Hospital charges for terminal care of cancer patients dying before age 65

The aim of this study was to determine whether the prevention of stroke with perindopril treatment in stroke-prone spontaneously hypertensive rats (SHRSP) is associated with the preservation of the myogenic properties of the cerebral arteries. After weaning at 4 weeks of age, male SHRSP were fed a Japanese-style rat diet with high salt to induce stroke development. Treatment with perindopril was given by gavage every morning beginning at 6 weeks of age. There were three experimental groups: two groups treated with 4 mg.kg-1.day-1 perindopril for different durations (8 or 12 weeks) and one control group consisting of littermates given distilled water. All the control animals developed stroke and died within 14 weeks of age, and myogenic response of the middle cerebral arteries (MCA) to pressure increase was lost in these animals. In contrast, all the treated SHRSP survived during the treatment period, and myogenic response of the MCA was preserved. After withdrawal of the treatment, SHRSP treated for a longer period (12 weeks) also survived longer than those treated for a shorter period (8 weeks). The subsequent development of stroke and death following treatment withdrawal after 8 or 12 weeks of treatment was associated with the loss of pressure-dependent constriction in MCA. A longer treatment duration also increased the stiffness of the MCA, MCA from SHRSP after 12 weeks of treatment had smaller external and lumen diameters, and thicker walls than those from the 8-week treatment group. In a separate study, we found that treatment of SHRSP with 1 or 4 mg.kg-1.day-1 of perindopril for 24 weeks beginning at 6 weeks of age also protected them against death related to stroke, because these rats survived up to 43 weeks of age, when the experiment was terminated. We conclude that there is an association between the absence of myogenic response in cerebral arteries and stroke development in SHRSP. Perindopril treatment preserves the myogenic response of MCA in SHRSP and prevents the stroke development in these animals. A prolonged treatment could increase the survival of SHRSP through a remodelling of the MCA and increasing the stiffness of the cerebral arteries.     

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.     

Relationship between nifedipine sensitivity of aortae and blood pressure of stroke-prone spontaneously hypertensive rats

1. We have previously described an increased sensitivity to inhibition by nifedipine of noradrenaline-induced contractures of blood vessels in hypertension. In this study we have investigated whether changes in blood pressure (BP) change the sensitivity to nifedipine and K+ of aortic rings from normotensive (Wistar-Kyoto rats, WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were treated with: hydralazine plus hydrochlorothiazide; captopril plus hydrochlorothiazide; hydralazine plus guanethidine; or captopril alone. WKY rats were treated with deoxycorticosterone acetate (DOCA) and NaCl. Treatment commenced from 5 weeks of age and continued until 13-15 weeks. 3. The SHRSP treatments produced similar reductions in BP, and the BP of all the treated groups were significantly lower than the mean BP of untreated SHRSP (201.0 +/- 7.7 mmHg). The mean BP of the treated WKY rats (134.2 +/- 7.6 mmHg) was significantly higher than the mean BP of the untreated WKY rats (86.8 +/- 7.4 mmHg). 4. An area-under-curve (AUC) analysis of the inhibitory effects of nifedipine on responses of aortae to noradrenaline showed no differences between treated and untreated SHRSP groups (overall mean 40.6 +/- 1.9% and 43.4 +/- 3.4% inhibition of control AUC, respectively), or between DOCA-salt treated WKY and untreated WKY groups (58.8 +/- 5.9 and 64.8 +/- 2.3, respectively). Noradrenaline-induced contractures of aortae from all SHRSP groups were significantly more sensitive to inhibition by nifedipine than aortae from both WKY groups. 5. The molar concentration of agonist required to evoke 50% of the maximum response (EC50) values for potassium chloride (KCl) were significantly increased in the aortae of all treated SHRSP groups in comparison to those from untreated SHRSP (treated SHRSP groups, 15.53 +/- 0.68 mmol/L vs untreated SHRSP group, 11.36 +/- 1.10 mmol/L). The EC50 values for KCl for the aortae from the DOCA-treated WKY rats were significantly less than those from aortae of the untreated WKY (11.80 +/- 0.80 and 17.08 +/- 1.50 mmol/L, respectively). 6. We conclude that reduction (in SHRSP) or increase (in WKY) of the BP has no effect on the sensitivity of aortic smooth muscle to the inhibitory effects of nifedipine on responses to noradrenaline, suggesting that alterations in voltage-dependent Ca2+ mechanisms may be a primary phenomenon in the SHRSP. In contrast, the fact that sensitivity to KCl changes in the treated SHRSP and WKY aortae suggests such sensitivity is secondary to the BP and thus a separate phenomenon from voltage-dependent Ca2+ mechanisms.     

