THE EFFECT OF GRADED HAEMORRHAGE ON ERYTHROPOIETIN PRODUCTION IN THE IMMATURE OVINE FOETUS

1. Basal and haemorrhage-stimulated erythropoietin (Epo) and ACTH levels were measured in the chronically cannulated immature ovine foetus (less than 125 days) by radio immunoassay (RIA). 2. Basal erythropoietin levels were found to be higher than those previously reported in the late gestation (greater than 130 days) ovine foetus, but were lower than those observed in the neonatal lamb. 3. In control foetuses (Protocol 1) the small degree of haemorrhage associated with the sampling procedure increased the plasma Epo values from 11.4 +/- 3.0 (n = 5) mU/mL to 23.8 +/- 4.3 mU/mL at 24 h (mean +/- s.e.m.). There was a significant monotonic increase with time (F = 16.4; d.f. 1,19; P = 0.001). An initial haemorrhage of approximately 10% blood volume (Protocol 2) increased plasma Epo values from 7.3 +/- 2.3 to 24.2 +/- 7.1 mU/mL (n = 3). 4. Haemorrhage of 20% fetal blood volume (Protocol 3) produced an increase in plasma Epo from 9.3 +/- 1.7 to 54.7 +/- 15.5 mU/mL at 6 h and to 57.6 +/- 7.3 mU/mL at 24 h (n = 5). By repeated measures ANOVA, the effect of the 20% haemorrhage was significant when compared with the control group (F = 7.32, d.f. 2,16, P = 0.006). There was a significantly greater decrease in haematocrit (F = 6.7, d.f. 2,20, P = 0.004) and haemoglobin (F = 5.0, d.f. 2,20, P = 0.013) in animals of Protocol 3 than in those of Protocol 1. 5. Fetal blood gases and plasma adrenocorticotropic hormone (ACTH) did not alter with haemorrhage, indicating the tolerance of the foetus to this degree of haemorrhage.     

EFFECT OF DIETARY FISH OILS ON THE FORMATION OF LEUKOTRIENE B4 AND B5, THROMBOXANE AND PLATELET ACTIVATING FACTOR BY RAT LEUKOCYTES

1. This study investigates the effect of dietary eicosapentaenoic acid (EPA), in the form of 'Max EPA' fish oil, on leukotriene B4 (LTB4) production in ionophore-stimulated rat leukocytes. Male Wistar rats (200-250 g) were fed for 3 weeks on a synthetic chow supplemented with either 10% by weight Max EPA oil or a coconut oil/safflower oil mixture. 2. The EPA-rich diet significantly increased the EPA content of leukocyte phospholipids and decreased the arachidonic acid level by 35% (P less than 0.001) compared with the control diet. 3. The concentration of leukotrienes in the ionophore (A23187) stimulated leukocytes was measured by reverse-phase HPLC using prostaglandin B2 as the internal standard. The EPA-supplemented diet caused a 50% decrease in LTB4 production (P less than 0.001) and a concomitant increase in the formation of the biologically less active LTB5 compared with the control diet. The amount of LTB4 and LTB5 produced by stimulated leukocytes closely resembled the changes in arachidonic acid and EPA content of leukocyte phospholipids. 4. Thromboxane B2 (TxB2) production in stimulated leukocytes from the EPA-fed animals was also decreased compared with the control group. 5. Although the formation of platelet activating factor by stimulated leukocytes was not altered by dietary treatment, the ability of an EPA-rich diet to decrease LTB4 and TxB2 production suggests that these diets may attenuate leukocyte activity and have useful anti-inflammatory effects.     

