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)

The objective of this study was to characterize the effect of prostacyclin (PGI2) on ventricular function following total global ischemia in isolated working rat hearts and to investigate the mechanism of its action. Ischemia was initiated for 10, 15, 20 or 25 min with or without treatment with PGI2. Increasing durations of ischemia resulted in a progressive decline in high energy phosphate (HEP) stores, an elevation in tissue lactate, and incomplete recovery of function with reperfusion. Prostacyclin at either 1 or 10 ng/ml had no effect on HEP levels or total adenine nucleotides, and tissue lactate was not significantly affected by PGI2 in hearts made ischemic for 10 to 20 min, but both PGI2 concentrations significantly elevated lactate levels after 25 min ischemia. Reperfusion recovery of left ventricular function was complete following 10 and 15 min ischemia, but incomplete recovery was evident following 20 min ischemia (77% of pre-ischemic function); and although PGI2 had no direct effect on the function of aerobically perfused hearts, recovery of aortic flow with 1 ng/ml PGI2 after 20 min of ischemia was reduced to approximately 20% (P less than 0.01). This depression in recovery was associated with significantly increased lactate levels during reperfusion. At a concentration of 10 ng/ml PGI2 did not depress ventricular recovery or elevate lactate content after 20 min ischemia. When hearts made ischemic for 20 min were analyzed, a significant negative correlation was found between ventricular recovery (aortic flow rate) and lactate concentration; however, no correlation existed between recovery and ATP levels. After 25 min of ischemia, five of eight (62.5%) untreated hearts demonstrated some degree of ventricular recovery, however, only two of ten hearts studied demonstrated any measurable functional recovery with either PGI2 concentration. This effect of PGI2 to reduce or prevent recovery of ventricular function following either 20 or 25 min of ischemia as well as the corresponding elevation in lactate levels was prevented by treatment with the calcium channel blocker verapamil. This study therefore shows that PGI2 at critical low concentrations can depress left ventricular recovery following total ischemia. This effect of PGI2 becomes more pronounced as ischemia duration is prolonged and is associated with elevated tissue lactate levels. The studies with verapamil suggest that PGI2 may be acting via the slow calcium channel to increase lactate levels and depress ventricular recovery following prolonged periods of ischemia.
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PMID:Inhibition of post-ischemic ventricular recovery by low concentrations of prostacyclin in isolated working rat hearts: dependency on concentration, ischemia duration, calcium and relationship to myocardial energy metabolism. 266 90

The effects of gallopamil, a calcium channel blocker methoxy derivative of verapamil, recently introduced into clinical use in Germany, were evaluated in 20 patients with stable exertional angina. Two different dosages of the drug were used: 25 mg tid and 50 mg tid. It was observed that both dosages improved exercise tolerance (355 +/- 95 sec after placebo; 462 +/- 78 sec, p less than 0.01 and 511 +/- 97 sec, p less than 0.01 after the two doses) while the time taken to produce ischemia (-1 mm ST depression) was significantly prolonged only by the higher dose of the drug (204 +/- 101 sec after placebo; 324 +/- 135 sec after gallopamil 150 mg, p less than 0.05). Both dosages of gallopamil caused a significant reduction in the double product in the first phases of the exercise (double product 3 degrees min of exercise x 10(2): 173 +/- 140 after placebo; 153 +/- 34, p less than 0.05 and 145 +/- 30, p less than 0.05 after the two doses), while they did not affect this parameter at the end of the exercise. Our data seem to confirm that gallopamil works through a lowered myocardial metabolic demand as a consequence of the reduction of the afterload. Both dosages of the drug decreased the number of episodes of angina, but the higher dose was more effective. The drug is safe and well tolerated. All patients completed the study. Furthermore, no particular haemodynamic problems were observed.
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PMID:[Gallopamil in stable effort angina. Effects of 2 different dosages]. 274 13

Rabbits received twice-a-day doses of verapamil for 8 days and, on day 9 they were sacrificed in order to test contractile responses of the aorta in vitro. Isolated rings of aorta received graded doses of KCl, norepinephrine and norepinephrine along with either phentolamine, phenoxybenzamine or additional (acute) verapamil. Treated rings (those from animals that received verapamil chronically) developed significantly less tension (E) in response to depolarizing doses of KCl, but the degree of developed tension was restored and, in fact, enhanced when the aortic tissue was tested after cold storage 24 hr later (day 10). Responses (E) to norepinephrine in verapamil-pretreated rings were less than in controls by amounts that correlated with the daily verapamil dose and these too were enhanced after cold storage for 24 hr. The equilibrium dissociation constant (KA) of norepinephrine for the alpha 1-adrenoceptor, determined by the method of partial receptor blockade, was increased (reduction in affinity) by amounts that also depended on the daily verapamil dose. In contrast to agonist affinity, phentolamine affinity, determined from Schild-plot analysis, was not different from controls, even for the highest daily dosage of verapamil. Stimulus-effect curves were also the same in control and verapamil-pretreated groups, thus suggesting that the chronic treatment did not affect the basic contractile process distal to the receptor. Further, aortae from pretreated rabbits showed more depression to acute verapamil than was seen in controls and this depression in Emax could not be overcome with even high doses of norepinephrine. In addition to the known alpha-blocking and calcium channel blocking actions of verapamil, these data show that chronic verapamil affects norepinephrine, but not phentolamine-receptor affinity, thus suggesting that the chronic action of this calcium entry blocker may preferentially alter a site on the receptor to which norepinephrine binds.
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PMID:Effects of chronic treatment with verapamil on adrenoceptor-mediated contraction of rabbit aorta. 275 61