Canadian Association of Emergency Physicians Guidelines for the acute management of migraine headache

-The ability of endothelin receptor blockade to prevent and to treat established cerebral and renal injury was explored in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) with the endothelin receptor subtype-A antagonist A127722. SHRSP were subjected to 1% NaCl intake. The start of treatment with A127722 (35 and 70 mg. kg-1. d-1, respectively) was either synchronized with salt loading or initiated after the first observation of cerebral edema with T2-weighted magnetic resonance imaging. In untreated control animals median survival was 54 days (range, 32 to 80 days) after the start of salt loading. Early-onset A127722 treatment increased median survival to 233 days (range, 92 to 407 days; P<0.05 versus controls) with 35 mg/kg and to 124 days (range, 97 to 169 days; P<0.05 versus control) with 70 mg/kg. The development of cerebral edema was prevented, and systolic blood pressure and proteinuria were dose-dependently reduced. However, all rats in the 70-mg/kg treatment group developed hemorrhages in the basal ganglia shortly before death. Late-onset A127722 treatment failed to affect survival, systolic blood pressure, or proteinuria. Nevertheless, cerebral edema was reduced but not as well as in early-onset treatment. Development of hypertension, cerebral edema, and proteinuria was prevented in SHRSP when A127722 treatment was initiated at the start of salt-loading. However, A127722 treatment did not prolong survival in SHRSP with cerebral edema. This suggests that in SHRSP the endothelin A receptor participates actively in the development of increased blood pressure and initiation of organ damage but participates minimally in established malignant hypertension and progression of target-organ damage.     

Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.     

Effect of chronic treatment with ME3221 on blood pressure and mortality in aged stroke-prone spontaneously hypertensive rats

1. The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke-prone spontaneously hypertensive rats (SHRSP) was studied following long-term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril. 2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure. The reference drugs showed similar activity, but the antihypertensive effect of ME3221 was more potent. 3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age. 4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N-acetyl-beta-D-glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion). 5. These results indicate that ME3221 has a stable anti-hypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.     

Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors

Cyclooxygenase inhibitors may affect the hemodynamic status of patients with heart failure adversely and may also block the vasodilatory effects of angiotensin-converting enzyme (ACE) inhibitors in such patients. Relatively low doses of the cyclooxygenase inhibitor acetylsalicylic acid (ASA) are now used routinely in ischemic heart disease, the most important cause of heart failure. Therefore, we investigated the hemodynamic interaction between ASA and captopril in heart failure. In a randomized, cross-over study, 13 patients with congestive heart failure (CHF) who were already receiving maintenance treatment with an ACE inhibitor received a single dose of 25 mg captopril combined with 236 mg ASA or placebo. Peripheral blood flow was studied noninvasively by venous occlusion plethysmography of the calves. Liver blood flow was estimated from indocyanine green (ICG) clearance. Administration of captopril alone significantly decreased blood pressure (BP), and ICG clearance. Calf blood flow remained unchanged. However, after arterial occlusion, hyperemic calf blood flow persisted for longer. Captopril alone did not significantly change the plasma levels of the vasodilating prostaglandins PGI2 and PGE2 or the vasoconstricting thromboxane A2 (TXA2). In contrast, captopril combined with ASA reduced the plasma levels of these vasoactive substances, with significant decreases in PGE2 and TXA2 as compared with captopril alone, yet the hemodynamic alterations after captopril plus ASA were similar to those observed after captopril alone. A single antithrombotic dose of ASA (236 mg) in 13 patients with CHF [New York Heart Association (NYHA) class II-IV] undergoing chronic treatment with ACE inhibitors had no discernible effect on hemodynamic status.(ABSTRACT TRUNCATED AT 250 WORDS)     

