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Biomedical subjects

J B Gavin

Publications and source records attributed to J B Gavin.

At least 19 recordsLinked to original sources
PubMed2001

Diffusion of gamma globulin into the arterial wall identifies localized entry of lipid and cells in atherosclerosis.

BACKGROUND: The localization of atheromatous lesions in vulnerable arteries and their relatively rare occurrence in other arteries of the same subject cannot be explained by current theories of the aetiology of atherosclerosis. OBJECTIVE: To determine whether abnormal diffusion of gamma globulin into the arterial wall from the lumen will identify defects of barrier function allowing localized entry of lipid and cells in atherosclerosis. METHODS: Paraffin sections of left anterior descending coronary arteries and corresponding internal thoracic arteries from 80 human subjects aged 1-65 years were stained for gamma globulin by the immunoperoxidase technique. Duplicate sections were stained with orcein to demonstrate the elastin structure. RESULTS: The barrier function of the luminal surface of the thickened intima was associated with the presence of an elastin lamina beneath the endothelial cells. With advancing age, the coronary arteries exhibited breakdown of this barrier function in localized areas with entry into the arterial wall of gamma globulin, lipid and cells. This was rare in the internal thoracic artery. CONCLUSION: Lack of continuity or incomplete formation of this sub-endothelial lamina, which was seen particularly in the coronary artery, was associated with localized entry into the arterial wall of gamma globulin, lipid and cells from the circulating blood and with the development of atheromatous lesions.

Adolescent↗
PubMed2000

Endothelin antagonists diminish postischemic microvascular incompetence and necrosis in the heart.

The endothelin receptor antagonists BQ-610 and BQ-123 were used to clarify the role of endothelin in the pathogenesis of postischemic microvascular incompetence in the myocardium. Forty-five isolated rat hearts were perfused with Krebs-Henseleit buffer (KHB) for 15 min and then subjected to 0, 15, or 60 min of ischemia followed by 5 min of reperfusion with KHB, KHB + BQ-610, or KHB + BQ-123. They were fixed by perfusion with 2.5% glutaraldehyde and then perfused with nuclear track emulsion as an indicator of vascular flow. Transmural sections of resin-embedded myocardium were examined by scanning and transmission electron microscopy. Following 60 min of ischemia, the subendocardial third of the LV wall of hearts treated with BQ-123 showed nearly three times the proportion (P < 0.001) of competent capillaries in untreated hearts. Reperfusion after 15 min of ischemia of hearts treated with BQ-123 showed a 30% increase in the proportion of competent capillaries compared to controls (P < 0. 002). Treatment of corresponding groups with BQ-610 increased the proportion of competent capillaries but these differences were not statistically significant. In addition, both ET-I antagonists dramatically reduced the amount of ultrastructural change evident in myocardium reperfused after 60 min of ischemia. Thus endothelin plays a significant role in the pathogenesis of postischemic microvascular incompetence in the myocardium and, probably by its effects on Ca(2+) uptake, contributes also to the ultrastructural damage to the myocytes and endothelium which follows postischemic reperfusion of irreversibly injured myocardium.

Animals↗
PubMed1999

Increased temperature reduces the protective effect of University of Wisconsin solution in the heart.