Despite evidence from animal experiments to the contrary, nitrous oxide (N2O) reportedly does not induce myocardial ischemia when used as an adjunct to fentanyl anesthesia in patients with coronary artery disease who have well-preserved left ventricular (LV) function. However, the incidence of ischemia with N2O administration in similar patients with poor LV function may be different. The effects of N2O on segmental LV function, as determined by two-dimensional transesophageal echocardiography, changes in the ST-segment of the electrocardiogram were compared with the effects of an equal concentration of nitrogen (N2) (crossover design) in 70 patients who required elective coronary artery bypass grafting. Of these patients, 24% had left ventricular ejection fraction (LVEF) less than or equal to 40%. Myocardial ischemia was diagnosed in 14 patients during the study: four while awake, seven during induction of anesthesia and tracheal intubation, and four during the remainder of the study (one during N2O and three during 100% oxygen; one patient had two distinct periods of ischemia). No value for LVEF could be found that would distinguish between patients who did or did not have ischemia during the study. Patients treated with beta-adrenergic blocking drugs preoperatively were less likely to develop ischemia (P less than 0.05). Preoperative calcium channel blockers made no such differences. Onset of ischemia was not closely associated with hemodynamic changes. Thus, N2O does not induce clinically detectable myocardial ischemia in patients who have coronary artery disease, and poor LV function in situations in which the effects of deepening anesthetic depth and mild depression of global myocardial function are deemed desirable or harmless.
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PMID:Nitrous oxide does not induce myocardial ischemia in patients with ischemic heart disease and poor ventricular function. 280 10

The factors regulating calcium homeostasis in the cardiac plasma membrane of renal hypertension in the rat (two kidney-one clip, Goldblatt model) have been studied. Comparison of the cardiac sarcolemma from control (C) and hypertensive (H) rats indicates similar protein yield and purity. Study of longer term hypertension (4 to 12 weeks) shows a decrease in the number of calcium channel receptor binding sites (Bmax C: 549 +/- 122 fmol/mg; H: 334 +/- 74 fmol/mg) as well as a depressed calcium pumping ATPase activity (C: 7.6 +/- 2.5 nmol/mg/min; H: 3.8 +/- 1.5 nmol/mg/min). Furthermore, there is a decreased rate of Na+-Ca2+ exchange (C: 5.4 +/- 1.9 nmol/mg/5 s; H: 2.3 +/- 0.9 nmol/mg/5 s). Study of short-term hypertension (1 to 4 weeks) indicates that the earliest change occurs at 1 week with decreased calcium pumping ATPase due to a change of the Vmax of Ca2+ transport (C: 9.7 +/- 1.6 nmol/mg/min; H: 5.4 +/- 1.4 nmol/mg/min). This is then followed by the decreased calcium channel receptor binding. However, the rate and the extent of depression in Ca2+-ATPase activity are much greater than that of Ca2+ channel receptor binding. Since alteration of Ca2+-ATPase is accompanied by an increase in intracellular Ca2+ concentration and there is a temporal association with the onset of myocardial lesions in the hypertensive rats, it is suggested that elevated intracellular calcium concentration as a result of altered Ca2+-ATPase activity may play a significant role in the development of hypertensive cardiomyopathy.
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PMID:Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension. 284 6

Using a radiolabelling technique it was possible to measure changes of cholinergic nerve activity in human isolated taenia coli muscle. Loperamide (1.9-97.3 microM) depressed release of acetylcholine produced by electrical field stimulation to a greater degree than morphine (0.13-130 microM). The effect of loperamide was only partially sensitive to naloxone. Loperamide (7.8 microM) demonstrated calcium channel blocking-like properties as shown by its antagonism of CaCl2-induced contractions of depolarised muscle. Although an established calcium channel antagonist, verapamil, was also able to depress cholinergic nerve activity, the concentration was considerably greater than required for antagonism of CaCl2 contractions. The depression of acetylcholine release by loperamide may contribute to its anti-diarrhoeal properties.
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PMID:Opioid and non-opioid actions of loperamide on cholinergic nerve function in human isolated colon. 285 Feb 1