Psychotherapy in suicidal youth

Thrombotic potential and hemodynamic changes were assessed in the cerebral microcirculation in normal rats (WKY), non-stroke-prone spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) at the age of 4, 16 and 32 weeks. Whole blood platelet aggregation revealed that the platelet aggregability in vitro was significantly depressed in SHRSP compared to WKY at 16 and 32 weeks using 2 microg/ml collagen but was similar or higher than WKY at 32 weeks using 20 or 40 microg/ml collagen. Platelet-rich thrombi were induced using a helium-neon (He-Ne) laser technique in vivo. The numbers of laser pulses required to induce an occlusive thrombus in arterioles were similar in the three strains at the age of 4 weeks. In contrast, the numbers of laser pulses needed to induce vascular occlusion in SHR (5.5 +/- 0.7; n = 4) and SHRSP (4.9 +/- 0.3; n = 4) were lower than in WKY (7.4 +/- 0.3; n = 5) at the age of 16 weeks. Similar differences were observed at 32 weeks (SHR 5.8 +/- 0.2; n = 6; SHRSP 4.3 +/- 0.1; n = 4; WKY 7.0 +/- 0.2; n = 7). Red blood cell velocities were measured in pial arterioles using a fiber-optic laser Doppler anemometer microscope. Red cell velocities and wall shear rates in SHR and SHRSP were significantly lower than those in WKY (p < 0.05) at the age of 16 weeks and were markedly lower in SHRSP than in either WKY or SHR at the age of 32 weeks. The plasma concentration of nitrite/nitrate determined by the Griess reaction was significantly reduced in SHRSP at 32 weeks compared with 4-week-old rats. These changes could contribute to the enhanced tendency to cerebrovascular stroke in SHRSP.     

Hemodynamic action of captopril in coronary patients with heart failure tolerant to nitroglycerin

BACKGROUND: At present there is little dispute that clinical tolerance of organic nitrates occurs during long-term treatment of patients with stable angina pectoris and congestive heart failure. HYPOTHESIS: Captopril exerts a favorable hemodynamic effect in coronary patients with heart failure who are clinically tolerant to nitroglycerin. METHODS: Development of nitrate tolerance was observed during intravenous nitroglycerin treatment (10 mg/h) in 16 of 19 patients (7 women, 12 men; mean age 56 +/- 8 years) with coronary heart disease [stenosis > or = 75%, New York Heart Association (NYHA) classes II-III). The criterion applied was a loss of efficacy of at least 50% with regard to mean pulmonary capillary wedge pressure compared with the maximum effect of nitrate. The effect of captopril (50 mg p.o.) was determined in a blank test. Captopril (50 mg p.o.) was administered again at the stage of clinically manifest nitrate tolerance. RESULTS: Compared with the effect of captopril alone, significantly more pronounced reductions in mean pulmonary capillary wedge pressure (33% compared with 27%) and in mean pulmonary arterial pressure (36% compared with 17%) and significantly greater increases in cardiac index (14% compared with 7%) and stroke work index (34% compared with 18%) (p < 0.05 in each case; Wilcoxon test for linked random samples) were measured. Maintaining nitroglycerin infusion, the effect of captopril (at least 90% of the maximum effect) lasted for 123 +/- 24 min. The baseline values (at least 75% decline in the effect of captopril) were only reached after 369 +/- 34 min. CONCLUSION: The results document a favorable hemodynamic effect of captopril in nitrate tolerance which is significantly better than that of captopril alone.     

Lhermitte-Duclos disease: first report in Taiwan

Nutritional support is important in critically ill patients, with variable energy and nitrogen requirements (e.g., sepsis, trauma, postsurgical state) in this population. This study investigates how age, severity of illness, and mechanical ventilation are related to resting energy expenditure (REE) and nitrogen balance. Nineteen critically ill children (mean age, 8 +/- 6 [SD] y and range 0.4-17.0 y) receiving total parenteral nutrition (TPN) were enrolled. We used indirect calorimetry to measure REE. Expected energy requirements (EER) were obtained from Talbot tables. Pediatric Risk of Mortality (PRISM) and Therapeutic Intervention Scoring System (TISS) score were calculated. Total urinary nitrogen was measured using the Kjeldahl method. PRISM and TISS scores were 9 +/- 5 and 31 +/- 6 points, respectively. REE was 62 +/- 25 kcal.kg-1.d-1, EER was 42 +/- 11 kcal.kg-1. d-1, and caloric intake was 49 +/- 22 kcal.kg-1.d-1. Nitrogen intake was 279 +/- 125 mg.kg-1.d-1, total urinary nitrogen was 324 +/- 133 mg.kg-1.d-1, and nitrogen balance was -120 +/- 153 mg.kg-1.d-1. The protein requirement in this population was approximately 2.8 g.kg-1.d-1. These critically ill children were hypermetabolic, with REE 48% higher (20 kcal.kg-1.d-1) than expected. Nitrogen balance significantly correlated with caloric and protein intake, urinary nitrogen, and age, but not with severity of illness scores or ventilatory parameters.     