BACKGROUND: The protective effect of University of Wisconsin solution (UW) for hypothermic storage of donor hearts has been demonstrated in the laboratory. However, clinical usage is associated with occasional primary graft failures. We postulated that this could be related to adverse effects of UW on the coronary vasculature during cardiac implantation and rewarming. We therefore assessed recovery of contractile function and coronary flow in rat hearts after cardioplegic arrest using UW compared with St. Thomas' solution (ST) at 4 degrees C or 25 degrees C. METHODS: Cardioplegia was induced in isolated rat hearts using either UW or ST at 4 degrees C. Hearts were then maintained at 4 degrees C or 25 degrees C. In some hearts, UW at 4 degrees C was used for inducing arrest followed by flushing with ST at 4 degrees C and then rewarming to 25 degrees C. After 40 minutes of arrest, recovery of function and coronary flow were measured. Nuclear track emulsion was used to assess microvascular competence. RESULTS: Compared with ST-treated hearts, UW-treated hearts showed significant reduction in recovery of function at 25 degrees C (76.2% +/- 4.0% versus 25.0% +/- 4.1%; p < 0.01) but not at 4 degrees C (88.0% +/- 1.6% versus 87.1% +/- 2.6%). Recovery of coronary flow in the UW-treated hearts at 25 degrees C was significantly lower than that in the ST-treated hearts at 25 degrees C (71.7% +/- 3.0% versus 94.5% +/- 6.3%; p < 0.01). At 25 degrees C, microvascular competence was reduced in the UW group compared with the ST group. At 25 degrees C, flushing out UW with ST resulted in greater recovery of function compared with UW throughout (73.4% +/- 7.1% versus 25.0% +/- 4.1%; p < 0.01). CONCLUSIONS: University of Wisconsin solution provides effective donor heart protection under hypothermic conditions but can be deleterious at warmer temperatures.

Adenosine↗
PubMed1998

Microvascular involvement in cardiac pathology.

Abnormalities of the microvasculature are centrally involved in the pathogenesis of some forms of heart disease, but in others are consequences of it. Microvascular abnormalities may contribute to the progression of viral myocarditis and Chagas' disease. Focal abnormalities may occur early in some cardiomyopathies and do occur later in most types of myocarditis. The thickening of arteriolar walls in chronic hypertension is likely to contribute significantly to the impairment of coronary haemodynamics associated with adaptive ventricular hypertrophy and the consequent diminution of coronary reserve, increasing diffusion distances and failure of angiogenesis to compensate. However, the resulting myocyte necrosis stimulates inflammatory angiogenesis. When ischemic myocyte injury becomes irreversible there is a concomitant loss of capacity for reperfusion, the no-reflow phenomenon. Less severe temporary ischemia reduces the proportion of functional capillaries. Multiple mechanisms are involved in this microvascular stunning, including: reperfusion injury; leukocyte activation; adhesion and accumulation; and impaired endothelium-dependent vasodilation. Many of the microvascular changes are those of the inflammatory response to cell death and form part of a final common pathway in myocarditis, cardiomyopathy, cardiac hypertrophy and failure, and ischemic heart disease. Stimulation of angiogenesis prior to myocyte necrosis in hypertrophy and control of leukocyte activity in ischemic heart disease could minimize myocyte loss.

Cardiomyopathies↗
PubMed1996

Functional, metabolic and ultrastructure evidence for improved myocardial protection during severe ischaemic stress with MBS, a new crystalloid cardioplegic solution.

The duration of aortic clamping and the temperature of the arrested heart are two important factors in the overall strategy of myocardial protection with cardioplegic solutions. The isolated working rat heart was used to compare the cardioprotection effects (function, metabolism and ultrastructure) of the new "extracellular" crystalloid solution, MBS (containing glucose, aspartate and lactobionate) and St. Thomas' Hospital No. 2 (STH) during prolonged moderate hypothermic ischaemia (30 degrees C, 2 hours and 4 hours) with multidose reinfusion (2 min every 30 min interval). All MBS treated hearts (n = 9 per group) rapidly resumed spontaneous regular sinus rhythm (0.8 +/- 0.2 min) and had similar high degree of functional recovery (cardiac output: 90.2 +/- 4.5% & 80.9 +/- 3.5%, stroke volume: 89.1 +/- 4.7% & 81.9 +/- 3.4% and aortic pressure: 102.0 +/- 4.0% & 100.0 +/- 7.3% of pre-arrest values for 2 hours and 4 hours groups, respectively) during 30 min post-ischaemic reperfusion. In contrast, hearts protected with STH showed significantly (p<0.01) less recovery of left ventricular function (cardiac output: 64.3 +/- 2.9% & 5.5 +/- 3.9%, respectively) with two of the nine hearts failing to regain any cardiac pump function after 4 hours. MBS increased lactate efflux (glycolysis) and completely abolished the progressive increase in the coronary vascular resistance during 4 hours ischaemic arrest. These improvements were directly related to the significantly (p<0.01) reduced depletion of the myocardial adenosine triphosphate (13.32 +/- 1.65 vs 2.42 +/- 0.09 micromol/g dry wt) and guanosine triphosphate (1.56 +/- 0.08 vs 0.74 +/- 0.04 micromol/g dry wt) during arrest; to their enhanced repletion after reperfusion (ATP: 96% vs 36%, TAN: 90% vs 40% and GTP: 69% vs 48%); and to the absence of ultrastructural injury to cardiac myocytes and the microvasculature. We conclude that the new crystalloid cardioplegic solution MBS provides markedly improved myocardial protection particularly during severe ischaemic stress.

