The effects of a converting enzyme inhibitor (captopril) and angiotensin II on fetal renal function

1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses. 4. It is concluded that the small fall in fetal arterial pressure partly contributed to the fall in fetal GFR but in addition, efferent arteriolar tone fell so that the filtration pressure fell further. Thus maintenance of fetal renal function depends on the integrity of the fetal renin angiotensin system. These findings explain why use of ACE inhibitors in human pregnancy is associated with neonatal anuria.     

Cerebellar granule cell GABA(A) receptors studied at the single-channel level: modulation by protein kinase G

BACKGROUND: This study was designed to evaluate the adenosine-triphosphate-sensitive potassium channel opener pinacidil as a blood cardioplegic agent. METHODS: Using a blood-perfused, parabiotic, Langendorff rabbit model, hearts underwent 30 minutes of normothermic ischemia protected with blood cardioplegia (St. Thomas' solution [n = 8] or Krebs-Henseleit solution with pinacidil [50 micromol/L, n = 81) and 30 minutes of reperfusion. Percent recovery of developed pressure, mechanical arrest, electrical arrest, reperfusion ventricular fibrillation, percent tissue water, and myocardial oxygen consumption were compared. RESULTS: The percent recovery of developed pressure was not different between the groups (52.3 +/- 5.9 and 52.8 +/- 6.9 for hyperkalemic and pinacidil cardioplegia, respectively). Pinacidil cardioplegia was associated with prolonged electrical and mechanical activity (14.4 +/- 8.7 and 6.1 +/- 3.9 minutes), compared with hyperkalemic cardioplegia (1.1 +/- 0.6 and 1.1 +/- 0.6 minutes, respectively; p < 0.05). Pinacidil cardioplegia was associated with a higher reperfusion myocardial oxygen consumption (0.6 +/- 0.1 versus 0.2 +/- 0.0 mL/100 g myocardium/beat; p < 0.05) and a higher percent of tissue water (79.6% +/- 0.7% versus 78.6% +/- 1.2%; p < 0.05). CONCLUSIONS: Systolic recovery was not different between groups, demonstrating comparable effectiveness of pinacidil and hyperkalemic warm blood cardioplegia.     

Presynaptic modulation by VIP, secretin and isoproterenol of somatostatin release from enriched enteric synaptosomes: role of cAMP

The release of somatostatin-like immunoreactivity was studied in isolated synaptosomes. A significant release of somatostatin-like immunoreactivity was observed in the presence of vasoactive intestinal polypeptide (VIP) (10(-6) M: 53.0 +/- 12.4 pg/mg, basal: 14.3 +/- 1.7 pg/mg, n = 5, P < 0.05), secretin (10(-6) M: 56.1 +/- 3.8 pg/mg, basal: 25.8 +/- 1.6 pg/mg, n = 6, P < 0.01) and isoproterenol (10(-5) M: 54.0 +/- 13.4 pg/mg, basal: 20.0 +/- 3.4 pg/mg, n = 8, P < 0.05). Forskolin, an unspecified activator of the adenylate cyclase, caused a significant release of somatostatin-like immunoreactivity (10(-6) M: 57.3 +/- 13.2 pg/mg, basal: 30.0 +/- 5.8 pg/mg, n = 13, P < 0.01) which was further augmented in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX 10(-4) M) (77.0 +/- 17.8 pg/mg, n = 13, P < 0.01). 3-Isobutyl-l-methylxanthine and N6, 2'-O-dibutyryladenosine-3',5'-cyclic monophosphate mimicked at effect of forskolin and VIP. The release of somatostatin was paralleled by an increase of cAMP immunoreactivity in the presence of VIP (10(-6) M: 37.1 +/- 9.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.05), isoproterenol (10(-5) M: 42.4 +/- 9.8 pmol/mg basal: 16.7 +/- 2.4 pmol/mg, n = 12, P < 0.01) and forskolin (10(-6) M: 47.1 +/- 12.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.01). The effect of nitric oxide (NO) which acts as an inhibitory neurotransmitter in the enteric nervous system was studied. NO is known to activate guanylate cyclase to induce transmitter release. The NO-generating compound sodium nitroprusside and bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) had no effect on the release of somatostatin-like immunoreactivity. These data demonstrate the stimulatory effect of VIP, secretin and isoproterenol on release of somatostatin-like immunoreactivity from enteric synaptosomes, which is presumably mediated by cAMP-dependent mechanisms. cGMP-dependent mechanisms seem to be of minor relevance.     

