Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gram-negative sepsis septic shock continues to produce significant mortality and therefore remains a major medical problem. Vasodilators have been studied in the treatment of circulatory shock. However, the effectiveness of calcium channel blockers in the treatment of newborn endotoxic shock has not been well documented. In the present study, diltiazem, a calcium channel blocker, and nitroprusside, a vasodilator, were used for the treatment of endotoxic shock in 10-day-old rats. Mortality rate, hemodynamics, and glucose metabolism were monitored. Diltiazem at a dose of 0.3 mg/kg attenuated the hypotension, bradycardia, hypoglycemia, and lactacidemia in newborn endotoxic shock. Diltiazem treatment resulted in reduced 24-hour mortality. However, 0.6 mg/kg diltiazem enhanced the hypotension, bradycardia, and lactacidemia in endotoxic shock. Nitroprusside blunted the hypoglycemia and decreased the mortality rate among rats with endotoxic shock. Afterload reduction may be responsible for the beneficial effects of 0.3 mg/kg diltiazem and nitroprusside. Diltiazem at a dose of 0.3 mg/kg reduced the lactacidemia of endotoxic shock more than nitroprusside. Therefore the effects of diltiazem may be due not only to afterload reduction but also to inhibition of cellular calcium influx. We conclude that 0.3 mg/kg diltiazem and 1.0 mg/kg nitroprusside are beneficial for the treatment of endotoxic shock in newborn rats.
 ...
PMID:Diltiazem treatment of endotoxic shock in suckling rats. 151 92

Although often not considered, the heart is one of the targets of multiple organ failure in sepsis and septic shock, with myocardial depression being a prominent component of this "acute septic cardiomyopathy". Hypotheses concerning the etiology of this depression are increasingly elucidated on a cellular level, including dysfunction of the beta-adrenoceptor/G protein/adenylate cyclase system, calcium channel blockade by cardiodepressant factor, contractile impairment by activated leucocytes, as well as inhibition of protein synthesis by Pseudomonas exotoxin A. In the search for "mechanisms of myocardial depression in sepsis", isolated cardiomyocytes may play a role as research tools with respect to: a) discrimination between direct and indirect cardiodepressant effects; b) identifying not only the acute, but also chronic toxin- and mediator-induced cardiodepression; c) clarification of the mechanism of action of cardiodepressant bacterial toxins and sepsis mediators; d) establishment of in vitro models of leucocyte-mediated cardiodepression in sepsis.
 ...
PMID:Mechanisms in acute septic cardiomyopathy: evidence from isolated myocytes. 166 46

Various beneficial effects of calcium channel blockers on cell and organ function following endotoxic shock, organ ischemia, and reperfusion have been reported; however, it is not known whether these agents have any salutary or deleterious effects on immune responses after low-flow conditions. Therefore, the aim of this study was to determine (a) the effect of hemorrhage on lymphocyte IL-2, IL-3, IL-6, and IFN-gamma synthesis, and (b) whether diltiazem has any salutary or adverse effects on these parameters when administered following hemorrhage and resuscitation. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg, maintained at that level for 60 min, and resuscitated with shed blood plus twice that volume of Ringer's lactate. Immediately following resuscitation mice received either diltiazem (2400, 800, or 400 micrograms/kg body wt), or an equivalent volume of saline. The mice were sacrificed 24 hr later, splenic lymphocytes were obtained, and their capacity to produce lymphokines was assessed. The results indicated that in the vehicle-treated animals, hemorrhage significantly decreased (P less than 0.05) IL-2, IL-3, IL-6, and IFN-gamma synthesis by 82 +/- 19%, 64 +/- 28%, 71 +/- 11%, and 86 +/- 14%, respectively. However, diltiazem (400 but not 2400 micrograms/kg) treatment after hemorrhage restored lymphocyte capacity to produce IL-2, IL-3, IL-6, and IFN-gamma (P less than 0.05). Additional groups of animals were subjected to sepsis by cecal ligation and puncture 3 days following hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Diltiazem restores IL-2, IL-3, IL-6, and IFN-gamma synthesis and decreases host susceptibility to sepsis following hemorrhage. 190 99

