Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of the phorbol ester, phorbol myristate acetate (PMA) were examined on function and energy metabolism in the isolated working heart of the rat. 2. At a concentration of 10(-9) M PMA produced a rapid loss in cardiac function in terms of aortic flow rate (AFR) and coronary flow rates (CFR) whereas a similar concentration of 4 alpha-phorbol 12,13-didecanoate was ineffective. At a concentration of 10(-10) M, the PMA-induced depression was more gradual but nevertheless very pronounced with an almost total loss in AFR after 30 min perfusion. The reduction in CFR was more moderate than that observed with respect to AFR. 3. The protein kinase C (PKC) inhibitor (+/-)-1-O-hexadecyl-2-O-acylglycerol significantly attenuated the loss in AFR and CFR following addition of PMA. 4. Two inhibitors of Na+/H+ exchange, amiloride and quinacrine, totally prevented the reduction in AFR. Although the PMA-induced depression in CFR was also attenuated by both amiloride and quinacrine, these effects were not significant, probably reflecting the less pronounced effect of PMA on this parameter. 5. Nifedipine, a dihydropyridine calcium channel blocker reduced PMA toxicity to a similar degree as Na+/N+ exchange inhibition whereas the calcium channel agonist Bay K 8644 was without effect. 6. Tissue content of energy metabolites including high energy phosphates, total adenine nucleotides or lactate were not significantly affected by PMA perfusion. 7. We conclude that PKC activation is necessary for phorbol ester-induced cardiac dysfunction. The consequence of PKC stimulation includes (1) Na+/H+ exchange activation and a subsequent elevation in intracellular calcium [Ca2+]i via Na+/Ca2+ exchange and (2) PKC-dependent phosphorylation of the calcium channel, both of which would produce toxicity by elevation of [Ca21]i. Pharmacological manipulation of any of these steps prevents PMA toxicity by virtue of a reduction in the accumulation of [Ca21]i. PMA effects or their prevention are unrelated to any changes in energy metabolism.
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PMID:Mechanisms for cardiac depression induced by phorbol myristate acetate in working rat hearts. 220 2

In a double blind crossed ten-week study with a randomized beginning the authors compared in 25 patients with chronic stable angina pectoris (II-III according to NYHA classification) and with normal blood pressure the effect of placebo, nifedipine, diltiazem and in 16 of the patients (who completed treatment with the combined drugs) also a combination of nifedipine and diltiazem. Nifedipine, 60 mg per day, and diltiazem, 270 mg per day, improved significantly the total amount of performed work as compared with placebo, they delayed significantly the onset of stenocardias and reduced the ST depression in lead V5 during ergometry, they reduced significantly the rate of stenocardias per day as well as the nitroglycerin consumption. Diltiazem, as compared with nifedipine, increased significantly the total volume of performed work and delayed the development of stenocardias during ergometry, the symptomatic improvement of the patients being similar. A combination of 30 mg nifedipine per day with 180 mg diltiazem per day did not lead to improvement, as compared with a higher dose of diltiazem alone, as compared with a higher dose of diltiazem alone. A combination of 60 mg nifedipine per day with 270 mg diltiazem per day did not improve the exercise tolerance, as compared with diltiazem alone, however, it reduced significantly the rate of stenocardias. However, the combination of the latter amounts was tolerated without side-effects only by 13% of the patients (2 of 15 patients), 53% (8 of 15 patients) terminated treatment prematurely because of several side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effectiveness of nifedipine, diltiazem and their combination in the treatment of chronic stable angina pectoris]. 220 31

The effect of two calcium channel inhibitors, diltiazem and nifedipine in animal models of depression: a) behavioral despair test and b) behavioral deficit produced by uncontrollable footshock was investigated. Additionally, the influence of both drugs on mouse killing (muricide) behavior induced by chronic isolation was studied. Both drugs given in single doses increased the active behavior of rats in behavioral despair test. Nifedipine but not diltiazem was partially effective in the test when administered chronically (14 days). Both drugs also attenuated stress-induced behavioral depression in the open field and forced swim test. Diltiazem was markedly more active in the former whereas nifedipine in the latter test. Neither compound influenced killing behavior in muricidal rats. Our data support the notion that calcium channel inhibitors may possess antidepressant activity, although there appear to exist certain differences in their scope of action depending on the model applied.
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PMID:Activity of diltiazem and nifedipine in some animal models of depression. 227 70