WHOLE BLOOD AGGREGATION AND PLASMA LYSO-PAF RELATED TO SMOKING AND ATHEROSCLEROSIS

1. Aggregation of diluted whole blood (impedance method) and thromboxane B2 production during aggregation were measured in cigarette smokers and non-smokers, aged 41-68 years, with (n = 14) and without (n = 15) major symptomatic peripheral vascular disease. The plasma level of the lyso derivative of platelet activating factor (lyso-PAF) was also measured using a bioassay with 14C-serotonin labelled rabbit platelets, after extraction and acetylation to active PAF. 2. Aggregation to ADP and collagen was significantly less in non-smokers without vascular disease (n = 8) than in the other three groups (P less than 0.01; ANOVA). Thromboxane B2 production was not significantly different between the groups. There was no significant difference in plasma lyso-PAF between groups. No change was found in any variable after smokers smoked two cigarettes. 3. In these older age subjects, both vascular disease and the smoking habit were associated with greater whole blood aggregation. However, current smoking and the smoking of two cigarettes did not affect aggregation in subjects with vascular disease and plasma lyso-PAF levels were not consistently related to either smoking or vascular disease.     

β-ADRENOCEPTORS IN THE HYPERTROPHIED RIGHT VENTRICLE OF THE DOG WITH PULMONARY STENOSIS

1. Right ventricular hypertrophy was produced in dogs by banding of the pulmonary artery for 28 days (n = 7) and results were compared with those in sham-operated dogs (n = 5). 2. Myocardial noradrenaline and adrenaline levels were depressed in both the hypertrophied right ventricle and the non-hypertrophied left ventricle and plasma levels were increased compared to the control dogs. 3. Myocardial beta-adrenoceptors were assessed in membrane preparations of both ventricles by 3H-dihydroalprenolol binding. No change in binding site concentration (pmol/mg membrane protein) or in binding affinity was found in either the hypertrophied right ventricle or in the left ventricle. 4. Divergent results of studies on beta-adrenoceptors in ventricular hypertrophy are difficult to reconcile.     

A COMPARISON OF THE EFFECTS OF SALBUTAMOL, ETILEFRINE AND DEXTRAN DURING HYPOTENSION AND LOW CARDIAC OUTPUT STATES IN RABBIT

The effects of salbutamol (25 and 50 micrograms/kg), etilefrine (50 and 200 micrograms/kg) and dextran (8 ml/kg) on cardiovascular function have been studied in the rabbit. The three drugs raised the resting cardiac output (with salbutamol producing delta max 52%, P less than 0.001, n = 5) and right heart filling pressure (RHFP, delta max from dextran 3.5 cmH2O; P less than 0.001, n = 6) and lowered total peripheral resistance (TPR, delta max from salbutamol 46%, P less than 0.001, n = 5). However, TPR rose with the 200 micrograms/kg etilefrine (P less than 0.05, n = 5). Pulse pressure rose with salbutamol (P less than 0.001, n = 6) and etilefrine (P less than 0.05, n = 6). Etilefrine raised resting BP (delta max, P less than 0.001, n = 6); salbutamol lowered resting BP (delta max, P less than 0.001, n = 6) while dextran (n = 6) had little effect on resting BP. The actions of salbutamol are mediated mainly through beta 2-adrenoceptors although the drug also has some minor beta 1-adrenoceptor action. With etilefrine, the increase in cardiac output and the reduction in TPR are mediated through beta-adrenoceptors while the increases in RHFP, blood pressure and TPR are a direct action on the alpha-adrenoceptors. However, during haemorrhage the fall in diastolic pressure produced by salbutamol was considerably reduced while the reduction in mean BP and systolic pressure (which sometimes rose) was abolished. Dextran raised BP during hypotension produced by either sympathectomy or haemorrhage but not during normotension. The reflex recovery in RHFP and the reflex tachycardia were slightly attenuated during lower body negative pressure (LBNP) after salbutamol or dextran. The reflex recovery in blood pressure was complete and the pressure sometimes exceeded the resting level by up to 10 mmHg during LBNP after salbutamol, etilefrine (50 micrograms/kg only) and dextran. The reduced TPR (presumably due to vasodilation) and the increases in cardiac output and RHFP at an adequately maintained blood pressure produced by suitable doses of the three drugs may be useful in the management of circulatory shock and related states.     