Centralized i.v. team provides inpatient and home-care treatment

AIM: The study of the effects of the inhibitor of angiotensin converting enzyme ramipril (tritace) on the 24-h profile of blood pressure (BP) in patients with mild and moderate arterial hypertension. MATERIALS AND METHODS: Ramipril was given to 21 males aged 45-68 years with essential hypertension stage II (WHO criteria) with stable elevated diastolic blood pressure (95-114 mm Hg) in a single dose 2.5-10 mg/day. Captopril controls received 100 mg twice a day. BP was monitored using "SpaceLabs Medical" unit (model 90207, USA). RESULTS: Compared to placebo, ramipril lowered systolic and diastolic blood pressure both for the 24-h period and in the day time; captopril lowered only diastolic BP in the day time. Side effects of long-term application of ramipril occurred 2 times less frequently than in application of captopril. CONCLUSION: Long-term treatment with ramipril in the above regimen provides more effective control of BP than captopril in the above doses in patients with mild and moderate hypertension.     

Primary leiomyosarcoma of the fallopian tube

Chronic renal failure occurs in about 20% of long-term survivors treated with bone marrow transplant (BMT) regimens that include total-body irradiation (TBI); this syndrome is called BMT nephropathy. In a previous study in a syngeneic rat BMT model it was shown that captopril (an inhibitor of angiotensin-converting enzyme) could be used to treat experimental BMT nephropathy. Current studies were designed to determine whether captopril could also be used to prevent BMT nephropathy. Rats received 14 to 18.5 Gy TBI in six fractions over 3 days followed by syngeneic BMT. Seven days before TBI half the rats were started on captopril (500 mg/liter in the drinking water). Blood urea nitrogen, ratios of urine protein to creatinine, serum creatinine, and blood pressure were used to assess renal function. In animals receiving TBI alone, BMT nephropathy developed 3 to 6 months after transplant. At 6 months after TBI, captopril-treated animals had lower systolic blood pressure and better-preserved renal function than animals receiving TBI alone, with dose-modifying factors of about 1.3. The captopril treatment had no effect on bone marrow ablation by TBI. Captopril appears to be safe and effective in the prophylaxis of BMT nephropathy.     

Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice

The effect of the angiotensin-converting enzyme (ACE) inhibitor, captopril, on the development of atherosclerosis was determined in the apolipoprotein (apo) E-deficient mice. These mice develop severe hypercholesterolemia and extensive atherosclerotic lesions on chow diet, similar to those found in humans. Furthermore, in these mice, accelerated atherosclerosis is associated with increased plasma lipid peroxidation, a phenomenon that may play a crucial role in the buildup of the atherosclerotic lesions. Mice received either placebo or 50 mg/kg/day of captopril. After 12 weeks of treatment, captopril reduced the aortic-lesion area by 70% compared with that of the placebo-treated group. Captopril also increased the resistance of low-density lipoprotein (LDL) to CuSO4-induced oxidative stress, as shown by a significant reduction in the LDL content of malondialdehyde (MDA) by 30%, as well as by the prolongation of the lag time required for LDL oxidation from 55 min in the placebo-treated mice to 70 min in the captopril-treated mice, and reduction of the maximum LDL oxidation at 150 min by 35%. In vitro studies demonstrated that preincubation of LDL with captopril, inhibited the onset of CuSO4-induced LDL peroxidation up to 120 min, and reduced the LDL content of MDA by 90%. We conclude that captopril attenuates atherosclerosis in the apo E-deficient mice, and this phenomenon may be related to its inhibitory effect on the plasma LDL oxidation.     

