (SIDS) is believed to be connected with respiration problems due to immature and developing brain breathing control, and many other factors. Currently heart rate and respiration monitoring is considered of major importance to be applied in the hospital and eventually at hoinc. The objective is accurate detection of bradycardia (heart rate below a selected limit, usually between 80 and 100 beats/min) and apnea (cessation of breathing for more than 20 s). A telemetric instrument was developed for monitoring the heart rate and respiration by extraction of the respiration signal from the electrocardiogram QRS complex peak-to-peak amplitude. It makes use of two electrodes integrated in a transmitter module, thus avoiding use of leads and also reducing artifacts to an acceptable minimum. The receiver station can be a simple detector with apnea and bradycardia alarms, a more complicated recorder or a fully developed signal analyser.
Artifacts↗
Modulation of potassium-evoked [3H]dopamine release from rat striatal slices by voltage-activated calcium channel ligands: effects of omega-conotoxin-MVIIC.
We examined the involvement of voltage-activated Ca2+ channels (VACCs) on K+(50 mM)-evoked [3H]dopamine ([3H]DA) release from superfused rat striatal slices. Neither nifedipine nor nitrendipine modified K(+)-evoked [3H]DA release, indicating that L-type VACCs are not involved. K(+)-evoked [3H]DA release was partially inhibited by omega-CTx-GVIA and omega-Aga-IVA, and was abolished by 3 microM omega-CTx-MVIIC (IC50 approximately 128 nM), suggesting the involvement of N-, P-, or Q-type VACCs, respectively. Moreover, even subnanomolar concentrations of omega-CTx-MVIIC (0.1-0.5 nM) inhibited K(+)-evoked [3H]DA release by approximately 25%, suggesting the possible involvement of a still not classified (perhaps O-type?) Ca2+ channel subtype. The effects of omega-CTx-MVIIC (10-100 nM) and omega-CTx-GVIA (1 microM) were additive, suggesting that low nanomolar concentrations of omega-CTx-MVIIC does not interact with N-type VACCs. In conclusion, the K(+)-evoked [3H]DA release from rat striatal slices is mediated by entry of Ca2+ through omega-CTx-GVIA sensitive (N-type) as well as through omega-Aga-IVA (P-type) and omega-CTx-MVIIC (probably Q-type) sensitive VACCs.
Animals↗
Restriction and functional changes of dopamine release in rat striatum from young adult and old rats.
In order to investigate the age-related changes in dopaminergic activity in rats, we have utilized the K(+)- and veratridine-stimulated [14C]dopamine release from striatum in vitro as a functional index of responsiveness to these stimuli in aging. We found that the K(+)-stimulated dopamine release from old (12 months) rats decreased by more than 50% compared to that from young adult rats (3 months). Reserpine (5 mg/kg) led to a pronounced decrease of the K(+)-stimulated dopamine release of young adult as well as old rats. Whereas ouabain (10 mumol/l) decreased the K(+)-stimulated dopamine release from young adult rats, in old rats the K(+)-induced dopamine release was increased up to 250%. However, in old rats which were reserpine pretreated, ouabain was unable to stimulate the K(+)-induced dopamine release. In contrast, the veratridine-stimulated dopamine release of old rats was increased up to 200% compared to that of young adult rats and was highly sensitive to reserpine pretreatment but not to ouabain. However, reserpine did not alter this veratridine-stimulated dopamine release from young adult rats. The present data indicate that the age-related reduction of exocytosis-related, Ca(2+)-dependent release mechanisms (K+) are probably compensated via an increase in Ca(2+)-independent, uptake carrier-mediated release processes (veratridine).
Age Factors↗
[The bioequivalence of metoclopramide in two tablet formulations].
An investigation on the bioavailability of a tablet with 10 mg metoclopramide-HCl (CAS 363-62-5) Cerucal was performed in a two-way cross-over study with 12 volunteers. Metoclopramide was determined in serum by HPLC. The relative bioavailability (mean and nonparametric 95% confidence interval) with respect to a reference preparation was 0.95 (95% CI 0.88-1.02) for AUC and 0.92 (95% CI 0.79-1.07) for Cmax. A positive decision for bioequivalence was derived from the usual confidence intervals for both parameters. The tmax-values did not differ significantly. Statistical evaluation of all parameters revealed bioequivalence between the two preparations.
Adult↗
[A sensitive HPLC-method for determination of triamterene in serum].