EFFECT OF CIGARETTE SMOKING ON THE FREQUENCY OF VENTRICULAR PREMATURE COMPLEXES IN NORMAL SUBJECTS

1. Ambulatory ECG monitoring was undertaken in healthy cigarette smokers (33) and non-smokers (20) of similar age (21-66 years). 2. The frequency of ventricular premature complexes (VPC) was less in habitual smokers (P less than 0.05; Mann-Whitney rank test) and an average of more than 1 VPC per hour occurred in a higher proportion of non-smokers than smokers: eight of 20 (40%) vs two of 33 (6%) (P less than 0.01; Chi-square test).     

Exercise-induced increase in plasma arachidonic acid and thromboxane B2 in healthy men: effect of beta-adrenergic blockade

We examined the effects of beta-blockade with the nonselective antagonist propranolol, the cardioselective antagonist atenolol, and the cardioselective antagonist with partial agonist activity, practolol, on the levels of free arachidonic acid (AA), thromboxane B2 (TxB2), prostaglandin (PG) E2, and 6-keto-PGF1 alpha in plasma, and TxB2 production by platelets during clotting in six normal subjects during submaximal dynamic exercise. The drugs were given intravenously in equipotent increasing doses before the exercise test. Exercise induced a clear increase in AA, TxB2, and 6-keto-PGF1 alpha in plasma. During the first 60 min of exercise all three beta-blockers decreased the plasma levels of AA and TxB2. Propranolol (0.19 mg/kg) was slightly more effective than atenolol (0.19 mg/kg) or practolol (0.64 mg/kg); however, at exhaustion, propranolol was markedly more effective than the other two blockers. Plasma 6-keto-PGF1 alpha and PGE2 levels were less affected by beta-blockade during exercise, and no significant effect was seen on TxB2 formation by platelets. The plasma 6-keto-PGF1 alpha/TxB2 ratio was markedly higher after propranolol treatment than after treatment with the other two blockers during the exercise period. These results suggest that the capability of a nonselective blocker to inhibit both beta 1- and beta 2-adrenergic receptors may be of advantage because of the more effective inhibition of thromboxane formation than with a cardioselective blocker, especially when the sympathetic tone is markedly increased.     

EFFECTS OF DOPAMINE ON RENAL FUNCTION IN THE RAT ISOLATED PERFUSED KIDNEY

The renal effects of dopamine, the dopamine antagonist spiperone and the combination of dopamine and spiperone were examined in the isolated perfused rat kidney preparation. Studies were carried out at constant perfusion pressure and the following were measured at 10 min intervals for 1 h: perfusate flow; GFR (3H-inulin); urine flow rate; sodium, potassium and kallikrein excretion; perfusate renin concentration; perfusate and urinary-dopamine levels. Low-dose dopamine infusion (6 X 10(-10) mol/min) resulted in significant diuresis, natriuresis and kaluresis but little change in GFR. These effects were blocked by spiperone (10(-10) mol/min) which had no significant effects when infused alone. At a higher dose (10(-8) mol/min) dopamine significantly increased urine flow alone; this too was reversed by spiperone. Dopamine had no significant effects on perfusate flow, renin release or kallikrein excretion. Perfused control kidneys excreted amounts of dopamine (328 pmol/h, s.e.m. = 57, n = 6) far in excess of kidney dopamine content (49 pmol/g, s.e.m. = 6, n = 32). Renal handling of infused dopamine was dose-related; the fraction of the administered dose taken up and/or metabolized by the kidney on the higher dose infusion was considerably less than on the lower dose (40%, s.e.m. = 3 vs. 82%, s.e.m. = 6) while more was excreted (13%, s.e.m. = 3 vs. 2%, s.e.m. = 1). These studies indicate that dopamine at low doses can produce diuresis, natriuresis and kaluresis independently of extrarenal or haemodynamic influences and not mediated by renal renin or kallikrein systems. The kidney also exhibits a saturable capacity for dopamine uptake and/or metabolism.     

Aspirin inhibits the early myocardial release of thromboxane B2 and ventricular ectopic activity following acute coronary artery occlusion in dogs.