Effects of renin inhibition compared to angiotensin converting enzyme inhibition in conscious dogs with pacing-induced heart failure

OBJECTIVE: To compare the effects of angiotensin converting enzyme inhibition (ACEI) (captopril 1 mg/kg i.v.) to direct renin inhibition (CP80794 3 mg/kg i.v.) on left ventricular and systemic hemodynamics and peripheral blood flows in advanced congestive heart failure (CHF). METHODS: Conscious chronically instrumented dogs (n = 14) were treated with captopril, 1 mg/kg, i.v., or CP80794, 3 mg/kg, i.v., before and after development of advanced CHF induced by 4-7 weeks of rapid ventricular pacing. After advanced CHF, comparisons between the inhibitors were made at equihypotensive doses. RESULTS: In advanced CHF, both agents caused comparable reductions in mean arterial pressure (MAP) (-22% from 79 +/- 4 mmHg) and comparable increases (P < 0.01) in cardiac output (CP80794, 1.4 +/- 0.3 to 1.8 +/- 0.1 l/min; captopril, 1.4 +/- 0.1 to 1.9 +/- 0.1 l/min). Neither agent had a significant effect on LV contractility. In contrast, CP80794 caused a greater (P < 0.05) increase in renal blood flow (66 +/- 6% from 64 +/- 5 ml/min) compared to captopril (33 +/- 4% from 66 +/- 7 ml/min). CONCLUSIONS: Renin inhibition with CP80794 and ACEI with captopril caused comparable hemodynamic effects in advanced CHF. However, CP80794 caused significantly greater increases in renal blood flow and suppressed renin activity to a greater degree than captopril.     

Endothelin-1 levels in ischaemia, reperfusion, and haemorrhagic shock in the canine infrarenal aortic revascularisation model

Endothelin-1 (ET-1) is a potent vasoconstrictive polypeptide produced from vascular endothelial cells. The effects of ischaemia, reperfusion, and exsanguination on plasma ET-1 levels were studied and compared in the mongrel dog after infrarenal aortic cross clamping. Ischaemia produced a trend toward increased ET-1 serum levels (p < 0.07 with Bonferroni correction) that did not reach significance. Plasma ET-1 levels were significantly increased during reperfusion and even further elevations were found following exsanguination. We found a 2-3 fold increase in ET-1 levels following reperfusion (Initial 3.19 +/- 0.27 pg/ml vs. Reperfusion maximum 6.32 +/- 0.72 pg/ml, Bonferroni p < 0.01). Haemorrhagic shock was associated with a 3-4 fold increase in ET-1 levels (Initial 3.19 +/- 0.27 pg/ml vs. Exsanguination maximum 8.37 +/- 0.97 pg/ml Bonferroni p < 0.001). These data reveal that ET-1 is released during reperfusion and exsanguination and may mediate remote vascular events associated with infrarenal aortic cross clamping and acute blood loss.     

Modulation of endothelial cell function by antiphospholipid antibodies

AIM: To observe the effect of captopril (Cap) on intracellular pH (pHi) in aortic smooth muscle cells (ASMC). METHODS: Cultured ASMC derived from rat and rabbit aortae were loaded with the fluorescent dye BCECF and pHi was determined using digital image processing method. RESULTS: The pHi of untreated SHR and WKY rats were 7.37 +/- 0.29 and 7.19 +/- 0.31, respectively. Oral Cap decreased pHi (7.11 +/- 0.26, P < 0.05) and exaggerated pHi response to angiotensin II (Ang-II, 0.1 mumol.L-1) in ASMC of SHR rats vs WKY rats (0.14 +/- 0.05 vs 0.21 +/- 0.05 pH units, P < 0.01). Cap in vitro had no effect on Ang-II induced intracellular alkalinization in ASMC of rabbits. CONCLUSION: Oral Cap inhibits Na+(-)H+ exchange activity in ASMC of SHR rats.     

Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.     

Renal 11 beta-hydroxysteroid dehydrogenase activity is enhanced by ramipril and captopril

Changes of renal 11 beta-hydroxysteroid dehydrogenase activity may contribute to variations of sodium excretion by modulating inactivation of cortisol or corticosterone and thus their access to mineralocorticoid receptors. Angiotensin-converting enzyme inhibitors enhance sodium excretion but by mechanisms still incompletely understood. To test the hypothesis that the angiotensin-converting enzyme inhibitors ramipril and captopril act in part by enhancing renal 11 beta-hydroxysteroid dehydrogenase activity, the effects of these agents in slices of rat renal outer medulla were examined. Conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone was 58% greater in tissue from fasted rats than from fed rats (mean +/- SE 2467 +/- 146 vs. 1584 +/- 102 pmol/mg protein.h, P < 0.01). Incubation of tissue from fed rats with physiological concentrations of ramiprilat, the active form of ramipril, enhanced activity (1497 +/- 76) to fasted levels (2323 +/- 120, P < 0.02). Captopril had a similar in vitro effect (1557 +/- 92 to 2109 +/- 116, P < 0.01). Ramipril given in vivo to fed rats also increased activity to fasted levels (1716 +/- 101 to 2737 +/- 396, P < 0.05). Angiotensin II incubated with renal tissue from fasted rats suppressed activity to fed levels, but this effect was prevented by the presence of ramiprilat. Both ramipril and captopril enhance renal 11 beta-hydroxysteroid dehydrogenase activity, and this effect is only partly explained by limitation of endogenous angiotensin II production.     

Acute and delayed hormonal changes in mitral stenosis treated by balloon valvulotomy

The role of left atrial and aortic pressures on the secretion of the main hormones controlling blood volume is still subject to debate in humans. Because of increased mean left atrial pressure and decreased mean aortic pressure produced by balloon inflation in patients with mitral stenosis treated with balloon valvulotomy, the hormonal changes occurring acutely (group II of patients) were measured. The same studies (group I patients) were also performed 48 hours after this treatment, a period at which left atrial pressure permanently diminished. Inflation of the balloon resulted in a decrease in plasma renin activity and increases in plasma atrial natriuretic factor (ANF) and plasma arginine vasopressin (AVP). Forty-eight hours after balloon valvulotomy, which had produced a decrease in left atrial pressure, plasma ANF was lower (58.9 +/- 7.9 vs 95.3 +/- 11.9 pg/ml; p < 0.001), and plasma renin activity (2,575 +/- 533 vs 960 +/- 113 pg/ml/hour; p < 0.01), plasma angiotensin II (25.0 +/- 4.1 vs 9.3 +/- 1.3 pg/ml; p < 0.001) and plasma aldosterone (181.7 +/- 36.7 vs 139.9 +/- 19.8 pg/ml; p < 0.05) were higher than their respective control levels 24 hours before treatment of the stenosis. In contrast, plasma AVP (3.7 +/- 0.25 vs 4.4 +/- 0.31 pg/ml; p = 0.001) diminished moderately along with plasma osmolality (282.4 +/- 0.1 vs 286.2 +/- 0.6 mOsm/kg; p < 0.001). Urinary sodium excretion was also examined before and after balloon valvulotomy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischaemic myocardium