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Chromatography, High Pressure Liquid↗
[Changes in the heart rhythm studied by the PWC170 test following physical loading].
By application of the two-component test PWC170, the changes in the heart rate (HR) and the difference in the duration of the minimal and maximal cardiac cycles (SAr), were studied. The indices (HR and SAr) were recorded by electrocardiography prior to the test (initial values), during the three-minute pause between the two loadings and in the three-minute recovery period following the second loading. It was found that SAr in the pause after the first loading with lower intensity of the test was more markedly expressed with respect to its initial values, while in the recovery period after the more intensive second loading of the test it was not only less expressed but in a number of cases did not reach the initial values. It was assumed that the relationship between the expressed in each moment influences of the vagal and sympathetic neuroregulatory mechanisms of the heart was significant for the expression of the observed rhythmic fluctuations.
Electrocardiography↗
[Manometry of the upper gastrointestinal tract in esophageal reflux disease].
Infusion manometry of the esophagus and the stomach after the permanent dynamic method of Winans [correction of Wynas] and Harris was carried out on 52 patients (30 women and 22 men) with hiatal hernia, volvulus of the stomach or peptic ulcer disease. Altogether 75 examinations were performed--35 preoperative and 40--postoperative. The mean preoperative pressure of the inferior esophageal sphincter was 9.1 (from 0 to 15) mmHg and the mean postoperative pressure was 18 (from 12 to 211 mmHg). The mean preoperative length of the inferior esophageal sphincter was 1.4 (from 0 to 4) cm and the mean postoperative length was 2.5 (from 1 to 6) cm. In 12 patients motor disturbances of the tubular esophagus were found: symmetric, hyperpersistaltic waves (Richter's nutcracker symptom)--in 3 patients, hypomotility--in 5 patients, diffuse esophageal spasm--in 4 patients. Esophageal manometry is a valuable noninvasive method for the functional diagnostic of the reflux disease and the motor esophageal disturbances as well as for the assessment of the postoperative function of the inferior esophageal sphincter.
Digestive System↗
[Changes in the high-density lipoprotein level in patients with diabetes mellitus type II].
In 62 patients with diabetes mellitus type II, 22 patients with obesity I degree and 40 patients with normal body mass (28 with ischemic heart disease and 12 without ischemic heart disease) the blood sugar profile and the composition of the high density lipoproteins (HDL) were examined. In decompensated diabetes mellitus type II reduction of cholesterol and phospholipid contents of HDL and of apoprotein A were found. With compensation of the carbohydrate metabolism the composition of HDL becomes normal. In the obese diabetics the changes of these indices are more pronounced. In diabetic patients with ischemic heart disease the cholesterol and phospholipid contents and that of apoprotein A in HDL are lower than those in diabetic patients without ischemic heart disease. These data show that changes of HDL in diabetes mellitus favor the development of atherosclerosis changes.
Adult↗
[Unsaturated fatty acids in diabetes mellitus].
The following unsaturated fatty acids were examined in the serum and in the high density lipoproteins of 38 patients with diabetes mellitus type Il and 20 healthy controls: linolic, linolenic, eicosandienoic, eicosanetrienoic, arachidonic and eicosanepentaenoic. In decompensates diabetes mellitus a decrease of linolenic, eicosanedienoic, arachidonic and eicosanepentaenoic acids and an increase of linolic and eicosanetrienoic acids were found. After compensation of carbohydrate metabolism the last fatty acids showed a tendency toward normalization. The parallel changes of the fatty acids studied in the serum and in the high density lipoproteins suggest that the fatty acids contents of the HDL depends on the serum fatty acids. It is most probable that the variable changes of the individual unsaturated fatty acids play a role in the complex mechanism of vascular lesions in diabetes mellitus.
Aged↗
[Lipoproteins in diabetes mellitus].
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Apoproteins↗
[Fine-needle aspiration biopsy in the diagnosis of thyroid diseases].
On 105 patients with thyroid gland diseases thin needle aspiration biopsy was performed. The cytologic examinations proved to be of great importance for the diagnosis of thyroiditis and thyroid cancer. When lymphoid cells were found immunocytochemical examination was made additionally. It allows the differentiation of the subacute thyroiditis from the chronic and recurrent thyroiditis. The thin needle aspiration biopsy is practically a harmless manipulation. The great frequency of the asymptomatic chronic thyroiditis and of thyroid gland cancer supports the recommendation of a wider application of the method in all patients with thyroid gland diseases.
Biopsy, Needle↗