Acute coronary artery occlusion in anaesthetized open-chest greyhounds led to early release of thromboxane B2 (TxB2) into venous blood draining the ischaemic region. No release occurred from the remainder of the left ventricular wall (coronary sinus sampling). TxB2 release and ventricular ectopic activity were positively correlated (r = 0.863) 2 min post-occlusion. Aspirin (3 mg/kg i.v.) suppressed both local TxB2 release and ectopic activity and prevented ventricular fibrillation. It is suggested that TxB2 release is a factor contributing to early post-infarction arrhythmias.     

THE EFFECT OF PREGNANCY ON MINERALO- AND GLUCO-CORTICOID SECRETION IN THE SHEEP

1. The peripheral blood concentrations of aldosterone, corticosterone and cortisol were measured during pregnancy in conscious, undisturbed sheep. 2. Aldosterone levels did not change during pregnancy and the mean pregnant value, 1·2 s.d. 1·4 ng/100 ml (n= 12) was not significantly different from the non-pregnant value, 2·1 s.d. 1·7 (n= 16). 3. Cortisol levels likewise were unchanged by pregnancy–non-pregnant values were 0·56 s.d. 0·50 μg/100 mi (n= 12) compared with 0·46 s.d. 0·40 μg/100 ml (n= 16) in pregnant sheep. 4. Sheep of 110–140 days gestation had a 400 mmol greater total exchangeable sodium than non-pregnant sheep. Plasma volume and plasma renin concentration tended to be elevated near to term. 5. Very high aldosterone secretion rates and peripheral blood levels could be produced in pregnant sheep by stress, intravenous ACTH or angiotensin II infusions, and by sodium deficiency. It is suggested that the pregnant sheep may show increased sensitivity in contrast to non-pregnant sheep to these stimuli and the enlarged size of their adrenals may be a contributing factor.     

EFFECT OF INHIBITION OF NITRIC OXIDE SYNTHASE AND GUANYLATE CYCLASE ON HYDRALAZINE-INDUCED VASODILATATION OF THE HUMAN FETAL PLACENTAL CIRCULATION

1. The vasodilator effects of hydralazine in vitro, using the Krebs’ perfused human placental lobule was studied. Single placental lobules were bilaterally perfused (maternal and fetal sides 5 mL/min each, 95% O₂, 5% CO₂, 37°C) and changes in fetal arterial pressure (FAP) and venous outflow (VO) were recorded. 2. Submaximal vasoconstriction was induced by KCl (20–50 mmol/L), which increased basal FAP from 22.8 ± 1.7 to 91.3 ± 3.9 mmHg (n = 9 , P<0.001), and decreased VO from 4.1 ± 0.6 to 0.2 ± 0.1 mL/min (n = 6 , P<0.01). 3. Hydralazine caused vasodilatation (IC₅₀ 1.9 mmol/L, n = 9) and increased VO in the presence of KCl-induced vasoconstriction. 4. Infusion of N^ω-nitro-L-arginine (100 μmol/ L) to block nitric oxide synthase caused the basal FAP to increase from 30.9 ± 5.9 to 47.4 ± 6.7 (n = 6 , P<0.05) and significantly potentiated hydralazine-induced vasodilatation (n = 7 , P<0.05). 5. The soluble guanylate cyclase inhibitor LY 83583 (6-anilino-5,8-quinolinedione) (1 μmol/L) significantly antagonized the vasodilatation produced by hydralazine (n = 5 , P<0.05). 6. Thus, hydralazine appears to activate guanylate cyclase, leading to increased cyclic GMP in fetal arterial vascular smooth muscle to cause vasorelaxation. No evidence was obtained to suggest that hydralazine exerted its action by either releasing nitric oxide from endothelial cells in the placenta or acting as a nitric oxide donor.     

The COX-2 selective inhibitor,valdecoxib, does not impair platelet function in the elderly: results of a randomized controlled trial

The effects of the new cyclooxygenase (COX)-2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65-85 years) in this 7.5-day, randomized, single-center, double-blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8. Valdecoxib had no platelet effects, while ibuprofen significantly decreased platelet aggregation, significantly increased bleeding time (2-4 h postdose on each day), and significantly decreased TxB2 levels at all time points. In conclusion, unlike ibuprofen, valdecoxib 40 mg bid spares platelet COX-1 function in healthy elderly subjects. Valdecoxib's lack of effect on platelet aggregation and bleeding time suggests that it will have an improved clinical profile over nonselective NSAIDs, particularly in patients for whom bleeding complications are a concern.     