Adenosine Triphosphate↗
PubMed1995

Cardioplegic protection of hearts with pre-arrest ischaemic injury: effect of glucose, aspartate, and lactobionate.

This study compared the cardioprotective effects of three oxygenated "extracellular" crystalloid cardioplegic solutions. These were MBS (containing glucose, aspartate, and lactobionate [GAL]), St. Thomas' Hospital No. 2 (STH), and modified STH (added glucose, aspartate, and lactobionate) (STHGAL). Isolated working rat hearts (45) were initially injured with 10 min of global normothermic ischaemia and then arrested for 4 hr at (30 degrees C) with multidose cardioplegia (2 min every 30 min). The hearts (n = 9 per group) were then reperfused for 7 min in the non-working mode and for a further 23 min in the working mode. MBS-treated hearts rapidly resumed spontaneous sinus rhythm (0.69 +/- 0.06 minutes) with nearly complete recovery of function (aortic flow 93.3 +/- 5.4%, cardiac output 95.7 +/- 3.6%, stroke volume 95.3 +/- 3.7%, heart rate 102.2 +/- 3.7%, and aortic pressure 88.3 +/- 3.2% of pre-ischaemic control values). With either STH or STHGAL these indices were significantly (p < 0.01) lower (aortic flow 25.5 +/- 10.4% or 69.5 +/- 6.5%, cardiac output 30.1 +/- 11.1% or 67.6 +/- 6.6%, aortic pressure 36.5 +/- 7.7% or 63.9 +/- 8.0%, respectively). Total lactate efflux (indicating glycolysis) during cardioplegia was increased (p < 0.01) by inclusion of GAL (MBS 63.7 +/- 1.8, STHGAL 68.7 +/- 2.2, STH 28.5 +/- 1.3 mumol/heart). Progressive increase in coronary vascular resistance was observed during STH-based cardioplegia but not during MBS-based. The improved recovery of function was associated with reduced depletion of adenosine triphosphate (MBS 9.44 +/- 0.79, STHGAL 8.21 +/- 1.00, STH 1.02 +/- 0.10 mumol/g dry wt), total adenine nucleotide pool (14.61 +/- 0.83, 16.81 +/- 0.85, 7.33 +/- 0.52 mumol/g dry wt) and energy charge (0.767 +/- 0.019, 0.620 +/- 0.037, 0.248 +/- 0.012) during arrest, and significantly (p < 0.01) better resynthesis during reperfusion (ATP: 66%, 16%, 40%; TAN: 64%, 22%, 43% of control respectively). These findings indicate that the novel cardioplegic solution MBS (US Pat. No. 5,290,766) provides better myocardial protection than STH in hearts with pre-arrest ischaemic injury not only by providing metabolic substrates but also because of its more appropriate balance of cations.

Animals↗
PubMed1995

Microvascular incompetence and the failure of hearts to recover contractile function after cardioplegia.