The relative extent of the vasodilator versus direct negative inotropic effects of nifedipine was studied in 15 male patients with documented coronary artery disease and normal left ventricular function. At the time of diagnostic cardiac catheterization, three groups of five patients received dose of 1, 2, and 3 mg intravenous nifedipine at a rate of 0.33 mg/min. Hemodynamic measurements and blood collections were made before, during, and every 5 minutes for 30 minutes after infusion of nifedipine. Heart rate increased and mean arterial pressure decreased significantly after the 2 and 3 mg doses of nifedipine. Systemic vascular resistance was significantly decreased and cardiac index increased after all doses of nifedipine. Maximal left ventricular dp/dt (dp/dtmax) was significantly decreased after the 3 mg infusion. The reduction in dp/dtmax was most consistent with a reduction in left ventricular contractility as opposed to changes in loading conditions. Plasma concentrations of nifedipine were significantly correlated with bidirectional changes in dp/dtmax (r = 0.86). Nifedipine concentrations below 28.2 ng/ml were associated with a rise in dp/dtmax, whereas concentrations above that level were associated with a reduction in dp/dtmax. These data indicate that intravenous nifedipine produces dose- and concentration-dependent depression of myocardial contractility in patients with coronary artery disease. Nifedipine concentrations associated with negative inotropic effects are readily achievable with common oral and sublingual doses.
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PMID:Negative inotropic effect of intravenous nifedipine in coronary artery disease: relation to plasma levels. 230 Dec 17

Rodent muscles were exposed to several organic calcium antagonists, and mechanical responses to direct electrical stimulation were recorded. Verapamil and D600, at 25 microM, depressed twitch and tetanus tension and caused fading of the tetanus plateau. These effects increased with frequency of stimulation, and were not reversed by doubled extracellular calcium. Depression of tension progressed to complete paralysis after 60-90 min exposure to verapamil. Bepridil and diltiazem both caused depression of tension and tetanus fade. Nifedipine caused marked, and nitrendipine caused slight, potentiation of twitch tension but did not alter tetanic tension. The magnitude of the observed effects on tension (either depression or potentiation) correlated with neither the relative calcium antagonist potencies of the drugs in other tissues nor with the ability of the drugs to cross the cell membrane. The continued decline in tension observed on prolonged exposure indicates that chronic exposure to low levels in vivo might lead to significant muscle weakness.
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PMID:Effects of calcium antagonists on mechanical responses of mammalian skeletal muscles. 241 76

The effects of a new dihydropyridine, FR-34235, were compared with those of the dihydropyridine, nifedipine, and verapamil on the normal fast action potentials (APs), slow APs, and contractions of guinea pig papillary muscles and Purkinje fibers. FR-34235 (10(-6) M) blocked the contractions of papillary muscles superfused with normal Tyrode solution within 10-12 min. Maximal upstroke velocity (+Vmax) and overshoot of the fast APs were not affected, whereas the AP durations at 50 and 90% repolarization (APD50 and APD90) were shortened. The effects of FR-34235 on the fast APs and contractions were reversed within 10 min on washout. To determine the effects of the calcium antagonists on slow APs, the fast Na+ channels were inactivated by partial depolarization (to approximately -45 mV) by elevated [K]0, and isoproterenol (10(-6) M) or histamine (10(-5) M) was used to induce slow APs on stimulation. Nifedipine (10(-7) M) and verapamil (2 X 10(-6) M) completely blocked the slow APs. FR-34235 depressed (3 X 10(-8) M) and blocked (10(-7) M) the slow APs in a frequency-dependent manner. The effects were reversed by elevated [Ca]0 or washout of the drug. The contractions accompanying the slow APs were depressed and blocked in parallel with the depression of +Vmax. In guinea pig Purkinje fibers, FR-34235 had no significant effect on the fast AP parameters but produced a marked depression of automaticity. FR-34235 also blocked the slow APs of the Purkinje fibers in a frequency-dependent manner; all drug effects were reversed within 10 min on washout.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electropharmacological effects of a new dihydropyridine analog on isolated guinea pig papillary muscles and Purkinje fibers. 242 57