Licofelone, an inhibitor of cyclooxygenase and 5-lipoxygenase, specifically inhibits cyclooxygenase-1-dependent platelet activation

5-Lipoxygenase/cyclooxygenase inhibitors, possessing anti-inflammatory action and gastric safety due to cyclooxygenase-2 and 5-lipoxygenase inhibition and antiplatelet activity due to cyclooxygenase-1 blockade, would be beneficial in the treatment of ischemic disease because they may reduce, at the same time, inflammation, underlying the atherosclerotic process, and platelet activation, responsible for acute thrombotic events. In this study, we characterized the antiplatelet effects of the new 5-lipoxygenase/cyclooxygenase inhibitor licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-acetic acid. Licofelone completely prevented platelet aggregation induced in platelet-rich plasma by threshold aggregating concentrations of arachidonic acid (0.87+/-0.14 mM) at threshold inhibitory concentrations of 0.75+/-0.35 microM (n=5). Platelet-rich plasma aggregation induced by threshold aggregating concentrations of collagen/adrenalin (0.3+/-0.05 microg/ml and 0.4+/-0.1 microM, respectively) was reduced to 3.2+/-2% of control at licofelone 100 microM, (P<0.05, n=6). Washed platelet aggregation induced by threshold aggregating concentrations of thrombin (0.07+/-0.01 U/ml) was only partially affected by licofelone at concentrations one or two order of magnitude higher than those fully preventing arachidonic acid-induced aggregation (44+/-11% of control at 100 microM, P<0.05, n=7). Failure to prevent aggregation triggered by high concentrations of collagen/adrenalin in aspirin-treated platelets supports cyclooxygenase-1 as a specific target of licofelone. In fact, licofelone inhibited thromboxane B(2) (TxB(2)) production by all the agonists tested at concentrations between 0.5 and 50 microM. At this concentration, TxB(2) production was reduced at values similar to those of unstimulated platelets. These results indicate that, at clinically relevant concentrations, licofelone exerts a potent antiplatelet effect mediated by the inhibition of cyclooxygenase-1 activity.     

INTERRELATIONSHIP BETWEEN CORTISOL AND ATRIAL NATRIURETIC FACTOR IN THE IMMATURE OVINE FETUS

1. In chronically cannulated ovine fetuses (100-130 days of gestation) the infusion of cortisol (86.7 +/- 15 micrograms/h for 4 h) or human atrial natriuretic factor (ANF; 4.4 micrograms for 2 h) resulted in highly significant increases in the excretion of sodium, chloride, potassium and water. 2. Cortisol had no significant effect on fetal plasma ANF concentrations. All values are mean and s.e.m. Plasma immunoreactive ANF was 53 +/- 5 and 67.3 +/- 13 pmol/L in the 4 h saline infused fetuses, and 51.3 +/- 14.3 and 74 +/- 13.3 pmol/L in cortisol-infused fetuses (n = 7). A separate group of fetuses received 2 h infusions of saline or hANF (4.4 micrograms/h), and plasma IR-ANF values were measured (n = 3). The values, at 0, 60, 90 and 120 min were, respectively, 19.7 +/- 3, 17.3 +/- 0.7, 18.7 +/- 3.7 and 20.7 +/- 3.7 pmol/L in the saline infused group, and 25.3 +/- 5.3, 80.7 +/- 32.3, 123.3 +/- 4.3 and 100 +/- 15 pmol/L in the ANF-infused fetuses. 3. Blood cortisol concentrations, in fetuses infused for 4 h with 0.9% NaCl, were 3.1 +/- 0.8 nmol/L (n = 7); in fetuses infused with 0.9% NaCl for 2 h were 3.6 +/- 1 nmol/L (n = 3); in fetuses infused for 4 h with cortisol were 19.9 +/- 1.9 nmol/L (n = 7); and in fetuses infused with hANF for 2 h were 6.0 +/- 3.0 nmol/L (n = 5). 4. There was no effect of fetal hANF infusion on maternal or fetal blood aldosterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECTS OF NG-NITRO-l-ARGININE ON PRESSURE NATRIURESIS IN ANAESTHETIZED RABBITS