The relationship between the development of microvascular incompetence and the loss of potential for functional recovery following cardioplegia was investigated using St. Thomas' Hospital No. 2 solution (STH) in isolated working rat hearts. Cardiac function was measured prior to cardioplegia and again after 30 min of reperfusion at 37 degrees C following 1, 2 or 4 h arrest at 30 degrees C (n=5). The hearts were then fixed by perfusion with 2.5% glutaraldehyde and then nuclear track emulsion was perfused as an intravascular marker of competent capillaries. Following cardioplegia for 1 h hearts showed 95.4% recovery of aortic flow in the working mode, and a high proportion of the capillaries in the subendocardial (84.6 +/- 2.3%), middle (94.6 +/- 3.0%) and subepicardial (89.1 +/- 4.9%) thirds of the left ventricular myocardium transmitted perfusate. Two hours arrest resulted in significantly diminished recovery of left ventricular function (aortic flow: 56.6 +/- 7.6% and aortic pressure: 64.4 +/- 2.5% and heart rate 56.0 +/- 23.1%). This loss of the remaining two thirds of the potential for functional recovery was associated with significant (P<0.02) reductions in the proportions of competent capillaries (subendocardial, middle and subepicardial thirds to 10.9%, 19.2% and 14.2%, respectively). These non-functional capillaries had open lumina and showed no sign of structural alteration, obstruction or compression, although some focal collections of myocytes (<30%) showed evidence of reperfusion damage including contraction band necrosis. Despite reductions in microvascular competence overall, coronary flow rates (non-working) did not decline, suggesting shunting via large arterio-venous channels. It seems likely that the loss of the first third of the potential for rapid functional recovery following cardioplegia is due to loss of high energy phosphates, whereas the loss of the remaining two-thirds is associated with endothelial cell mediated constriction of small arterial vessels which produces the capillary incompetence demonstrated in this study.

Analysis of Variance↗
PubMed1995

Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog.

We have studied the three-dimensional arrangement of ventricular muscle cells and the associated extracellular connective tissue matrix in dog hearts. Four hearts were potassium-arrested, excised, and perfusion-fixed at zero transmural pressure. Full-thickness segments were cut from the right and left ventricular walls at a series of precisely located sites. Morphology was visualized macroscopically and with scanning electron microscopy in 1) transmural planes of section and 2) planes tangential to the epicardial surface. The appearance of all specimens was consistent with an ordered laminar arrangement of myocytes with extensive cleavage planes between muscle layers. These planes ran radially from endocardium toward epicardium in transmural section and coincided with the local muscle fiber orientation in tangential section. Stereological techniques were used to quantify aspects of this organization. There was no consistent variation in the cellular organization of muscle layers (48.4 +/- 20.4 microns thick and 4 +/- 2 myocytes across) transmurally or in different ventricular regions (23 sites in 6 segments), but there was significant transmural variation in the coupling between adjacent layers. The number of branches between layers decreased twofold from subepicardium to midwall, whereas the length distribution of perimysial collagen fibers connecting muscle layers was greatest in the midwall. We conclude that ventricular myocardium is not a uniformly branching continuum but a laminar hierarchy in which it is possible to identify three axes of material symmetry at any point.

Animals↗
PubMed1994

The augmentation of leucocyte adhesion to endothelium by therapeutic ultrasound.

To determine the effects of exposure of endothelial cells to therapeutic ultrasound on leucocyte adhesion to these cells, confluent cultures of bovine aortic endothelial cells in tissue culture flasks and on collagen coated coverslips were exposed to a maximum of 1.6 W/cm2 1 MHz continuous ultrasound for 15 min, then incubated with neutrophil-rich suspensions containing a known number of viable human leucocytes for intervals from 1 to 240 min. After incubation, nonadherent cells were decanted, the number of leucocytes in the eluted suspension determined and the percentage of adhered cells calculated. Endothelial cell viability was not significantly reduced by ultrasound or by incubation with leucocytes. Whereas untreated endothelial cells were flattened and had surface microvilli, those exposed to ultrasound were plump, rounded and more widely separated along their borders. The percentage of leucocytes that adhered to sonicated endothelium was significantly higher, and this proportion increased with the duration of incubation. Thus, exposure of endothelial cells to ultrasound in vitro can cause intercellular separation and increase the adhesion to leucocytes. If such changes were also to occur in vivo, therapeutic ultrasound would potentiate the inflammatory response.

