Effects of ketamine and propofol on autonomic cardiovascular function in chronically instrumented rats.

In this study C. we systematically examined the effects of ketamine and propofol at various doses (5-20 mg/kg) on blood pressure, heart rate and renal sympathetic nerve activity in chronically instrumented Wistar rats. We also assessed the effects of these anesthetics on the baroreflex control of heart rate and renal sympathetic nerve activity. Ketamine (10 mg/kg) increased blood pressure by 30.0+/-4.5%, heart rate by 17.7-3.3% and renal sympathetic nerve activity by 38.8+/-14.6%, while propofol (10 mg/kg) decreased blood pressure by 18.9+/-3.5%, heart rate by 5.5+/-2.5% and renal sympathetic nerve activity by 7.5+/-2.1%. These variables showed dose-dependent responses to both agents. Both ketamine and propofol decreased the range and maximum gain of the logistic function curve obtained by relating mean blood pressure to heart rate and blood pressure to renal sympathetic nerve activity. In conclusion, ketamine and propofol had different effects on autonomic cardiovascular function, but attenuated the baroreflex sensitivity of heart rate and renal sympathetic nerve activity in a dose-dependent manner. These results suggest the possibility that baroreflex sensitivity may reflect the depth of anethesia.

Integrative effects of nitric oxide and endothelium-derived hyperpolarizing factor induced by acetylcholine and bradykinin in rat hindquarter perfusion.

We investigated the roles of endothelium-derived vasodilative factors in rat hindquarter perfusion using a system for the direct measurement of nitric oxide (NO). Acetylcholine (ACh) induced the dose-dependent release of NO with a concomitant decrease in perfusion pressure. Under the influence of N(G)-monomethyl-l-arginine (l-NMMA), NO release in response to ACh was blocked, while the perfusion pressure still decreased. In the presence of tetraethylammonium (TEA), the decrease in perfusion pressure in response to ACh was attenuated compared to the control value. The decrease in perfusion pressure in response to ACh was almost abolished in the presence of both l-NMMA and TEA or with deendothelialization. Bradykinin (BK) also induced NO release and biphasic effects on the perfusion pressure. The perfusion pressure decreased with a lower concentration of BK and increased with a higher concentration. l-NMMA and TEA each abolished the decrease in perfusion pressure induced by BK. Furthermore, in the presence of both l-NMMA and TEA, the perfusion pressure actually increased in response to BK. These results suggest that ACh and BK induce vasodilation through NO release and a potassium channel dependent mechanism via endothelium.

Sustained-release procainamide-induced reversible granulocytopenia after myocardial infarction.

A 71-year-old man with paroxysmal atrial fibrillation who had a previous anterior myocardial infarction exhibited granulocytopenia 8 days following the administration of oral sustained-release procainamide (750 mg/day). The plasma concentrations of procainamide and N-acetyl procainamide were at subtherapeutic levels. Discontinuation of procainamide led to complete recovery. A bone marrow aspiration showed slight hypoplasia with normocellular marrow. Lupus erythematosus (LE) and antinuclear antibody (ANA) tests were negative. The frequency and relationship of granulocytopenia caused by sustained-release procainamide in patients with tachyarrhythmias are briefly discussed, and prior reported cases are reviewed. Precautionary measures for the early recognition of this grave hazard in exposed patients are advocated. The physician should be aware of this complication before in initiating treatment with this drug.

Effect of bone marrow transplantation on antiphospholipid antibody syndrome in murine lupus mice.

The (NZW x BXSB)F1 (W/BF1) mouse is known to be an animal model of systemic lupus erythematosus (SLE) and immune thrombocytopenic purpura (ITP). These mice produce not only anti-DNA antibodies but also anti-platelet antibodies, resulting in decreased platelet counts. They show a high level of proteinuria, increased white blood cell (WBC) counts, hypertension, and myocardial infarction due to the high levels of anti-cardiolipin antibodies. When W/BF1 mice (4-5 months) were lethally irradiated and then reconstituted with T cell-depleted bone marrow cells of normal BALB/c mice (8 weeks), 60% of the mice survived more than one year. The WBC and platelet counts in the mice were normalized, and the levels of anti-DNA and anti-platelet antibodies decreased. The renal dysfunction was also ameliorated as indicated by a lower level of proteinuria, lower levels of serum creatinine (S-CRTN) and blood urea nitrogen (BUN), and by improved histology. The blood pressure (BP) of the treated W/BF1 mice decreased due to the improved renal functions. In contrast to the non-treated W/BF1 mice which died of myocardial infarction or renal failure by the age of 7 months, the treated W/BF1 mice showed no evidence of myocardial infarction even one year after BMT. This was due to the lower cardiolipin levels.

Antithrombotic effect of ticlopidine on occlusive thrombi of small coronary arteries in (NZWxBXSB)F1 male mice with myocardial infarction and systemic lupus erythematosus.