OBJECTIVE: Myocardial reperfusion following brief period of ischaemic is associated with prolonged, reversible periods of metabolic dysfunction. As the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is inhibited in vitro by reactive oxygen species, we hypothesized that production of reactive oxygen species during reperfusion would lead to inhibition of GAPDH in post-ischaemic myocardium. METHODS: Anaesthetized closed-chest-dogs were subjected to 20 min balloon occlusion of the left anterior descending coronary artery. Biopsy samples were taken after 3 and 24 h of reperfusion, to determine the activity of GAPDH and the concentrations of glycolytic intermediates in post-ischaemic and remote, non-ischaemic territories. RESULTS: A significant reduction in GAPDH activity was observed in post-ischaemic relative to remote tissue after 3 h reperfusion (4.8 +/- 0.5 vs. 2.9 +/- 0.2 mumol/min/mg protein; P < 0.01). Western blotting revealed no reduction in the levels of GAPDH protein. Analysis of enzyme kinetics showed the loss of activity to be associated with decreased Vmax (5.9 +/- 0.5 vs. 3.2 +/- 0.2 mumol/min/mg protein; P < 0.01) with no significant change in the Km for glyceraldehyde-3-phosphate (GAP). Incubation of the inhibited enzyme under both mild and strong reducing conditions failed to reactivate the enzyme. The acute reduction in enzyme activity in post-ischaemic tissue was accompanied by regional differences in glycolytic intermediates, notably a twofold accumulation of GAP (P < 0.05), and a reduction in the glucose metabolic rate (GMR) determined by positron emission tomography and [18F]2-fluorodeoxyglucose. By 24 h reperfusion, no regional differences in GAPDH activity, reaction Vmax or Km, GAP concentrations or GMR were detectable. CONCLUSIONS: These results suggest that inhibition of GAPDH activity may represent an important point at which glycolysis is limited during reperfusion, and further, that the mechanisms of enzyme inhibition do not involve simple oxidation or S-thiolation of critical active site thiol groups.     

Effects of captopril on ventricular arrhythmias in the early and late phase of suspected acute myocardial infarction. Randomized, placebo-controlled substudy of ISIS-4

The antiarrhythmic effect of oral captopril was studied during the early (day 3) and late (day 14) phase of acute myocardial infarction among 304 patients in a randomized placebo-controlled substudy of ISIS-4. Ventricular arrhythmias (ventricular ectopic beats per hour) occurred significantly less frequently among captopril-allocated patients than among those allocated placebo at day 3 (logarithmic scale: 0.48 +/- 0.8 captopril vs 0.84 +/- 1.3 placebo; P < 0.003) and at day 14 (0.51 +/- 1.0 vs 0.77 +/- 1.3; P < 0.05). The number of patients with frequent ventricular arrhythmias (more than 10 ventricular ectopic beats per hour) was also significantly lower among those allocated captopril at day 3 (7.3% vs 14.4%; P < 0.05) and at day 14 (7.3% vs 14.8%; P < 0.05). These results support the hypothesis that the activation of the renin-angiotensin-aldosterone and sympathetic system may underlie heart rhythm disturbances in acute myocardial infarction, and that early use of converting enzyme inhibitor therapy may ameliorate these disturbances.     

Molecular basis of type III hyperlipoproteinemia in Germany

1. The aim of the present investigation was to evaluate the effect of cloricromene on myocardial infarct size, regional myocardial blood flow and neutrophil accumulation in a canine model of ischaemia-reperfusion. 2. Dogs were instrumented to measure blood pressure, left anterior descending (LAD) coronary flow (flow probe) and regional myocardial blood flow (coloured microspheres). Two groups were studied: (i) CLO (n = 8) received an infusion of cloricromene (15 micrograms/kg per min); and (ii) VEH (n = 8) received saline. Infusions began at the onset of ischaemia (60 min) and continued through reperfusion (180 min). 3. Haemodynamic responses were not different between groups. Cloricromene reduced the area of necrosis expressed as a percentage of the area at risk from 35 +/- 3% in the VEH group to 23 +/- 4% in the CLO group (P < 0.05). Regional myocardial blood flow in the ischaemic region was different between groups; VEH dogs showed an early reperfusion hyperaemia followed by a progressive reduction in flow, while CLO dogs exhibited a gradual increase in reflow in the absence of an early hyperaemic response (P < 0.05). Left anterior descending flow was enhanced during the reperfusion period in the CLO group compared with VEH (P < 0.05). Cloricromene reduced polymorphonuclear neutrophil (PMN) infiltration (myeloperuxidase activity) in all myocardial regions when compared with VEH (non-ischaemic zone, 0.34 +/- 0.54 vs 0.05 +/- 0.01 IU/100 mg; ischaemic zone, 2.03 +/- 0.80 vs 0.24 +/- 0.08 IU/100 mg; and necrotic zone, 0.56 +/- 0.04 vs 3.59 +/- 1.09 IU/100 mg for VEH vs CLO groups, respectively; P < 0.01). In a separate in vitro preparation, cloricromene reduced adherence of platelet-activating factor (PAF)-stimulated PMN to canine coronary endothelium. Stimulation of PMN by 100 nmol/L PAF resulted in adherence of 176 +/- 36 compared with 48 +/- 12 cells/mm2 in PAF-stimulated PMN treated with 100 mumol cloricromene (P < 0.001). 4. These data indicate that cloricromene reduces myocardial infarct size in a canine model of ischaemia-reperfusion injury. Postischaemic blood flow patterns are significantly different in cloricromene-treated dogs. Cloricromene-mediated reductions in infarct size, neutrophil accumulation and adherence may play a role in this effect.     