Animals↗
PubMed1994

The morphological effects of the anti-tumor agents flavone acetic acid and 5,6-dimethyl xanthenone acetic acid on the colon 38 mouse tumor.

Flavone acetic acid and 5,6-dimethyl xanthenone acetic acid have a broad spectrum of anti-tumor activity in mice, and act by stimulating immune cells and inhibiting tumor blood flow, resulting in hemorrhagic necrosis within 24 hrs. To study the evolution of hemorrhagic necrosis, subcutaneous Colon 38 tumors were examined by light and electron microscopy from 30 min to 24 hrs after treatment with these agents, and measurements of tumor energy metabolites made. The results show that both agents cause apoptosis beginning at 30 min, and that by 4 hrs necrosis supervenes, accompanied by rupture of tumor blood vessels. The absence of early endothelial cell damage or thrombosis suggests that vessel rupture, and consequent loss of blood flow and energy metabolite depletion, is caused by loss of extravascular mechanical support by the tumor parenchyma.

Adenocarcinoma↗
PubMed1994

Correlation between immune and vascular activities of xanthenone acetic acid antitumor agents.

To determine whether xanthenone acetic acid (XAA) analogues of flavone acetic acid (FAA) have similar ischemic and nonischemic mechanisms of antitumor action to FAA, a series of such compounds was evaluated in vivo and in vitro. Necrotising activity and changes in tumor blood flow were measured in Colon 38 tumors, and morphological changes assessed in immune cell-infiltrated EMT6 tumor cell spheroids, after treatment with FAA, XAA and its derivatives (5-methyl XAA, 5,6-dimethyl XAA, 3-O-methyl XAA, 8-methyl XAA and xanthenone-4,5-diacetic acid). FAA, XAA and the 5-methyl and 5,6-dimethyl analogues of XAA were active in inducing tumor necrosis, falls in tumor perfusion and characteristic morphological changes in multicellular spheroids. The other XAA analogues lacked these activities. 5-methyl XAA and 5,6-dimethyl XAA were more potent than FAA or XAA. The results suggest that XAA and its analogues have the same mechanisms of action as FAA, and that both the vascular and the immune effects of these compounds are mediated via a common biochemical receptor.

Adjuvants, Immunologic↗
PubMed1994

Myocardial protection during prolonged ischaemic cardiac arrest: experimental evaluation of three crystalloid cardioplegic solutions.

The aim of this study is to define the cardioprotective effects (functional and metabolic) of our modified "extracellular" cardioplegic solution (MBS: containing glucose, aspartate and lactobionate), St. Thomas' Hospital No. 2 (STH) and Bretschneider's No. 3 (Bret) solutions during prolonged hypothermic ischaemia (20 degrees C, 6 hours) in the isolated working rat heart. hearts (n = 9-10 in each group) were arrested with, and exposed to, multidose reinfusion (2 minutes every 40 minutes interval) throughout the ischaemic period with cold (4 degrees C) MBS, STH or oxygenated (95% O2: 5% CO2) Bret. All MBS treated hearts resumed spontaneous regular sinus rhythm (0.51 +/- 0.01 minutes) of contraction during post-ischaemic reperfusion for 30 minutes at 37 degrees C with the complete recovery of all the functional indices (aortic flow: 87.4 +/- 3.4%, cardiac output: 94.1% +/- 3.3%, coronary flow: 101.8 +/- 4.1%, heart rate: 99.8 +/- 2.8% and aortic pressure: 105.7 +/- 4.6% of prearrest control values). In contrast, hearts protected with either STH or Bret showed the poor or no post-ischaemic recovery of cardiac pump function (aortic flow: 7.2 +/- 4.8% and 0%, respectively). Recovery of all other left ventricular function indices were also significantly (p < 0.001) decreased with increasing more hearts failing to regain function (MBS: 0/10, STH: 7/9 and Bret: 9/9). The efflux of lactate during 6 hours ischaemic arrest was increased [52.40 +/- 1.50 v 36.8 +/- 1.70 (STH) or 14.45 +/- 0.70 (Bret) mumol/heart, p < 0.001] and the progressive increase in the coronary vascular resistance was completely abolished in MBS treated hearts. These improvements were associated with the reduction in the decline of the myocardial adenosine triphosphate (23.44 +/- 1.08 v 3.79 +/- 1.08 or 4.51 +/- 0.71 mumol/g dry wt), creatine phosphate (30.23 +/- 1.52 v 8.01 +/- 2.21 or 5.41 +/- 0.03 mumol/g dry wt) and guanosine triphosphate (2.26 +/- 0.23 v 0.24 +/- 0.11 or 0.59 +/- 0.07 mumol/g dry wt) during ischaemia, and total resynthesis after reperfusion (ATP: 92% v 36% or 25% and CP: 126% v 92% or 59% of control). These results indicate that the new cardioplegic solution, MBS can meet the metabolic demand of the ischaemic myocardium because of the greater synthesis of intramyocardial ATP and CP during cardioplegic arrest, provide substantially improved protection of hearts from injury and thus increase (double) the safe duration of cardiac arrest.