The mortality of sepsis/septic shock continues to be high in newborns. However, there is no established method in its treatment. Although calcium channel blockers ameliorate the hemodynamic deterioration of adult circulatory shock, their effects on newborn endotoxic shock have not been elucidated. This study was performed in newborn dogs to investigate the effects of diltiazem on newborn endotoxic shock. Endotoxic shock was induced in newborn dogs (2-10 days old, 300-800 g) by an intravenous injection of E. coli lipopolysaccharide (LPS; 1.5 mg/kg), and diltiazem (DZ) at the dose of 300, 600 or 1200 micrograms/kg was administered intravenously 20 min prior to LPS injection. Hemodynamic changes were serially observed until 120 min after LPS injection. The heart rate, mean arterial pressure and cardiac output decreased after LPS injection, and systemic vascular resistance decreased. DZ at the dose of 600 micrograms/kg attenuated the decreases of MAP and cardiac output, but 300 and 1200 micrograms/kg of DZ exacerbated them. DZ at the dose of 1200 micrograms/kg decreased the heart rate, and DZ at all three doses attenuated the increase of systemic vascular resistance. Therefore, 600 micrograms/kg of DZ is beneficial in the treatment of endotoxic shock in newborn dogs.
 ...
PMID:Diltiazem treatment in newborn canine endotoxic shock. 208 81

Hemorrhage induces a severe suppression of the immune system resulting in increased susceptibility to sepsis. Although studies indicate beneficial effects of calcium channel blockers on cell and organ functions after low-flow conditions, it remains unknown whether such agents have any effects on different immune responses after hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg and were maintained for 60 minutes, followed by resuscitation with their own shed blood and adequate fluid. The mice received either the water-soluble calcium channel blocker diltiazem (400 or 2400 micrograms/kg body weight) or saline solution (vehicle). Peritoneal macrophages were obtained by lavage 24 hours later. Antigen presentation was measured by coculturing peritoneal macrophages with the D10.G4.1 helper T-lymphocyte clone. Immune associated antigen (Ia) expression was determined by direct immunofluorescence. Interleukin (IL)-1, 6, and tumor necrosis factor-alpha (TNF) levels in peritoneal macrophage supernatants were measured by use of cytokine-specific cellular assays. Hemorrhage caused a significant decrease in peritoneal macrophage antigen presentation function, Ia expression, and IL-1 and IL-6 synthesis in the vehicle-treated group, whereas TNF levels were increased. However, both doses of diltiazem significantly improved peritoneal macrophage antigen presentation, Ia expression, and IL-1 synthesis. IL-6 synthesis was only increased with high doses of diltiazem, whereas both diltiazem doses decreased TNF production. These results indicate that the calcium channel blocker diltiazem can markedly improve macrophage functions after hemorrhage. The use of diltiazem might offer a new therapeutic modality in the treatment of immunosuppression and in decreasing the susceptibility to sepsis after hemorrhagic shock.
 ...
PMID:Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, major histocompatability class II antigen expression, and interleukin-1 synthesis after hemorrhage. 238 17

Membrane Ca2+ flux and net protein catabolism were studied in the skeletal muscle during experimental sepsis. Sterilized rat fecal pellets with (septic) or without (sterile) gram-negative bacteria, Escherichia coli [10(2) colony-forming units (cfu)] and Bacteroides fragilis (2 x 10(3) cfu), were implanted into the abdomens of male Sprague-Dawley rats (110-120 g). Septic and sterile rats were febrile and hyperlactacidemic on day 1 postimplantation. These responses subsided by day 2 in sterile but not septic rats. Initial Ca2+ flux, estimated from measurements of 45Ca uptake by soleus muscles in vitro, was elevated on day 1 in both sterile and septic rats and on day 2 and 3 in septic rats only. The septic rat soleus muscle showed a significantly increased net protein catabolic response (measured as tyrosine release by soleus muscle, in vitro) over that found in muscles of sterile rats on day 1-3 postimplantation. The increase in Ca2+ flux in septic (day 1-3 postimplantation) and sterile (day 1 only) rats was abolished when the rats were treated with the calcium channel blocker diltiazem. In unoperated control rat soleus muscles the Ca2+ ionophore, ionomycin, concomitantly caused an increase in Ca2+ flux and net protein catabolism. Overall, the present study suggested that altered cellular Ca2+ regulation plays a role in the net protein catabolic response in the skeletal muscle during sepsis.
 ...
PMID:Skeletal muscle Ca2+ flux and catabolic response during sepsis. 821 38