Homeobox genes in hematopoiesis and leukemogenesis

The effect of cold and warm intermittent antegrade blood cardioplegia, on the intracellular concentration of taurine in the ischaemic/reperfused heart of patients undergoing aortic valve surgery, was investigated. Intracellular taurine was measured in ventricular biopsies taken before institution of cardiopulmonary bypass, at the end of 30 min of ischaemic arrest and 20 min after reperfusion. There was no significant change in the intracellular concentration of taurine in ventricular biopsies taken after the period of myocardial ischaemia in the two groups of patients (from 10.1 +/- 1.0 to 9.6 +/- 0.9 mumol/g wet weight for cold and from 9.3 +/- 1.3 to 10.0 +/- 1.3 mumol/g wet weight for warm cardioplegia, respectively). Upon reperfusion however, there was a fall in taurine in both groups but was only significant (P < 0.05) in the group receiving cold blood cardioplegia (6.9 +/- 0.8 mumol/g wet weight after cold blood cardioplegia versus 8.0 +/- 0.8 mumol/g wet weight following warm blood cardioplegia). Like taurine, there were no significant changes in the intracellular concentration of ATP after ischaemia in the two groups of patients (from 3.2 +/- 0.32 to 2.95 +/- 0.43 mumol/g wet weight for cold and from 2.75 +/- 0.17 to 2.62 +/- 0.21 mumol/g wet weight for warm cardioplegia, respectively). However upon reperfusion there was a significant fall in ATP in both groups with the extent of the fall being less in the group receiving warm cardioplegia (1.79 +/- 0.19 mumol/g wet weight for cold and 1.98 +/- 0.27 mumol/g wet weight for warm cardioplegia, respectively). This work shows that reperfusion following ischaemic arrest with warm cardioplegia reduces the fall in tissue taurine seen after arrest with cold cardioplegia. Accumulation of intracellular sodium provoked by hypothermia and a fall in ATP, may be responsible for the fall in taurine by way of activating the sodium/taurine symport to efflux taurine.     

Adenosine-enhanced ischemic preconditioning provides enhanced cardioprotection in the aged heart

BACKGROUND: Recently we have reported a novel myo-protective protocol "adenosine-enhanced ischemic preconditioning" (APC), which extends and amends the protection afforded by ischemic preconditioning (IPC) by both reducing myocardial infarct size and enhancing postischemic functional recovery in the mature rabbit heart. However, the efficacy of APC in the senescent myocardium was unknown. METHODS: The efficacy of APC was investigated in senescent rabbit hearts and compared with magnesium-supplemented potassium cardioplegia (K/Mg) and IPC. Global ischemia (GI) hearts were subjected to 30 minutes of global ischemia and 120 minutes of reperfusion. Ischemic preconditioning hearts received 5 minutes of global ischemia and 5 minutes of reperfusion before global ischemia. Magnesium-supplemented potassium cardioplegia hearts received cardioplegia just before global ischemia. Adenosine-enhanced ischemic preconditioning hearts received a bolus injection of adenosine in concert with IPC. To separate the effects of adenosine from that of APC, a control group (ADO) received a bolus injection of adenosine 10 minutes before global ischemia. RESULTS: Infarct size was significantly decreased to 18.9%+/-2.7% with IPC (p<0.05 versus GI); 17.0%+/-1.0% with ADO (p<0.05 versus GI); 7.7%+/-1.3% with K/Mg (p<0.05 versus GI, IPC, and ADO); and 2.1%+/-0.6% with APC (p<0.05 versus GI, IPC, ADO, and K/Mg; not significant versus control). Only APC and K/Mg significantly enhanced postischemic functional recovery (not significant versus control). CONCLUSIONS: Adenosine-enhanced ischemic preconditioning provides similar protection to K/Mg cardioplegia, significantly enhancing postischemic functional recovery and decreasing infarct size in the senescent myocardium.     