1. We tested the effects of blockade of nitric oxide synthesis on renal function under conditions of controlled renal artery pressure. Our hypothesis was that endogenous nitric oxide plays a role in the natriuresis that accompanies increased renal perfusion pressure. We used a novel technique which employed an extracorporeal circuit to produce step changes over a wide range of renal artery pressures in pentobarbitone-anaesthetized rabbits. 2. Rabbits were treated with either N^G-itro-l-arginine (NOLA, 20 mg/kg, i.v.; n = 8) or its vehicle (n= 8). Renal artery pressure was set (by adjusting the extracorporeal circuit) at 65, 80, 95, 110 and then 130mmHg respectively, at the beginning of each of five 30 min experimental periods. 3. NOLA treatment caused profound renal vasoconstriction that was largely independent of the level of renal artery pressure, renal blood flow being 35–43% lower in NOLA-treated than in vehicle-treated rabbits across the range of renal artery pressures tested (P= 0.002). NOLA treatment increased filtration fraction (P = 0.02), and tended to reduce glomerular filtration rate (P= 0.09). 4. NOLA-treatment affected sodium excretion in a manner dependent on the level of renal artery pressure, with the slope of the relationship between sodium excretion and renal artery pressure being lower in NOLA-treated than in vehicle-treated rabbits (P= 0.006). 5. These data provide direct evidence that in anaesthetized rabbits endogenous nitric oxide (i) tonically dilates the renal vasculature across a wide range of renal perfusion pressures, and (ii) enhances sodium excretion to a progressively greater degree as renal artery pressure is increased. It may therefore play a role in pressure-induced natriuresis.     

ABNORMALITY OF THE GLOMERULAR ANGIOTENSIN II RECEPTOR IN EXPERIMENTAL DIABETIC NEPHROPATHY

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18–21 mmol/L (uncontrolled diabetes) and 4–8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 ± 62 and 388 ± 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 ± 2.7, 38 ± 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P= 0.04 and uncontrolled P= 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.     

ARTERIAL PRESSURE AND HEART PERIOD IN THE CONSCIOUS RABBIT: DIURNAL RHYTHM AND INFLUENCE OF ACTIVITY

Mean-arterial pressure (MAP), heart period (HP) and the level of physical activity were measured in conscious rabbits and averaged over one-hour periods during 14 consecutive days. Serial autocorrelation coefficients and serial crosscorrelation coefficients were computed, to analyse periodicity. Measurements were started immediately after implantation of the cannula (group A, n = 11) or 10-46 days after implantation of the cannula (group B, n = 6). In the course of 14 days, in group A, MAP decreased 9 mmHg and HP increased 21 ms (P less than 0.05). In group B, MAP decreased and HP increased in a similar way. Percentage activity did not show a trend. Significant diurnal rhythms were found. MAP and percentage activity reached the lowest values at noon, and the highest late in the evening. HP reached the highest values at noon and the lowest late in the evening. MAP and HP fluctuated exactly in antiphase. This suggests a common origin for both rhythms. During physical activity MAP was 10-15 mmHg higher and HP was 35-40 ms shorter than during rest. These differences did not show a trend or a diurnal variation. In individual animals MAP and HP varied greatly from hour to hour. These biological variations in MAP and HP as well as the influence of activity should be taken into account when conclusions are drawn from short-term measurements.     

Effect of glutathione depletion on tissue and plasma prostacyclin and thromboxane in rats.