Genetically determined chloride-sensitive hypertension and stroke

The stroke-prone spontaneously hypertensive rat (SHRSP) is a genetically determined model of "salt-sensitive" stroke and hypertension whose full phenotypic expression is said to require a diet high in Na+ and low in K+. We tested the hypothesis that dietary Cl- determines the phenotypic expression of the SHRSP. In the SHRSP fed a normal NaCl diet, supplementing dietary K+ with KCl exacerbated hypertension, whereas supplementing either KHCO3 or potassium citrate (KB/C) attenuated hypertension, when blood pressure (BP) was measured radiotelemetrically, directly and continually. Supplemental KCl, but not KB/C, induced strokes, which occurred in all and only those rats in the highest quartiles of both BP and plasma renin activity (PRA). PRA was higher with KCl than with KB/C. These observations demonstrate that with respect to both severity of hypertension and frequency of stroke the phenotypic expression of the SHRSP is (i) either increased or decreased, depending on whether the anionic component of the potassium salt supplemented is, or is not, Cl-; (ii) increased by supplementing Cl- without supplementing Na+, and despite supplementing K+; and hence (iii) both selectively Cl--sensitive and Cl--determined. The observations suggest that in the SHRSP selectively supplemented with Cl- the likelihood of stroke depends on the extent to which both BP and PRA increase.     

Influence of benazepril and captopril on blood pressure, glucocorticoids and progesterone in essential hypertensives

The antihypertensive activity and the influence of adrenal cortex hormones of benazepril versus captopril were studied in 30 essential hypertensives in a double-blind, randomised, placebo-controlled trial during eight weeks of treatment. Patients started with 50 mg of captopril or 10 mg of benazepril once daily; if normotension had not been obtained after four weeks of treatment the doses were increased to 50 mg twice daily or 20 mg once daily, respectively. 11-Oxycorticosteroids and progesterone in males were measured in blood and daily urine at baseline and at the 4th and the 15th days of drug administration, as well as aldosterone in daily urine by radioimmunoassay, and compared with these data in 15 healthy subjects. Following eight weeks of treatment in 64% and 56% of patients treated with benazepril and captopril respectively, blood pressure was normalised. In the corresponding remaining 14% and 13%, diastolic blood pressure decreased by 10 mmHg and more but not below 90 mmHg. Before treatment excretion of 11-oxycorticosteroids, progesterone and aldosterone was significantly increased without changes in blood levels. After two weeks of treatment 11-oxycorticosteroids and aldosterone excretion decreased (P < 0.05) without progesterone changes, benazepril treatment being more effective in decreasing 11-oxycorticosteroids levels in blood (P < 0.05). In patients with high pretreatment levels of 11-oxycorticosteroids in urine we have noticed the highest antihypertensive effect of both drugs. The main conclusions are that both the ACE inhibitors are effective in mild to moderate essential hypertensives and might decrease glucocorticoids in urine and blood.     

Captopril and spironolactone therapy for refractory congestive heart failure

Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. Captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril (or another ACE inhibitor) and high doses of loop diuretics, provided renal function is adequate.     

Comparative catabolism of prothrombin and antithrombin in normal and alloxan-diabetic rabbits

Previous studies have shown that alloxan-induced diabetes in rabbits effects a slower release of plasma proteins from the liver, a slower synthesis of 35S-glycosaminoglycan in the extracellular matrix of the arterial wall, and a concurrent reduction in the fractional catabolic rates of several plasma proteins. In the present study, the catabolism of two hemostatic proteins, prothrombin and antithrombin, are compared in alloxan-induced diabetic rabbits (of 6 months' duration) and age-matched control rabbits. Differentially radiolabeled prothrombin and antithrombin were injected intravenously, and arterial blood was sampled over a 7-day period to measure the clearance from plasma. A three-compartment model was used to determine the fractional catabolic rate and compartmental distribution of the two proteins. As observed for other plasma proteins, the whole-body fractional catabolic rates (jt) for prothrombin and antithrombin were significantly less in diabetic rabbits (prothrombin, 0.33 d-1; antithrombin, 0.27 d-1) than in control rabbits (prothrombin, 0.37 d-1; antithrombin, 0.30 d-1; P < .001 and P < .005, respectively). In absolute terms, the catabolism of antithrombin and prothrombin in diabetic rabbits was 5.1 and 6.2 mg.kg-1.d-1, respectively, equivalent to a molar ratio for antithrombin to prothrombin of 0.94. For the control rabbits, catabolism accounted for 6.3 mg.kg-1.d-1 of antithrombin and 7.3 mg.kg-1.d-1 of prothrombin, equivalent to a molar ratio of 1.01. The fractional distribution of these proteins was not significantly different within the intravascular and extravascular spaces in diabetic and control rabbits. The decreased catabolic rates observed for prothrombin and antithrombin in diabetic rabbits conform with results obtained previously for other plasma proteins, and probably reflect a generally decreased rate of plasma protein production by diabetic rabbit liver compared with control liver.     