1H-MRS, MRI-based hippocampal volumetry, and 99mTc-HMPAO-SPECT in normal aging, age-associated memory impairment, and probable Alzheimer''s disease

AIM: To study whether the effect of captopril (Cap) on vascular structure and function may be seperated from its effect on blood pressure. METHODS: Captopril treatment (group Cap A and B, 20 and 100 mg.kg-1.d-1) was given to SHR rats during pregnancy, weaning, and up to 16 wk of age. Study performed at 40 wk. Blood pressure (BP) was measured by tail-cuff sphygmomanometer, and wall/lumen ratio of mesenteric artery 3rd grade branch was assessed by morphometric assay. Resistance vessel properties were determined by hindquarter perfusion pressure responses to incremental doses of phenylephrine, in the presence of N omega nitro-L-arginine methyl ester (L-NAME) or the L-arginine, the precursor of nitric oxide synthesis. RESULTS: Both doses of Cap prevented hypertrophy of blood vessels to an extent comparable to that of the untreated WKY rats (wall/lumen ratio of mesenteric artery, Cap A: 0.38 +/- 0.08, Cap B: 0.29 +/- 0.05 vs WKY: 0.34 +/- 0.11, P > 0.05, respectively). The parameters derived from hindquarter perfusion pressure curves in Cap treated group were almost identical to that of WKY, significantly different from that of untreated SHR (EC50, Cap B 4.05 +/- 2.58 vs SHR 1.15 +/- 0.96 mL.L-1, P < 0.01; vs WKY 5.13 +/- 1.97 mL.L-1, P > 0.05). Addition of L-NAME or L-arginine in the perfusate augmented or attenuated the vasoconstriction responses in the Cap treated group. CONCLUSION: Cap initiated from intrauterine period normalized the vascular structure and vasoconstrictive responses in SHR when BP still sustained at a higher level vs WKY.     

Autonomic contribution to the blood pressure and heart rate variability changes in early experimental hyperthyroidism

A great deal of uncertainty persists regarding the exact nature of the interaction between autonomic nervous activity and thyroid hormones in the control of heart rate (HR) and blood pressure (BP). Thyrotoxicosis was produced by a daily intraperitoneal (i.p.) injection of L-thyroxine (0.5 mg/kg body wt in 1 ml of 5 mM NaOH for 5 days). Control rats received i.p. daily injections of the thyroxine solvant. Autonomic blockers were administered intravenously: atropine (0.5 mg/kg), atenolol (1 mg/kg), atenolol + atropine or prazosin (1 mg/kg). Eight animals were studied in each group. Thyroxine treatment was sufficient to induce a significant degree of tachycardia (423 +/- 6 vs 353 +/- 4 bpm; p < 0.001, unpaired Student's tests), systolic BP elevation (142 +/- 3 vs 127 +/- 2 mmHg; p < 0.001), pulse pressure increase (51 +/- 2 vs 41 +/- 2 mmHg, p < 0.01), cardiac hypertrophy (1.165 +/- 0.017 vs 1.006 +/- 0.012 g, p < 0.001), weight loss (-21 +/- 2 g; p < 0.001) and hyperthermia (37.8 +/- 0.1 vs 37.0 +/- 0.1 degrees C, p < 0.001). The intrinsic HR observed after double blockade (atenolol + atropine) was markedly increased after treatment with thyroxine (497 +/- 16 vs 373 +/- 10 bpm, p < 0.05). Vagal tone (difference between HR obtained after atenolol and intrinsic HR) was positively linearly related to intrinsic HR (r = 0.84; p < 0.01). Atenolol neither modified HR nor BP variability in rats with hyperthyrodism. The thyrotoxicosis was associated with a reduction of the 0.4 Hz component of BP variability (analyses on 102.4 sec segments, modulus 1.10 +/- 0.07 vs 1.41 +/- 0.06 mmHg; p < 0.01). Prazosin was without effect on this 0.4 Hz component in these animals. These data show a functional diminution of the vascular and cardiac sympathetic tone in experimental hyperthyroidism. Increased intrinsic HR resulting from the direct effect of thyroid hormone on the sinoatrial node is the main determinant of a tachycardia leading to a subsequent rise in cardiac output. The resulting BP elevation could reflexly induce a vagal activation and a sympathetic (vascular and cardiac) inhibition.     