A retrospective analysis of patients with hypertrophic obstructive cardiomyopathy treated by left ventricular myotomy and myectomy from 1972 to 1994 is reported. There were 158 patients (81 male and 77 female) with a mean age of 50.2(+/-17.2) years (range 12 to 80 years). One hundred nine patients (69%) were 60 years of age or younger, and 49 patients (31%) were older than 60 years. The overall mean follow-up period was 6.1(+/-4.8) years (range 0.1 to 19.3 years) and was 94% complete with a cumulative total of 956 patient-years. Preoperative exertional dyspnea was present in 84%, chest pain in 70%, presyncope in 54%, syncope in 31%, and cardiac arrest in 5% of patients. Preoperative cardiac catheterization was done in 150 patients, with mitral regurgitation detected in 104 patients (67%). The average maximal provocable left ventricular outflow tract gradient was 118 (+/-46) mm Hg (range 25 to 250 mm Hg). The average preoperative echocardiographic gradient at rest was 64 mm Hg, 20 mm Hg in the early postoperative period and 10 mm Hg in the late postoperative period. The mean septal thickness was 2.2 (+/-0.6) cm, 1.9 (+/-0.7) cm in the early postoperative period (p < 0.05 vs preoperative) and 1.7 (+/- 0.5) cm in the late postoperative period (p < 0.05 vs preoperative). The overall 30-day operative mortality rate was 3.2% (5/158), and 0% for 109 patients 60 years of age or younger. Causes of death included myocardial infarction and left ventricular free wall rupture, myocardial failure from septal perforation, sepsis, cerebrovascular accident caused by thromboembolism, and delayed cardiac tamponade in one patient each. Concomitant coronary artery bypass grafting was performed in 22 patients (19.3% of patients > or = to 40 years of age) and mitral valve replacement in 5 patients (3.2%). One hundred nine patients (69%) are alive, 10 patients (6.3%) were lost to follow-up, and 39 patients died (24.7%), including operative deaths). Actuarial survivals at 1, 5, 10, and 15 years were 92.4% +/- 2.2%, 85.4% +/- 3.1%, 71.5 +/- 4.6%, and 46% +/- 9%, respectively. The overall linearized death rate for discharged patients was 1.9%/pt-yr, and for cardiac related deaths it was 1.7%/pt-yr. Thirty-nine (36%) of the 109 survivors received beta-adrenergic blockers, and 30 (28%) received calcium channel blockers. Ninety-four patients had improvement in New York Heart Association functional class, 10 had improvement in symptoms but not in functional class, and 5 had no improvement in functional class or symptoms. Neither preoperative hemodynamic values nor routine echocardiographic measurements significantly correlated with quality of postoperative results. Left ventricular myotomy and myectomy is a safe and reproducibly effective operative treatment for medically refractory hypertrophic obstructive cardiomyopathy, especially for patients 60 years of age or younger. Improvement in functional class and symptoms can be expected in nearly all patients 60 years of age or younger. Improvement in functional class and symptoms can be expected in nearly all patients. The results of myotomy and myectomy serve as a standard for comparison with other interventions for medically refractory cardiomyopathy.
 ...
PMID:Long-term results of left ventricular myotomy and myectomy for obstructive hypertrophic cardiomyopathy. 860 73