We examined the antithrombotic effect of ticlopidine on occlusive thrombi of small coronary arteries in (NZWxBXSB)F1 [(WxB)F1] male mice with myocardial infarction (MI) and systemic lupus erythematosus (SLE). Ticlopidine (3 and 10 mg/kg) was given to the mice as an additive to a standard laboratory diet from the time the mice were aged 16-24 weeks. The higher dose of ticlopidine significantly increased survival rate of the mice. In mice that received 10 mg/kg ticlopidine, the incidence of MI, the percentage of MI area (%MI), and the incidence and number of small coronary arteries with significant stenosis were significantly lower than in controls. The stenosed lesions were divided into occlusive thrombi related to acute MI and intimal thickening related to old MI. No mice had evidence of significant stenosis or thrombosis in the extramyocardial coronary arteries. Glomerulonephritis, blood urea nitrogen (BUN), and circulating immune complexes were not significantly different among the three groups. A high dose of ticlopidine prevented small coronary artery disease and MI and increased the survival of (WxB)F1 male mice, suggesting that this agent has an antithrombotic effect on occlusive thrombi of the small coronary arteries in such mice.

A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice.

We have found a new spontaneous autosomal recessive mutation in mice that causes a systemic absence of lymph nodes and Peyer's patches. The name "alymphoplasia", with the gene symbol "aly", is proposed for this mutant. The spleen of aly/aly mice is devoid of well-defined lymphoid follicles, and the thymus does not show a clear cortical-medullary distinction. The mutant homozygotes are deficient in both humoral and cell-mediated immune functions, and are highly susceptible to infections. They have a reduced level of IgM and severely depressed levels of IgG and IgA in their sera, and do not reject allogeneic skin grafts. However, they have mature T and B cells as determined from their cell surface antigens. The results of bone marrow transplantation experiments suggest a mesenchymal disorder as a possible cause of the lack of lymph nodes and of immunodeficiency in the aly mouse. The aly mutant mouse may be a useful animal model of primary immunodeficiency, as are the nu (nude) and scid (severe combined immunodeficiency) mice.

Effect of actarit on type II collagen-induced arthritis in mice.

The effect of actarit (MS-932, CAS 18699-02-0), an antirheumatic drug, on type II collagen (CII)-induced arthritis in DBA/1J mice was studied. Mice were immunized twice with bovine CII, actarit being given orally once a day for 35 days after the 1st immunization. Clinical assessment showed that actarit had no effect on the incidence or day of onset of arthritis but that it lowered the arthritis score dose-dependently. Radiography showed that actarit reduced new bone formation in the limbs, and a histopathologic examination showed that it reduced synovitis, erosion of cartilage and bone destruction. Actarit suppressed the delayed-type mouse ear skin reaction to CII but had no effect on the level of serum anti-CII antibodies. These results suggest that actarit inhibits the development of CII-induced arthritis in mice by suppressing delayed-type hypersensitivity to CII.

Effect of etodolac on type-II collagen-induced arthritis in mice.

We tested the effect of etodolac on the development of type-II collagen-induced arthritis in DBA/1J mice. It was administered orally once daily for 35 days after the primary immunization with type-II collagen. Etodolac (10 mg/kg) significantly inhibited the development of signs of arthritis on day 28 to day 35. Indomethacin (1 mg/kg) also significantly inhibited it on day 29 to day 34. Radiographic examination showed that etodolac (10 mg/kg) significantly prevented the development of osteopenia, bone erosion and new bone formation of the joints on day 35, while indomethacin (1 mg/kg) significantly prevented only the development of bone erosion. Histopathological examination showed that both etodolac (10 mg/kg) and indomethacin (1 mg/kg) significantly prevented the development of synovitis, erosion of cartilage of the joints and bone destruction of the limbs on day 35. Etodolac and indomethacin did not affect the serum level of anti-type-II collagen antibodies. These results suggest that etodolac and indomethacin suppress type-II collagen-induced arthritis without affecting humoral immune responses.

Morphological analysis of autoimmune disease in MRL-lpr,Yaa male mice with rapidly progressive systemic lupus erythematosus.

We analyzed morphologically autoimmune disease in MRL/MpJ mice bearing both the Yaa and lpr genes (MRL-lpr,Yaa mice), and compared it with that in MRL/MpJ-lpr/lpr (MRL-lpr) mice, in order to examine the effect of the Yaa gene on lpr-induced tissue-specific immunopathologies. MRL-lpr,Yaa male mice developed glomerulonephritis more rapidly than did MRL-lpr males. The glomerular damage in MRL-lpr,Yaa males, as evaluated by histologic and immunofluorescent methods, was significantly greater than that in age-matched MRL-lpr males. In contrast, no differences in the development of vasculitis and arthritis were noted between the two groups. Pathological examination of the dead mice revealed a similar incidence of lethal glomerulonephritis in the two groups. Lymphoid hyperplasia in the spleen consisted predominantly of unusual T cells (B220+, Thy-1+, CD4-, CD8-) in the two groups, and an increased number of B cells was not found in MRL-lpr,Yaa mice. The histological nature of the autoimmune diseases was similar in MRL-lpr,Yaa and MRL-lpr males. These results indicate that the Yaa gene accelerates the development of glomerulonephritis but not that of vasculitis or arthritis, suggesting that the mechanisms underlying the initiation of glomerulonephritis are different from those leading to vasculitis or arthritis in MRL-lpr mice.