Animals↗
PubMed1993

The myocardial vasculature during ischemia and reperfusion: a target for injury and protection.

Ischemia and reperfusion may result in injury to one or more of the cellular components of the heart. In addition to damaging myocytes and their contractile capability, ischemia and reperfusion may inflict early and severe injury on the vasculature which, in turn, may further jeopardize the survival of the myocytes. While ischemia is known to cause progressive injury to endothelium and vascular smooth muscle it now appears that reperfusion can inflict additional, possibly severe, injury on the microcirculation which may compromise the return of normal coronary perfusion. This post-ischemic/reperfusion microvascular incompetence ranges from a transient exacerbation of the increase in vascular resistance initiated during ischemia, to a sustained loss of competent capillaries and eventually to the "no reflow" phenomenon which is characterized by the total inability of the affected tissue to be reperfused. Whereas "no reflow" may be of little importance if it occurs in already infarcted tissue, post-ischemic microvascular incompetence in potentially salvable myocardium could be of considerable significance. Evidence is presented that the vascular endothelium, and its ability to regulate coronary vascular tone, play a central and early role in the pathogenesis of myocardial injury. Mechanisms underlying microvascular injury have been identified and pharmacological strategies now exist for the effective manipulation of this injury--a prospect that is of considerable importance in the light of the widespread use of thrombolytic procedures for the reperfusion of the human myocardium.

Animals↗
PubMed1993

Improvement of doxorubicin induced cardiomyopathy in rats treated with insulin-like growth factor I.

OBJECTIVES: This study was designed to assess the effects of treatment with insulin-like growth factor-I (IGF-I) on cardiac function and structure in rats with an established cardiomyopathy. METHODS: Adult male Wistar rats were injected with doxorubicin (2 mg.kg-1 subcutaneously) weekly for 12 weeks and either rhIGF-I (0.8 mg.kg-1.day-1; n = 16, D-I group) or saline (n = 25, D-S group) subcutaneously via an osmotic pump from weeks 9 to 12. A non-doxorubicin injected control group was also studied. After 12 weeks survivors were anaesthetised and cardiac output determined with radiolabelled microspheres. At postmortem pleural effusion and ascitic volumes were measured and the heart was removed for histological examination by light and transmission electron microscopy. RESULTS: Doxorubicin treated animals showed less mean weight gain from week 2 than the untreated control group. Animals treated with IGF-I from week 9 showed a significant (p < 0.05) but non-sustained increase in weight. Survival to 12 weeks was 56% in the D-I group and 44% in the D-S group (p = 0.2). Evidence of cardiac failure was seen in the D-I and the D-S groups, but there was a tendency (p = 0.06) for less ascites in the D-I group (21 (SEM 8) ml) than in the D-S group (46 (10) ml). Cardiac output was significantly higher in the D-I than in the D-S group (132 (7.2) v 91.4 (6.4) ml.min-1, p < 0.01), as was stroke volume (0.323 (0.03) v 0.226 (0.02) ml, p < 0.01). There was focal cardiac damage in both D-I and D-S animals. Scattered groups of myocytes showed prominent vacuolation of the nuclear envelope, sarcoplasmic reticulum, and t tubular system, mild to severe mitochondrial swelling, and loss of orientation and definition of myofibrils. No clear morphological differences were evident between the two groups. CONCLUSIONS: Administration of IGF-I may improve the function of damaged myocardium, although the mechanisms are unclear. Further studies with earlier coadministration of IGF-I, quantitative histological analysis, and with other models of cardiac injury are indicated.