Activated macrophages are important cell effectors in sepsis/endotoxemia. Superoxide (SO) and nitric oxide (NO) are produced by activated macrophages and are responsible for host defense against microorganisms. Using laser scanning confocal microscopy, we investigated the role of intracellular free calcium ([Ca2+]i) on SO and NO production by rat peritoneal macrophages activated by lipopolysaccharide (LPS). Calcium influx from the extracellular space versus release of calcium from intracellular stores was determined using calcium channel blockers (diltiazem [DIL], verapamil [VER], and nicardipine [NIC]) and dantrolene (DAN), respectively. Cells incubated with LPS had a 30-50 nM increase in [Ca2+]i, (p < .05) compared with non-LPS-treated cells. When stimulated with phorbol myristate acetate, both control and LPS-treated cells sustained a comparable increase in [Ca2+]i, but [Ca2+]i, remained elevated 30 min later in LPS-treated cells. Calcium channel blockers and DAN reduced phorbol myristate acetate-stimulated SO and LPS-stimulated NO production at all concentrations tested (p < .05). Although increased extracellular calcium influx and calcium from intracellular stores are important regulators of SO and NO production in macrophages, extracellular calcium influx seems to have the predominant effect. Calcium antagonists may modulate the inflammatory response via their effects on macrophages.
 ...
PMID:Calcium antagonists inhibit oxidative burst and nitrite formation in lipopolysaccharide-stimulated rat peritoneal macrophages. 937 63

The onset of liver injury is a pivotal event during endotoxemia. Lipopolysaccharide (LPS) activates the Kupffer cells (KC), the resident macrophages of the liver, to generate an abundance of inflammatory substances, including nitric oxide (NO). Elevated levels of NO are thought to contribute to the propagation of liver injury during sepsis. Calcium, a major second messenger in several cellular signaling events, is required by the KC for the generation of inducible nitric oxide synthase (iNOS). The purpose of this study was to determine whether calcium channel antagonists limit hepatic injury and iNOS expression in vivo following LPS exposure and to evaluate their effects on the regulation of iNOS expression in cultured KC. In rats subjected to LPS for 6 h, the serum alanine aminotransferase (ALT) level was elevated significantly; this response was accompanied by an increase in iNOS mRNA formation in the intact liver. Pretreatment of rats with calcium channel antagonists (i.e., diltiazem, nifedipine, or verapamil) before LPS exposure attenuated the serum ALT level and iNOS mRNA expression in the liver. Pretreatment of cultured KC with calcium channel antagonists for 1 h followed by the addition of LPS markedly repressed iNOS protein and mRNA expression. Time-course studies revealed that calcium channel antagonists were most effective at inhibiting LPS-induced iNOS mRNA formation by KC when added before LPS. Treatment of KC with calcium channel antagonists prior to the addition of LPS decreased nuclear levels of the p65 subunit of nuclear factor-kappaB and prevented the LPS-dependent degradation of the inhibitory protein IkappaBalpha. Thus our findings indicate that under endotoxemic conditions calcium channel antagonists limit hepatocellular injury that is accompanied by an inhibition of LPS-mediated iNOS expression in rat liver KC.
 ...
PMID:Effects of calcium channel antagonists on LPS-induced hepatic iNOS expression. 1044 49

Continuous intravenous epoprostenol improves exercise capacity, haemodynamics, and survival in severe primary pulmonary hypertension. Pulmonary hypertension can also be life-threatening in patients with connective tissue diseases. In a prospective open monocentre uncontrolled study, the effects of epoprostenol were evaluated in patients with severe pulmonary hypertension secondary to connective tissue diseases who were unresponsive to oral vasodilators (including calcium channel blockers) and continued to be in the New York Heart Association (NYHA) functional class III or IV despite conventional medical therapy. Seventeen patients received epoprostenol administered by a portable infusion pump associated with conventional therapy (oral anticoagulants, diuretics, supplemental oxygen). During the first six weeks of therapy, two (12%) patients died, of pulmonary oedema (n = 1) and severe sepsis (n = 1). In the fifteen remaining subjects, clinical and haemodynamic parameters improved significantly at six weeks. These patients were subsequently monitored for 80+/-48 (range 14-154) weeks after initiation of epoprostenol. Five (33%) patients died, of right heart failure (n = 2), severe sepsis (n = 2) or syncope (n = 1) and two patients were successfully transplanted 24 and 52 weeks after initiation of epoprostenol. Seven of the remaining eight patients had a persistent clinical improvement. Short-term epoprostenol therapy is effective in some patients with connective tissue diseases as demonstrated by better clinical status and haemodynamics at six weeks. However, this study reports several cases of early and late major complications including severe sepsis and pulmonary oedema. Additional information is needed to evaluate the benefit: risk ratio of long-term epoprostenol therapy in pulmonary hypertension secondary to connective tissue diseases.
 ...
PMID:Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. 1044 11


1 2 3 Next >>