Diet-induced atherosclerosis in cynomolgus monkey aorta and regression by the sixth-month observation.

Pathomorphologic analysis was employed to evaluate diet-induced atherosclerosis in cynomolgus monkey aorta and regression by administration of a hypolipidemic agent for six months after the atherogenic ration. Twenty-seven male cynomolgus monkeys were divided into three groups. Group A was fed individually with a high-fat diet containing 0.3% cholesterol under identical conditions for six months. Group B was fed with normal monkey chow for six months after the same atherogenic ration. Group C was fed with normal monkey chow and administered a hypolipidemic agent 1% of 4-[2-(4-isopropylbenzamido)ethoxy] benzonic acid for six months after the same atherogenic ration. Each thoracic and abdominal aorta of animal models was separately analyzed. Lipid composition analysis and esterified cholesterol (CE) in aortic wall, ratio of free cholesterol to phospholipid, surface involvement, and atherosclerotic index after Sudan IV staining were studied for evaluation of progression and regression. The configurations of atherosclerotic involvement were histologically evaluated among each group. These observed lesions, features specific to cynomolgus lesions, mainly consisted of lipid-rich foam cells, lipid debris, and proliferated extracellular matrix. No different lesion composition was noted between the thoracic and abdominal aorta. This may suggest that some local factors play an important role for development of atherosclerosis after the initial event. Group C had remarkable reduction of foam cells and of CE accumulation in both the thoracic and abdominal aortic wall. Accelerated regression in group C as compared with group B was demonstrated both biochemically and pathohistologically. These results suggest that substantial regression of atherosclerosis in both the thoracic and abdominal aorta can be expected. This hypolipidemic agent exerts notable antiatherosclerotic activity, along with a lowering effect on plasma total cholesterol levels.

Effects of chronic oral administration of nifedipine and diltiazem on occlusive thrombus of small coronary arteries in (NZW x BXSB)F1 male mice.

OBJECTIVE: (NZWxBXSB)F1 male mice were used as a model to study the effects of chronic administration of nifedipine and diltiazem on small coronary artery disease and mortality. METHODS: 16 week old (NZWxBXSB)F1 male mice were given either nifedipine (n = 29) at 20 mg.kg-1.d-1 orally or diltiazem (n = 28) at 100 mg.kg-1.d-1 orally in two divided doses until they were 24 weeks old (ie, for 60 d). Age matched control mice were given an equivalent volume of vehicle (n = 30). Mice that died received immediate necropsy. After 60 d, all surviving mice were killed and hearts and kidneys were examined histologically. RESULTS: The survival rate at 24 weeks was significantly higher in mice given nifedipine than in the controls (71% and 47%, respectively, p less than 0.05). The number of mice with myocardial necrosis, scar formation, or both, the percentage of areas of the ventricular wall with myocardial necrosis and scar formation, and the number of mice with small intramyocardial arteries showing greater than or equal to 75% stenosis were all significantly lower in the mice given nifedipine than in the controls. In the mice given diltiazem, there were no such differences from the controls. There was no evidence of significant stenosis or thrombosis in the extramyocardial coronary arteries in any of the mice. Systolic blood pressure and the rate-pressure product at 24 weeks of age, as well as the histological score for glomerulonephritis changes, were significantly lower in mice given nifedipine or diltiazem than in the controls. CONCLUSIONS: Despite an equivalent improvement of systolic blood pressure, the double product, and renal disease in nifedipine treated and diltiazem treated mice, only nifedipine prevented small coronary artery disease and increased the survival of (NZWxBXSB)F1 male mice, suggesting that nifedipine prevents occlusive thrombi of small coronary arteries better than diltiazem.

Effect of etodolac, a new nonsteroidal anti-inflammatory drug, in MRL/lpr mice with articular lesions.

Etodolac, a new nonsteroidal anti-inflammatory drug, was administered orally at doses of 1 and 5 mg/kg to MRL/MpJ-lpr/lpr (MRL/lpr) mice, and its effect on articular lesions was compared with that of indomethacin. Both etodolac and indomethacin significantly reduced swelling of the hind paw. Histopathological examination showed that etodolac significantly reduced cartilage and bone damage, whereas indomethacin treatment did not achieve a statistically significant effect. Rheumatoid factors were not affected by either etodolac or indomethacin. These results indicate that etodolac delays the development of arthritis in MRL/lpr mice, and reduces cartilage and bone damage.