In this study the effects of a new calcium entry blocking agent, 2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-furoyl)-1, 4-dihydropyridine (MDL 72567), were compared with those of nifedipine on blood pressure, heart rate, ECG, and cardiac contractility indices in conscious sinoaortic baroreceptor-denervated (SA-denervated) rats and their sham-operated controls. In sham-operated rats, the calcium-entry blocking agents (0.1-2 mg/kg i.v.) produced equivalent falls in blood pressure. However, nifedipine caused a much greater reflex tachycardia which was accompanied by a negative inotropic effect, and with the highest dose (2 mg/kg), a prolongation of the PQ interval. MDL 72567 induced an increase in myocardial contractility. In SA-denervated rats, both drugs produced an enhanced fall in blood pressure accompanied by a negative inotropic effect. Nifedipine did not change heart rate in SA-denervated rats, whereas MDL 72567 caused bradycardia. Thus, in these experiments, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure than nifedipine and was less likely to cause myocardial depression. These effects of MDL 72567 may represent valuable, clinically relevant advantages over nifedipine.
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PMID:Comparison between the effects of MDL 72567 and nifedipine on various cardiovascular parameters in conscious sinoaortic-denervated rats and sham-operated controls. 244

The effect of antihypertensive drugs on receptor-dependent increase in Ca2+ basal level and its changes under stimulators action (thrombocytes activating factor, ADP and vasopressin) were studied by means of a fluorescent calcium probe "quin-2". Nifedipine blocked receptor-dependent increase of Ca2+ in thrombocytes in vitro as well as by oral administration, which was accompanied by decrease in vascular tone and BP. The degree of BP decrease correlated with that of depression of receptor-dependent increase of Ca2+ in thrombocytes. Combined therapy including nifedipine, propranolol and a diuretic resulted in more manifest inhibition of receptor-dependent calcium channels than monotherapy with nifedipine. Effect of antihypertensive drugs evidently depends on their influence on receptor-dependent Ca2+ cellular entrance.
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PMID:[Effect of hypotensive therapy on a receptor-dependent increase in Ca2+ in the thrombocytes of patients with hypertension]. 245 72

1. Twitches, tetanic contractions and potassium contractures were recorded isometrically from small bundles of rat soleus muscle fibres. 2. Solutions with reduced calcium concentrations (low-calcium solutions), whether buffered with EGTA (85 and 3 microM-Ca2+) or not (15 microM-Ca2+), caused an initial potentiation of contraction followed by depression. 3. The decay of potassium contractures (200 mM-potassium) was more rapid than normal in low-calcium solutions. 4. Recovery from the inactivation produced by a 200 mM-potassium contracture was slowed in low-calcium solutions but full recovery was seen within 10-15 min after return to a solution containing 2.5 mM-Ca2+. 5. Nifedipine (50 microM) in solutions containing 2.5 mM-Ca2+ potentiated contraction whereas, in low-calcium solutions, contraction was depressed and the depression was more pronounced the lower the Ca2+ concentration. 6. As with low-calcium solutions, potassium contractures decayed more rapidly in solutions containing nifedipine. Nifedipine slowed still further the rate of recovery from inactivation in low-calcium solutions. 7. (-) Bay K 8644 (50 microM) depressed contraction, increased the rate of decay of potassium contractures and slowed recovery from inactivation, like nifedipine. The racemate of Bay K 8644 was less effective. 8. In explanation of these and other observations, it is proposed that there is a dihydropyridine-binding molecule in the walls of the transverse tubular system that normally exists predominantly in a 'precursor' form at the resting membrane potential and is converted by membrane depolarization to an 'activator' form essential for excitation-contraction coupling. Conversion of the precursor to activator involves both conformational change and dissociation of calcium. Prolonged depolarization converts activator to an inactivated form by inducing further conformational change and dissociation of calcium. Recovery from inactivation requires reverse conformational changes and rebinding of calcium. The dihydropyridines affect contraction by reducing the affinity of the molecule for calcium.
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PMID:Effects of extracellular calcium concentration and dihydropyridines on contraction in mammalian skeletal muscle. 245 97

As many as 32 patients with moderate arterial hypertension were examined. According to unidimensional echocardiography, the improvement of early diastolic filling of the hypertrophied left ventricle of the heart was recorded during 4 weeks of the treatment with nifedipine, a dihydropyridine blocker of calcium channels. The favourable effect on diastolic filling function was combined with an efficient control over arterial pressure which was determined by a decrease in the systemic vascular resistance. Nifedipine did not produce any depression of contractile and pump functions of the heart.
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PMID:[Nifedipine in the treatment of hypertension. An echocardiographic assessment of the hemodynamic effects]. 253 75


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