Augmented exercise plasma noradrenaline with impaired chronotropic responsiveness in patients with hypertrophic cardiomyopathy

1. There is controversy regarding plasma catecholamine levels in patients with hypertrophic cardiomyopathy (HCM) and few data exist on serial plasma catecholamine measurements during exercise. The present study determined whether cardiovascular and plasma catecholamine responses to exercise were altered in patients with HCM. 2. Plasma noradrenaline (NA) and adrenaline were measured at rest, at the end of each stage during exercise and immediately and 5 min after submaximal treadmill exercise in 15 patients with non-obstructive HCM (13 males, two females; mean (+/- SEM) age 54 +/- 3 years) and in 15 age- and sex-matched controls. The ratio of the increment in heart rate (HR) divided by the increment in plasma NA during exercise (delta HR/delta NA) was used as an index of chronotropic sympathetic responsiveness to exercise. 3. Exercise duration was shorter (11.2 +/- 0.6 vs 8.7 +/- 0.6 min for control vs HCM, respectively; P < 0.01) and diastolic blood pressure was significantly higher at stages I and II of modified Bruce protocol HCM. 4. Resting plasma NA levels (149 +/- 17 vs 167 +/- 28 pg/mL for control vs HCM, respectively; NS) were not different, but plasma NA levels at stages I and II were significantly higher in HCM than in controls (243 +/- 26 vs 399 +/- 69 pg/mL (P < 0.05) and 308 +/- 30 vs 548 +/- 110 pg/mL (P < 0.05), respectively). 5. Peak plasma NA levels were not significantly higher in HCM than in controls (578 +/- 59 vs 918 +/- 184 pg/mL, respectively; NS). 6. The ratio delta HR/delta NA was significantly lower in HCM compared with control at stages I and II (0.49 +/- 0.10 vs 0.21 +/- 0.05 (P < 0.05) and 0.38 +/- 0.06 vs 0.20 +/- 0.05 (P < 0.05), respectively). There were no differences in plasma adrenaline responses during exercise between the two groups. 7. Patients with HCM had augmented plasma NA levels during submaximal exercise with a higher diastolic blood pressure response. Chronotropic sympathetic responsiveness was impaired during the early stages of exercise in patients with HCM.     

Effects of hypothermia in hypercapnia and hypercapnic hypoxemia

Anesthetized, paralyzed and mechanically ventilated pigs were hypoventilated to extreme hypercapnia (PaCO2 approximately 20 kPa) at FiO2 0.5, and allotted to a hypothermic group (31.5 +/- 0.1 degrees C, n = 6) or a control group (39.6 +/- 0.2 degrees C, n = 6). Compared with the controls, the hypothermic animals had higher PaO2 (19.2 vs 15.6 kPa, P < 0.05), SaO2 (97.2 vs 89.3%), SvO2 (78.7 vs 68.2%), end-tidal O2 (34.5 vs 24.8 kPa) and arterial pH (7.01 vs 6.91), (P < 0.01), but lower PvO2 (7.0 vs 10.2 kPa) and PaCO2 (13.2 vs 23.5 kPa), (P < 0.01). Hypothermia reduced O2 delivery (DO2), O2 consumption (VO2) and CO2 production by 40-45% (P < 0.05), but O2 extraction ratio, i.e. VO2.DO(2)-1 x 100(%), did not differ between groups. Hypothermic animals had lower heart rate (127 vs 223 beats.min-1, P < 0.05) and cardiac output (2.5 vs 3.9 l.min-1, P < 0.01). Subsequently, the inspired oxygen fraction (FiO2) was decreased stepwise (0.3, 0.25, 0.21, 0.15, 0.10) at 30-min intervals. At FiO2 0.3, the hypothermic group had higher PaO2 (10.0 vs 5.7 kPa), SaO2 (91.3 vs 28.5%), PvO2 (5.8 vs 3.4 kPa), SvO2 (70.7 vs 10.3%), end-tidal O2 (16.7 vs 8.5 kPa), O2 delivery (344 vs 155 ml.min-1), arterial pH (7.02 vs 6.94) and systemic vascular resistance (3850 vs 1652 dyn.s.cm-5 (38,500 vs 16,520 microN.s.cm-5)) compared with the controls (P < 0.01), while PaCO2 was lower (12.4 vs 22.7 kPa), as well as O2 extraction ratio (23 vs 63%) and O2 half saturation tension (4.3 vs 8.0 kPa) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Minor physical anomalies in schizophrenia and mood disorders