Calcium channel blocking agents function as negative inotropic agents when they are administered in vitro directly to the myocardium. In patients with coronary artery disease, however, such direct effects are attenuated by a number of other factors, including decreased afterload and resultant reflex sympathetic stimulation, increased coronary blood flow with improved myocardial perfusion, and protection of mitochondria. Nifedipine has not been observed to cause significant left ventricular depression in patients with angina pectoris; this is primarily due to peripheral arteriolar vasodilatation, which reduces impedance of left ventricular ejection. In addition, the relief of myocardial ischemia by nifedipine plays a major role in improving systolic and diastolic function. The clinical response to calcium channel blockers may differ in patients with idiopathic dilated cardiomyopathy, for whom the factor of fluctuating ischemia is less important.
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PMID:Effect of nifedipine on left ventricular function in patients with angina pectoris. 287 35

Using the cannula inserting method, we investigated the responsiveness of isolated skeletal muscle branches of the dog femoral artery to alpha-adrenoceptor agonists and potassium chloride, and the influence of cold storage (3 days and 5-7 days, at 4 degrees C). Epinephrine (EPI) and norepinephrine (NE) induced a marked vasoconstriction in a dose-related manner. A large dose of EPI and NE usually induced an increase in perfusion pressure of more than 100-200 mm Hg. Phenylephrine (PE) and methoxamine (MT) also induced a marked constriction, but clonidine (CLO) and xylazine (XYL) produced only a slight vasoconstriction, even in large doses. Tyramine (TYR) also induced a small vasoconstrictor response. A large dose of KCl induced a marked vasoconstriction. The order of potency of constriction was EPI greater than or equal to NE greater than PE = MT much greater than KCl greater than CLO greater than or equal to TYR greater than or equal to XYL. The vasoconstrictor responses to EPI and NE were significantly suppressed by 3-7 days of cold storage. Vasoconstrictor responses to MT were slightly suppressed by cold storage. However, XYL-, CLO- and TYR-induced vasoconstrictions were not significantly influenced by cold storage. KCl-induced constriction was clearly suppressed by cold storage. These observations suggest that the postjunctional alpha-adrenoceptor in skeletal muscle branches of the femoral artery is of the alpha 1-type. Moreover, it was shown that prolonged cold storage (3-7 days, at 4 degrees C) resulted in a decrease in sensitivity of these vessels to alpha-adrenoceptor agonists and in a marked decrease in sensitivity to KCl, suggesting a depression of the calcium channel by cold storage.
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PMID:Responsiveness of skeletal muscle branches of the dog femoral artery to alpha-adrenoceptor agonists before and after cold storage. 288 40

The widespread use of Holter monitoring has demonstrated that the majority of ischemic episodes occur during activities that do not require exertion. These episodes tend to occur at only minimal increases in heart rate above resting levels, well below the level of myocardial oxygen demand required to produce ischemia on formal exercise tolerance testing. In all likelihood, therefore, most ischemic events in ambulatory patients are due to a combination of flow-limiting coronary stenosis and superimposed vasoactive or thrombotic elements. Asymptomatic ischemic events are common in subsets of patients with angina pectoris. Traditionally, treatment with calcium channel blockers, beta-blockers, and long-acting nitrates has been aimed at reducing episodes of angina pectoris. Despite a reduction in anginal symptoms, however, it is likely that patients continue to experience silent ischemia, particularly at rest and during activities of daily living. The strategy for treatment in such patients should include the abolition of the patients' "total ischemic activity." It is conceivable that more aggressive anti-ischemic therapy may improve prognosis, as patients with ambulatory ST-segment depression experience frequent cardiac events. Other potential benefits of more aggressive treatment include the prevention of myocardial hibernation, which occurs as a result of a chronic ischemic state, and a reduction in episodes of myocardial stunning. This approach may lead to protection against transient and chronic left ventricular dysfunction, which is associated with a poor prognosis in patients with symptomatic coronary artery disease.
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PMID:Silent myocardial ischemia. Mechanisms and rationale for therapy. 291 88

Six point concentration-response curves were established for the contractile effect of prostaglandin E2 (PGE2) on helically-cut strips of human chorionic plate arteries. Tissues were then allocated to one of four treatment groups: a control group and 3 groups exposed to the calcium channel blocker nitrendipine at 10(-9), 10(-7) or 10(-5) M. The concentration-response curves were then repeated. The addition of nitrendipine was associated with a significant depression of the induced contraction. The contractile response to the lower doses of PGE2 was replaced by a small relaxation in 63% of the treated tissues. It is suggested that in these tissues PGE2 exerts its constrictor effect via the receptor-operated channels and that nitrendipine is blocking this effect. Similar experiments performed with PGE1 showed great variability in the initial response. Nitrendipine 10(-5) M failed to exert any detectable effect on this response. Pregnancy-induced hypertension is associated with vasoconstriction in both the maternal and placental circulations. There also appears to be a relative excess of vasoconstrictor eicosanoid production. Nitrendipine may be of use in the treatment of this condition.
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PMID:The effect of a calcium antagonist, nitrendipine, on the responses of isolated strips of human, chorionic plate artery to prostaglandins E2 and E1. 293 11


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