Animals↗
PubMed1993

The importance of a substantial elastic lamina subjacent to the endothelium in limiting the progression of atherosclerotic changes.

This study examines the hypothesis that progressive intimal thickening and atherosclerosis in the larger pulsatile arteries arise from failure to maintain, subjacent to the endothelial cells, a substantial elastin membrane, a component which has been shown to be of special structural significance. The internal thoracic arteries of 293 subjects of all ages up to 60 years were compared histologically with the anterior descending coronary arteries of the same individuals by light- and electronmicroscopy and immunoperoxidase staining for macromolecules. The internal thoracic arteries usually developed a new robust reduplicated internal elastic lamina at an early age, no further intimal thickening, and no significant entry of lipid or cells to the intima. The coronary arteries showed areas of rapid intimal thickening with poor and incomplete reduplicated internal elastic laminae, entry of lipid, macrophages, and other cells to the intima. The reduplicated internal elastic laminae appeared to be formed primarily by the endothelial cells themselves. An elastin membrane subjacent to the endothelial cells appears to be essential. It provides a secure attachment for the cells and a barrier to the entry of macromolecules and cells to the intima. Its absence is associated with progressive intimal thickening and atherosclerosis.

Adolescent↗
PubMed1992

Nitric oxide production in endotoxin-resistant C3H/HeJ mice stimulated with flavone-8-acetic acid and xanthenone-4-acetic acid analogues.

The production of nitric oxide in endotoxin-resistant C3H/HeJ mice in response to flavone-8-acetic acid (FAA), derivatives of xanthenone-4-acetic (XAA), endotoxin and recombinant human tumour necrosis factor-alpha (TNF-alpha) was investigated and compared with the induction of haemorrhagic necrosis in subcutaneous M16/C tumours. FAA and XAA analogues stimulated nitric oxide production both in vitro (activated macrophages) and in vivo (plasma nitrate elevation) in both C3H/HeJ and C3H/HeN mice (5,6-dimethyl-XAA greater than 5-methyl-XAA greater than FAA greater than XAA greater than 8-methyl-XAA). Recombinant human TNF-alpha stimulated nitric oxide production equally from both murine strains while endotoxin stimulated nitric oxide production only by C3H/HeN mice. The extent of induction of haemorrhagic necrosis in tumour-bearing mice treated with FAA, 5,6-dimethyl XAA or endotoxin paralleled the effects on nitric oxide production, showing a differential between the two strains of mice only in the case of endotoxin.

Animals↗
PubMed1992

Unusual dynamics of killing of cultured Lewis lung cells by the DNA-intercalating antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

The cytotoxicity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601,316), a new experimental DNA-intercalating antitumor drug, against a cultured Lewis lung adenocarcinoma cell line was compared with that of the DNA-intercalating antitumor drug amsacrine. In contrast to amsacrine, AC demonstrated self-inhibition of cytotoxicity following short (3-9 h) incubation periods and exponential killing (with a shoulder) after long (24-72 h) periods of incubation. The difference between these drugs was best demonstrated using a constant concentration x time (C x T) exposure (AC, 12 mumol h l-1; amsacrine, 3 mumol h l-1). In contrast to amsacrine, AC was minimally effective over exposure periods of less than or equal to 1 h and maximally effective over intermediate periods (4-6 h). The results suggest the possibility of designing AC administration protocols that maximise the drug's cytotoxicity towards solid tumors, which, because of diffusion barriers, are subjected to longer drug exposures than are well-vascularised tumours.

Acridines↗