The purpose of the present study was to examine the effect of a two day and a five day administration of 22-oxa-calcitriol (OCT) on calcium metabolism in rats with advanced chronic renal failure and severe secondary hyperparathyroidism. A first series of 27 uremic rats received either placebo, OCT or calcitriol (0.3 microgram i.p./rat) 48 and 24 hours before sacrifice. A second series of 18 uremic rats received either placebo, OCT (0.3 microgram i.p./rat) or calcitriol (0.05 microgram i.p./rat) for five days. We found that after 48 hours (series 1) both calcitriol and OCT increased blood ionized calcium (Ca2+) as compared to vehicle (1.23 +/- 0.04 and 1.10 +/- 0.02 mM, P < 0.01 and P < 0.05, respectively vs. control, 1.02 +/- 0.03 mM). Duodenal Ca transport (S/M) using the everted gut sac technique was not stimulated by OCT, even though it increased from 2.8 +/- 0.4 to 7.0 +/- 0.6 (P < 0.01) with calcitriol. In contrast, duodenal calbindin-D9k mRNA expression and protein content increased to a similar extent with OCT and calcitriol. Calcitriol was more potent in reducing plasma iPTH1-34 levels than OCT: 344 +/- 75 pg/ml (calcitriol) versus 632 +/- 46 pg/ml (OCT) compared with 897 +/- 74 pg/ml (control), P < 0.01. In the second series of rats, the injection of OCT (0.3 microgram i.p./rat) over five days was less effective than the lower dose of calcitriol (0.05 microgram i.p./rat) in reducing circulating iPTH: 110 +/- 26 (calcitriol) and 281 +/- 64 (OCT) versus 624 +/- 135 pg/ml (control), P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of pinacidil on rat hearts undergoing hypothermic cardioplegia

We studied the effect of pinacidil, a potassium-channel opener, on the hemodynamic, biochemical, and ultrastructural changes in rat hearts undergoing hypothermic cardioplegia. Fifty-four male Wistar rats weighing 250 to 300 g were used. Isolated hearts were prepared for modified Langendorff circulation in the working mode using modified Krebs-Henseleit bicarbonate solution bubbled with a 95% O2 and 5% CO2 gas mixture. Eighty minutes of cardioplegia at 25 degrees C was followed by normothermic reperfusion for 30 minutes. Pinacidil, 5, 10, or 50 mumol/L added to the cardioplegic solution, did not affect heart rate, but is significantly improved the recovery of aortic flow as compared with controls (88.1% +/- 4.3 [5 mumol/L]; 83.2% +/- 8.5% [10 mumol/L]; 90.3% +/- 5.3% [50 mumol/L] compared with 55.6 +/- 4.3% [control]; p < 0.05). Administration of pinacidil during reperfusion did not further enhance the recovery of aortic flow. The dose-response curve of aortic flow to the pinacidil concentrations was flat from 5 to 50 mumol/L. However, preservation of myocardial adenosine triphosphate and calcium concentrations and mitochondrial morphology suggested that the optimal concentration of pinacidil cardioplegia is 10 mumol/L.