Experiments were designed to determine the effects of glutathione (GSH) depletion with L-buthionine sulfoximine (BSO) or diethyl maleate (DEM) on tissue and plasma prostacyclin (6-keto-PGF1 alpha) and thromboxane (TxB2) levels in male Sprague-Dawley rats. Despite depleting hepatic GSH to as much as 34% of control, BSO at various levels (0.4, 0.8 and 1.2 g/kg body wt) had no effect on hepatic, renal, pulmonary or cardiac tissue levels of 6-keto-PGF1 alpha and TxB2 or circulating levels of 6-keto-PGF1 alpha in portal or arterial plasma. When rats were pretreated with 3-methylcholanthrene (3-MC) to induce cytochrome P450, BSO (0.8 g/kg body wt) also had no effect on tissue or plasma prostanoid levels with the exception of a slight, but significant, increase in hepatic 6-keto-PGF1 alpha in non-induced rats. In contrast, depletions of hepatic, renal and pulmonary tissue GSH by DEM (1 mL/kg body wt) to 12, 50 and 30% of control, respectively, were associated with elevations of 6-keto-PGF1 alpha in these tissues and in plasma obtained by right ventricular heart puncture. Pretreatment of rats with 3-MC had no significant effect on tissue GSH or prostanoid levels in controls or DEM-treated rats but plasma levels of 6-keto-PGF1 alpha were lower in comparison to non-induced rats. DEM with or without 3-MC pretreatment was associated with increased TxB2 in renal tissue, whereas DEM elevated TxB2 only in pulmonary tissue from non-induced rats. It appears that factors besides GSH depletion may be required to raise plasma and/or tissue 6-keto-PGF1 alpha levels in vivo.     

The effect of chronic tobacco smoking on arterial stiffness

AIMS: Cardiovascular disease caused by smoking is related to the pathophysiological burden placed on the vascular endothelium. We studied the effect of chronic cigarette smoking on arterial wave reflection (study 1) and smoking cessation on pulse wave analysis (study 2). METHODS: Fifty smokers and 50 age- and sex-matched nonsmokers participated in study 1. Study 2 recruited 20 volunteers from the stop smoking clinic at the Royal Hallamshire Hospital, Sheffield, UK. Systemic augmentation index (AIx) and carotid-femoral pulse wave velocity (PWV) were measured using the SphygmoCor system. Brachial blood pressure (BP) (Omron 705-CP-E), AIx and PWV were recorded at a single visit in study 1. Study 2 measured these variables on 'quit day' and 4 weeks later. RESULTS: In study 1, AIx was significantly higher in smokers than in nonsmokers (median 17.25 vs. 11.75%, P = 0.004). Multiple regression analysis showed a significant correlation between AIx and age, diastolic BP, smoking status (P < 0.001), blood glucose (P = 0.045) and weight (P = 0.049). In study 2, AIx significantly reduced after 4 weeks of abstinence in successful quitters (n = 10) compared with relapsed smokers (n = 4) (median 5.0 vs.- 9.5; P = 0.013). PWV did not reach significance in either study. CONCLUSIONS: Chronic tobacco smoking is associated with endothelial dysfunction and increased AIx in subjects of a wide age range free from additional cardiovascular risk factors, which is partially reversible after 4 weeks of smoking cessation.     

Protective effects of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, in splanchnic artery occlusion shock.

Splanchnic artery occlusion (SAO) shock was induced in anesthetized rats by clamping the celiac trunk and the superior mesenteric artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure (MAP), plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, and the phagocytotic activity of peritoneal macrophages were evaluated. Shocked animals died within 89 +/- 10 min, while all sham-shocked rats survived greater than 3 h. SAO shock produced relevant changes in MAP, significantly increased plasma levels of TxB2 and 6-keto-PFG1 alpha, and decreased peritoneal macrophage phagocytotic activity. The administration of G 619, a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist (50 mg/kg, 15 min before SAO shock) significantly increased survival time (190 +/- 13 min) and survival rate, reduced plasma levels of TxB2, and partially restored the impairment in peritoneal macrophage phagocytosis. Finally, the administration of G 619 had beneficial effects on changes in MAP-induced bay SAO shock. These data further confirm the involvement of TxA2 in SAO shock and suggest that G 619 may have positive effects in low-flow states.