Endothelial dysfunction in spontaneously hypertensive rats: consequences of chronic treatment with losartan or captopril

BACKGROUND: Hypertension is associated with endothelial dysfunction characterized by decreased endothelium-dependent relaxations and increased endothelium-dependent contractions. Angiotensin converting enzyme inhibitors and thromboxane A2 receptor antagonists decreased the endothelium dysfunction in hypertensive animals. OBJECTIVE: To investigate the effects of prolonged treatment with losartan on endothelium-dependent and -independent relaxations and contractions in aortic rings from spontaneously hypertensive rats (SHR). MATERIAL AND METHODS: Male SHR aged 16 weeks were treated for 12 consecutive weeks either with 10 mg/kg losartan per day or with 60 mg/kg captopril per day administered via their drinking water. The systolic blood pressure was evaluated basally and during week 12. At the end of the treatment period, the vascular reactivity in aortic rings was studies. A group of rats treated with captopril was studies as a reference group. RESULTS: Losartan and captopril reduced the blood pressure significantly and comparably. Both drugs enhanced acetylcholine-induced relaxations and reduced the maximal contractile response to acetylcholine in the presence of NG-nitro-L arginine methyl ester (L-NAME). Contractile responses to phenylephrine, endothelin-l and U46619 were not affected by these treatments. Increased relaxing responses to superoxide dismutase were observed only in captopril-treated rats. Losartan reduced the contractile response to angiotensin II. By contrast this contractile response was elevated in rats treated with captopril. CONCLUSIONS: Prolonged antihypertensive treatments with losartan and captopril decreased the endothelial dysfunction in aortic rings from SHR not only by enhancing NO-dependent relaxations but also by reducing the contractions in response to an endothelium-derived contracting factor. The results further confirm that an endothelium-derived contracting factor plays a role in vascular dysfunction in SHR and the relationships between this factor and angiotensin II.     

Drinking water turbidity and pediatric hospital use for gastrointestinal illness in Philadelphia

We measured nitrogen and energy requirements in adult North American porcupines (Erethizon dorsatum) fed three experimental diets differing primarily in crude protein content. Porcupines ingested 497.3-865.4 kJ kg-0.75 d-1, and there was no significant loss of body mass on any dietary treatment. Individuals maintained nitrogen balance on a total nitrogen intake of 389.4 mg N kg-0.75 d-1. The true digestibility of nitrogen was high (88%) but within the range for eutherians. We found metabolic fecal nitrogen to be 0.92 mg N g-1 dry matter intake and endogenous urinary nitrogen to be 223 mg N kg-0.75 d-1. The low value of metabolic fecal nitrogen found for porcupines affects the dry matter intake required for nitrogen balance, and it may allow these animals to exploit nitrogen-poor diets.     

Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat

BACKGROUND: After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density. The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure. METHODS AND RESULTS: Seven days after coronary ligation (MI), rats were randomized to enalapril (n = 8; 500 micrograms.kg-1.d-1), losartan (n = 9; 3 mg.kg-1.d-1), or placebo (n = 8) and treated for 6 weeks. Sham-operated rats (n = 10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg.kg-1.min-1 over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg.mL-1.min-1.g-1, all P < .05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol.mg protein-1.min-1, P < .05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol.mg protein-1.min-1, P < .05 versus MI-placebo). CONCLUSIONS: The present study demonstrates that both chronic ACE inhibition and AT1 receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV. These results suggest that inhibition of generation of angiotensin II and AT1 receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction.