Effect of Flu Vaccination on Severity and Outcome of Heart Failure Decompensations.

OBJECTIVE: To investigate the relationship of seasonal flu vaccination with the severity of decompensation and long-term outcomes of patients with heart failure (HF). METHODS: We analyzed 6147 consecutively enrolled patients with decompensated HF who presented to 33 Spanish emergency departments (EDs) during January and February of 2018 and 2019, grouped according to seasonal flu vaccination status. The severity of HF decompensation was assessed by the Multiple Estimation of Risk Based on the Emergency Department Spanish Score in Patients With Acute Heart Failure (MEESSI-AHF) + MEESSI scale, need of hospitalization and in-hospital all-cause mortality. The long-term outcomes analyzed were 90-day postdischarge adverse events and 90-day all-cause death. Associations between vaccination, HF decompensation severity and long-term outcomes were explored by unadjusted and adjusted logistic and Cox regressions by using 14 covariables that could act as potential confounders. RESULTS: Overall median (IQR) age was 84 (IQR = 77-89) years, and 56% were women. Vaccinated patients (n = 1139; 19%) were older, had more comorbidities and had worse baseline status, as assessed by New York Heart Association class and Barthel index, than did unvaccinated patients (n = 5008; 81%). Infection triggering decompensation was more common in vaccinated patients (50% vs 41%; P < 0.001). In vaccinated and unvaccinated patients, high or very-high risk decompensation was seen in 21.9% and 21.1%; hospitalization occurred in 72.5% and 73.7%; in-hospital mortality was 7.4% and 7.0%; 90-day postdischarge adverse events were 57.4% and 53.2%; and the 90-day mortality rate was 15.8% and 16.6%, respectively, with no significant differences between cohorts. After adjusting, vaccinated decompensated patients with HF had decreased odds for hospitalization (OR = 0.823, 95%CI = 0.709-0.955). CONCLUSION: In patients with HF, seasonal flu vaccination is associated with less severe decompensations.

Frequency, profile and results of patients with acute heart failure transferred directly to home hospitalisation from emergency departments. / Frecuencia, perfil y resultados de los pacientes con insuficiencia cardiaca aguda que ingresan directamente en hospitalización a domicilio desde urgencias.

OBJECTIVE: To describe the frequency, clinical characteristics and outcomes of patients with acute heart failure (AHF) transferred directly from emergency departments to home hospitalisation (HH) and to compare them with those hospitalised in internal medicine (IM) or short-stay units (SSU). METHOD: We included patients with AHF transferred to HH by hospitals that considered this option during the Epidemiology of Acute Heart Failure in Spanish Emergency Departments (EAHFE) 4-5-6 Registries and compared them with patients admitted to IM or SSU in these centres. We compared the adjusted all-cause mortality at 1 year and adverse events 30 days after discharge. RESULTS: The study included 1473 patients (HH/IM/SSU: 68/979/384). The HH rate was 4.7% (95% CI, 3.8-6.0%). The patients in HH had few differences compared with those hospitalised in IM and SSUs. The HH mortality was 1.5%, and the HH median stay was 7.5 days (IQR, 4.5-12), similar to that of IM (median stay, 8 days; IQR, 5-13; p=.106) and longer than that of SSU (median stay, 4 days; IQR, 3-7; p<.001). The all-cause mortality at 1 year for HH did not differ from that of IM (HR, 0.91; 95% CI, 0.73-1.14) or SSU (HR, 0.77; 95% CI, 0.46-1.27); however, the emergency department readmission rate during the 30 days postdischarge was lower than that of IM (HR, 0.50; 95% CI, 0.25-0.97) and SSU (HR, 0.37; 95% CI, 0.19-0.74). There were no differences in the need for new hospitalisations or in the 30-day mortality rate. CONCLUSIONS: Direct transfer from the emergency department to HH is infrequent despite being a safe option for a certain patient profile with AHF.

Comparative analysis of the outcomes of elective abdominal aortic aneurysm repair in England and Sweden.

BACKGROUND: There is substantial international variation in mortality after abdominal aortic aneurysm (AAA) repair; many non-operative factors influence risk-adjusted outcomes. This study compared 90-day and 5-year mortality for patients undergoing elective AAA repair in England and Sweden. METHODS: Patients were identified from English Hospital Episode Statistics and the Swedish Vascular Registry between 2003 and 2012. Ninety-day mortality and 5-year survival were compared after adjustment for age and sex. Separate within-country analyses were performed to examine the impact of co-morbidity, hospital teaching status and hospital annual caseload. RESULTS: The study included 36 249 patients who had AAA treatment in England, with a median age of 74 (i.q.r. 69-79) years, of whom 87·2 per cent were men. There were 7806 patients treated for AAA in Sweden, with a median of age 73 (68-78) years, of whom 82·9 per cent were men. Ninety-day mortality rates were poorer in England than in Sweden (5·0 versus 3·9 per cent respectively; P < 0·001), but were not significantly different after 2007. Five-year survival was poorer in England (70·5 versus 72·8 per cent; P < 0·001). Use of EVAR was initially lower in England, but surpassed that in Sweden after 2010. In both countries, poor outcome was associated with increased age. In England, institutions with higher operative annual volume had lower mortality rates. CONCLUSION: Mortality for elective AAA repair was initially poorer in England than Sweden, but improved over time alongside greater uptake of EVAR, and now there is no difference. Centres performing a greater proportion of EVAR procedures achieved better results in England.

Early experience with a split-bolus single-pass CT protocol in paediatric trauma.

AIM: To determine the adequacy of the split-bolus computed tomography (CT) technique in terms of vascular enhancement and solid-organ injury assessment in paediatric trauma. MATERIALS AND METHODS: A retrospective review was undertaken of all split-bolus trauma CT examinations performed in patients <16 years during the period from 1 January 2015 to 31 January 2016. Twelve examinations were performed in this time on patients with an age range of 2-15 years (mean 10.8) consisting of eight male and four female patients. Abdominal aortic and portal vein attenuation were measured using a region of interest tool. RESULTS: The mean aortic attenuation was 267 HU and mean portal vein attenuation was 203 HU. Five cases of solid-organ injury were detected and the image quality was sufficient to grade the injury and guide clinical management in all cases. DISCUSSION: Although the cohort is relatively small, good arterial and portal venous enhancement were achieved in all but one patient, where there was suboptimal portal venous opacification; however, there were no other patients in the same weight group making it difficult to determine whether this was a systematic problem or due to patient factors. Overall, these findings have reassured us locally that the current protocol should continue to be used, but the performance of the protocol will be audited continually.

Fat-free mass loss generated with weight loss in overweight and obese adults: What may we expect?

There is concern that intentional weight loss may generate excessive loss of fat-free mass (FFM). Idealists target minimal loss of FFM, while others consider that FFM loss of up to 25% of weight loss is acceptable. In a cross-sectional study of 275 weight-stable, overweight or obese adults, we used whole-body dual-energy X-ray absorptiometry to measure FFM. A range of models was used to estimate the expected ΔFFM/Δweight ratio required to attain the body composition of a weight-stable individual at a lower body mass index (BMI). Higher BMI was associated linearly with higher FFM in men and women. Proportional ΔFFM/Δweight was influenced by sex, BMI and age. Direct scatter plot analysis, quadratic curve fit modelling and linear FFM-BMI modelling provided similar estimates for each model of ΔFFM/Δweight ratio, with 40% for men and 33% for women. These results show that the 25% rule is inappropriate and our estimates are higher than those generally reported after intentional weight loss indicating favourable preservation of FFM.

The effects of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects.

AIM: Insulin resistance and visceral adiposity are predisposing factors for fatty liver disease. The main objectives of this study were (i) to compare the effects of caloric restriction (CR) alone or together with moderate-intensity aerobic exercise training (CR+EX) on liver enzymes, a surrogate marker of liver injury, in obese metabolic syndrome (MetS) subjects and (ii) to identify anthropometric, metabolic, cardiovascular and dietary predictors of changes in liver enzymes. METHODS: Sedentary men and women (n = 63), aged 55 ± 6 (s.d.) years with body mass index 32.7 ± 4.1 kg/m(2) and confirmed MetS, were randomized to 12-week CR, CR+EX or no treatment (Control). RESULTS: Weight loss averaged 7.6% in the CR and 9.1% in the CR+EX group (time effect, p < 0.001; group effect, p = 0.11); insulin sensitivity improved by 49 and 45%, respectively (both p < 0.001). Fitness (maximal oxygen consumption) increased by 19% in the CR+EX group only (p < 0.001). Alanine aminotransferase (ALT) levels decreased by 20% in the CR and 24% in the CR+EX group (time effect, both p < 0.001; group effect, p = 0.68); corresponding values for γ-glutamyltransferase (GGT) were -28 and -33%, respectively (time effect, both p < 0.001; group effect, p = 0.28). Reduction in abdominal fat mass (measured by DXA from L1 to L4) independently predicted ΔALT (r = 0.42, p = 0.005) and ΔGGT (r = 0.55, p < 0.001), whereas change in dietary saturated fat intake was independently associated with ΔALT (r = 0.35, p = 0.03). CONCLUSIONS: Reductions in central adiposity and saturated fat intake are key drivers of improvement in liver enzymes during lifestyle interventions. Exercise training did not confer significant incremental benefits in this study.

Evaluation of the HEFESTOS scale to predict outcomes in emergency department acute heart failure patients.

The HEFESTOS scale was developed in 14 Spanish primary care centres and validated in 9 primary care centres of other European countries. It showed good performance to predict death/hospitalisation during the first 30 days after an episode of acute heart failure (AHF), with c-statistics of 0.807/0.730 in the derivation/validation cohorts. We evaluated this scale in the emergency department (ED) setting, comparing it to the EHMRG and MEESSI scales in the ED and the EFFECT and GWTG scales in hospitalised patients, to predict 30-day outcomes, including death and hospitalisation. Consecutive AHF patients were enrolled in 34 Spanish EDs in January-February 2016, 2018, and 2019 with variables needed to calculate outcome scores. Thirty-day hospitalisation/death (together and separately) and post-discharge combined adverse event (ED revisit or hospitalisation for AHF or all-cause death) were determined for patients discharged home after ED care. Predictive capacity was assessed by c-statistic with 95% confidence intervals. Of 10,869 patients, 4,044 were included (median age: 83 years, 54% women). The performance of HEFESTOS was modest for 30-day hospitalisation/death, c-statistic=0.656 (0.637-0.675), hospitalisation, 0.650 (0.631-0.669), and death, 0.610 (0.576-0.644). Of 1,034 patients with scores for the 5 scales, HEFESTOS had the numerically highest c-statistic for hospitalisation/death at 30 days, 0.666 (0.627-0.704), vs. MEESSI= 0.650 (0.612-0.687, p=0.51), EFFECT=0.633 (0.595-0.672, p=0.21), GWTG=0.618 (0.578-0.657, p=0.06) and EHMRG=0.617 (0.577-0.704, p=0.07). Similar modest performances were observed for predicting hospitalisation [ranging from HEFESTOS=0.656 (0.618-0.695) to GWTG=0.603 (0.564-0.643)]. Conversely, prediction of 30-day death was good with the MEESSI=0.787 (0.728-845), EFFECT=0.754 (0.691-0.818) and GWTG=0.749 (0.689-0.809) scales, and modest with EHMRG=0.649 (0.581-0.717) and HEFESTOS=0.610 (0.538-0.683). Although the HEFESTOS scale was numerically better for predicting 30-day hospitalisation/death in ED AHF patients, its modest performance precludes routine use. Only 30-day mortality was adequately predicted by some scales, with the MEESSI achieving the best results.

Ambient temperature and atmospheric pressure at discharge as precipitating factors in immediate adverse events in patients treated for decompensated heart failure.

To investigate the relationship of ambient temperature and atmospheric pressure (AP) at patient discharge after an episode of acute heart failure (AHF) with very early post-discharge adverse outcomes. We analyzed 14,656 patients discharged after an AHF episode from 26 hospitals in 16 Spanish cities. The primary outcome was the 7-day post-discharge combined adverse event (emergency department -ED- revisit or hospitalization due to AHF, or all-cause death), and secondary outcomes were these three adverse events considered individually. Associations (adjusted for patient and demographic conditions, and length of stay -LOS- during the AHF index episode) of temperature and AP with the primary and secondary outcomes were investigated. We used restricted cubic splines to model the continuous non-linear association of temperature and AP with each endpoint. Some sensitivity analyses were performed. Patients were discharged after a median LOS of 5 days (IQR = 1-10). The highest temperature at discharge ranged from - 2 to 41.6 °C, and AP was from 892 to 1037 hPa. The 7-day post-discharge combined event occurred in 1242 patients (8.4%), with percentages of 7-day ED-revisit, hospitalization and death of 7.8%, 5.1% and 0.9%, respectively. We found no association between the maximal temperature and AP on the day of discharge and the primary or secondary outcomes. Similarly, there were no significant associations when the analyses were restricted to hospitalized patients (median LOS = 7 days, IQR = 4-11) during the index event, or when lag-1, lag-2 or the mean of the 3 post-discharge days (instead of point estimation) of ambient temperature and AP were considered. Temperature and AP on the day of patient discharge are not independently associated with the risk of very early adverse events during the vulnerable post-discharge period in patients discharged after an AHF episode.

Frequency, profile, and outcomes of patients with acute heart failure transferred directly to home hospitalization from emergency departments.

OBJECTIVE: To describe the frequency, clinical characteristics and outcomes of patients with acute heart failure (AHF) transferred directly from emergency departments to home hospitalisation (HH) and to compare them with those hospitalised in internal medicine (IM) or short-stay units (SSU). METHOD: We included patients with AHF transferred to HH by hospitals that considered this option during the Epidemiology of Acute Heart Failure in Spanish Emergency Departments (EAHFE) 4-5-6 Registries and compared them with patients admitted to IM or SSU in these centres. We compared the adjusted all-cause mortality at 1 year and adverse events 30 days after discharge. RESULTS: The study included 1473 patients (HH/IM/SSU:68/979/384). The HH rate was 4.7% (95% CI 3.8-6.0%). The patients in HH had few differences compared with those hospitalised in IM and SSUs. The HH mortality was 1.5%, and the HH median stay was 7.5 days (IQR, 4.5-12), similar to that of IM (median stay, 8 days; IQR, 5-13; p = .106) and longer than that of SSU (median stay, 4 days; IQR, 3-7; p < .001). The all-cause mortality at 1 year for HH did not differ from that of IM (HR, 0.91; 95% CI 0.73-1.14) or SSU (HR, 0.77; 95% CI 0.46-1.27); however, the emergency department readmission rate during the 30 days postdischarge was lower than that of IM (HR, 0.50; 95% CI 0.25-0.97) and SSU (HR, 0.37; 95% CI 0.19-0.74). There were no differences in the need for new hospitalisations or in the 30-day mortality rate. CONCLUSIONS: Direct transfer from the emergency department to HH is infrequent despite being a safe option for a certain patient profile with AHF.

Expanding the Distinctive Neuroimaging Phenotype of ACTA2 Mutations.

BACKGROUND AND PURPOSE: Arg179His mutations in ACTA2 are associated with a distinctive neurovascular phenotype characterized by a straight course of intracranial arteries, absent basal Moyamoya collaterals, dilation of the proximal internal carotid arteries, and occlusive disease of the terminal internal carotid arteries. We now add to the distinctive neuroimaging features in these patients by describing their unique constellation of brain malformative findings that could flag the diagnosis in cases in which targeted cerebrovascular imaging has not been performed. MATERIALS AND METHODS: Neuroimaging studies from 13 patients with heterozygous Arg179His mutations in ACTA2 and 1 patient with pathognomonic clinicoradiologic findings for ACTA2 mutation were retrospectively reviewed. The presence and localization of brain malformations and other abnormal brain MR imaging findings are reported. RESULTS: Characteristics bending and hypoplasia of the anterior corpus callosum, apparent absence of the anterior gyrus cinguli, and radial frontal gyration were present in 100% of the patients; flattening of the pons on the midline and multiple indentations in the lateral surface of the pons were demonstrated in 93% of the patients; and apparent "squeezing" of the cerebral peduncles in 85% of the patients. CONCLUSIONS: Because α-actin is not expressed in the brain parenchyma, only in vascular tissue, we speculate that rather than a true malformative process, these findings represent a deformation of the brain during development related to the mechanical interaction with rigid arteries during the embryogenesis.

Blockade of AT1 receptors by losartan did not affect renin gene expression in kidney medulla.

This study was designed to determine particular changes in the renin gene expression and activity in renal cortex and medulla after AT(1) receptor blockade. It was found that two-week-treatment with AT(1) blocker losartan induced an increase in tissue renin activity in both parts of kidney causing subsequent elevation of plasma renin activity. Renin mRNA in losartan-treated rats was increased only in cortex, suggesting cortex origin of elevated renin activity in medulla. Medullary renin mRNA indicated local synthesis of renin within the whole kidney and supported the idea of the presence of tissue renin-angiotensin system. Our results show that gene expression of renin in kidney medulla is insensitive to AT(1) receptor blockade and this points out that the regulation of kidney renin-angiotensin system probably differs from that in cortex.

Norepinephrine transporter expression is inversely associated with glycaemic indices: a pilot study in metabolically diverse persons with overweight and obesity.

OBJECTIVE: The objective of this study was to examine the cross-sectional relationship between the expression of norepinephrine transporter (NET), the protein responsible for neuronal uptake-1, and indices of glycaemia and hyperinsulinaemia, in overweight and obese individuals. METHODS: Thirteen non-medicated, non-smoking subjects, aged 58 ± 1 years (mean ± standard error of the mean), body mass index (BMI) 31.4 ± 1.0 kg m-2, with wide-ranging plasma glucose and haemoglobin A1c (HbA1c, range 5.1% to 6.5%) participated. They underwent forearm vein biopsy to access sympathetic nerves for the quantification of NET by Western blot, oral glucose tolerance test (OGTT), euglycaemic hyperinsulinaemic clamp, echocardiography and assessments of whole-body norepinephrine kinetics and muscle sympathetic nerve activity. RESULTS: Norepinephrine transporter expression was inversely associated with fasting plasma glucose (r = -0.62, P = 0.02), glucose area under the curve during OGTT (AUC0-120, r = -0.65, P = 0.02) and HbA1c (r = -0.67, P = 0.01), and positively associated with steady-state glucose utilization during euglycaemic clamp (r = 0.58, P = 0.04). Moreover, NET expression was inversely related to left ventricular posterior wall dimensions (r = -0.64, P = 0.02) and heart rate (r = -0.55, P = 0.05). Indices of hyperinsulinaemia were not associated with NET expression. In stepwise linear regression analysis adjusted for age, body mass index and blood pressure, HbA1c was an independent inverse predictor of NET expression, explaining 45% of its variance. CONCLUSIONS: Hyperglycaemia is associated with reduced peripheral NET expression. Further studies are required to identify the direction of causality.

In vitro tissue potencies of converting enzyme inhibitors. Prodrug activation by kidney esterase.

The inhibition of angiotensin converting enzyme by ramipril, ramiprilat, enalapril, enalaprilat, and captopril was studied in the plasma and various tissues (lung, heart, renal cortex, renal medulla) of normotensive rats and spontaneously hypertensive rats. Displacement curves for [3H]ramiprilat were established on each tissue with the converting enzyme inhibitors, and their potencies were expressed as the concentration that inhibited 50% of the specific [3H]ramiprilat binding. In the plasma, lung, and heart, the order of activities was: ramiprilat greater than enalaprilat greater than captopril greater than ramipril greater than enalapril. This order was different in the kidney (cortex and medulla): ramiprilat greater than enalaprilat greater than ramipril greater than captopril greater than enalapril. For ramiprilat, enalaprilat, and captopril, there were no differences in their respective potencies between tissues or between rat strains. However, the two prodrugs ramipril and enalapril were 10-30 times more active in the kidney than in the other tissues in both groups of rats. This was due to the deesterification of the prodrugs: in the presence of an esterase inhibitor (diethyl nitrophenyl phosphate, 10 microM), the potencies of ramipril in the kidney were not different from that obtained in the lung, which was not affected by the presence of the esterase inhibitor. These results suggest that the variations in the tissue activities of an angiotensin converting enzyme inhibitor are probably not due to differences in tissue affinities of the angiotensin converting enzyme inhibitor but depend on the concentration of this angiotensin converting enzyme inhibitor in each tissue.

Brain mineralocorticoid receptor control of blood pressure and kidney function in normotensive rats.

Brain mineralocorticoid receptors appear to contribute to mineralocorticoid hypertension and may be involved in blood pressure control in normotensive rats. We examined the effect of blockade of central mineralocorticoid receptors with the use of a selective antagonist (RU28318) on cardiovascular and renal function in conscious normotensive rats. The contribution of renal innervation was evaluated in rats with bilaterally denervated kidneys. Young adult, male Wistar rats were trained for systolic blood pressure measurement by a tail sphygmographic method and accustomed to metabolic cages for collection of urine. One week before experimentation, an intracerebroventricular cannula was implanted. Systolic blood pressure was diminished 30 minutes after an intracerebroventricular dose of 10 ng of RU28318. The effect was maximal at 8 hours and was still present after 24 hours. Blood pressure returned to the basal level by 48 hours. During the period 0 to 8 hours after intracerebroventricular injection, rats treated with the antagonist showed an increase in diuresis and urinary electrolyte excretion. No significant effect on plasma renin activity, measured 8 and 30 hours after administration of RU28318, was observed. In denervated rats, the decrease in systolic blood pressure after administration of RU28318 was reduced. The difference was statistically significant compared with controls at 2 hours but not at 8 hours, and blood pressure returned to the basal value by 24 hours. The increases in diuresis and urinary electrolyte excretion induced by RU28318 were abolished in denervated rats. These results show that brain mineralocorticoid receptors are involved in blood pressure regulation and kidney function homeostasis in conscious normotensive rats. The renal nerves appear to participate in the brain mineralocorticoid receptor control of blood pressure.

Angiotensin converting enzyme variability in hypertensive and normotensive rats.

Recent data have revealed biological and genetic variability in normotensive Wistar-Kyoto rats, which are considered to be the most appropriate control strain for spontaneously hypertensive rats. To investigate the possibility that angiotensin converting enzyme activity could be affected by this variability, we measured plasma and tissue (lung, heart, renal cortex, renal medulla, and adrenal gland) angiotensin converting enzyme activity in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats from three commercial suppliers in France: Iffa-Credo, Janvier, and Charles River Laboratories. Angiotensin converting enzyme activity was measured in vitro with a fluorometric assay using carbobenzoxy-Phe-His-Leu as substrate. Angiotensin converting enzyme activity in both rat strains varied considerably from one supplier to another, and therefore, comparisons of spontaneously hypertensive rats and Wistar-Kyoto rats from the different suppliers produced conflicting results. For Wistar-Kyoto rats, angiotensin converting enzyme activity in the plasma, heart, kidney, and adrenal glands was highest in rats from Iffa-Credo and lowest in rats from Charles River. For spontaneously hypertensive rats, angiotensin converting enzyme activity in the plasma and tissues was highest in rats from Janvier, whereas no difference could be observed between rats from Iffa-Credo and Charles River. These data confirm the problem of how to interpret and compare studies that use spontaneously hypertensive and Wistar-Kyoto rat strains.

Plasma renin activity and changes in tissue angiotensin converting enzyme.

OBJECTIVES: Recent evidence suggests that tissue generation of angiotensins I and II depends on the level of the plasma components of the renin-angiotensin system and on tissue-specific processes. The present study was undertaken to clarify the possible relationship between plasma renin activity (PRA) and tissue angiotensin converting enzyme (ACE) activity in the heart, lung, kidney cortex and kidney medulla of Wistar-Kyoto rats. In the kidney cortex particular attention was focused on renal brush-border ACE. METHODS: Different experimental models known to have opposite effects on PRA were used: changes in salt intake, deoxycorticosterone acetate (DOCA) with or without salt supplements, and the Goldblatt two-kidney, one clip (2-K,1C) model. Two weeks after the start of the experiments the rats were killed, and PRA, and plasma and tissue ACE activity, were measured. RESULTS: At the end of the study the blood pressure in the treated rats was not significantly different from control. As expected, the PRA were highest in the 2-K,1C and depleted-salt groups and lowest in the DOCA, DOCA-salt and high-salt groups. ACE responses were different in different types of tissue, with no relationship between PRA and plasma or tissue ACE activity. For example, DOCA treatment led to increased ACE activity in the heart and the kidney only if the rats were maintained on a high salt intake. DOCA or salt alone failed to have this effect. In the 2-K,1C model the unclipped kidneys did not show any significant variation in ACE activity, but the clipped kidneys exhibited increased ACE activity compared with sham-operated rats. This increase, coupled with increased renal renin secretion, could play a role in the acceleration of local angiotensin II formation, and could thus initiate and sustain the development of hypertension in this model. CONCLUSION: The present results show that variations in ACE activity were organ-specific and were not linked either to hypertension or to changes in PRA.

Age-related variations in tissue angiotensin converting enzyme activities: comparison between spontaneously hypertensive and Wistar-Kyoto rats.

Angiotensin converting enzyme (ACE) activity was measured by fluorimetry in the plasma, lung, heart, aorta and kidney (cortex and medulla) of 3-, 5-, 8- and 11-week-old spontaneously hypertensive rats (SHR) and compared with that of age-matched Wistar-Kyoto rats (WKY). In the plasma, lung and kidney (cortex and medulla), ACE activity was lower in SHR than in WKY. This was evident as early as the age of 3 weeks. In contrast, there were no differences between SHR and WKY in the aorta and the heart. Age-related variations in ACE activities differed in each tissue and in both groups of rats, but no major modifications were correlated with the development of hypertension. A binding assay was performed with [3H]ramiprilat; affinity (KD) and the maximum number of binding sites (Bmax) were determined in plasma and tissues of 3-week-old SHR and WKY. The KD values were identical in the two groups but Bmax was lower in all SHR tissues except in the heart; these results might be related to the decrease in ACE activity. Our results probably reflect genetic differences in ACE activity between SHR and WKY, and suggest that ACE regulatory mechanisms act differently in each tissue.

Ramipril-induced decrease in renal lithium excretion in the rat.

1. The interaction of ramipril, an inhibitor of angiotensin I converting enzyme, with renal lithium handling was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with ramipril (1 mg kg-1 day-1 orally), indomethacin (2.5 mg kg-1 day-1 intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1 intraperitonealy) was given as a single dose on the fifth day and renal functions were measured. 3. Ramipril induced a decrease in renal lithium clearance which was correlated with the decrease in the quantity of filtered lithium and the increase in the tubular fractional reabsorption of the metal. Ramipril also reduced the systolic blood pressure of the rats by about 15 mmHg. 4. In the absence of any effect on creatinine clearance or systolic blood pressure, indomethacin increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels, as previously reported by our group. 5. In conclusions, our results indicate that ramipril decreases renal lithium excretion in Wistar rats, when given orally at a dose of 1 mg kg-1 day-1 over five days.

Anti-anginal arylalkylamines and sodium channels: [3H]-batrachotoxinin-A 20-alpha-benzoate and [3H]-tetracaine binding.

[3H]-batrachotoxinin-A 20-alpha-benzoate ([3H]-BTX-B) and [3H]-tetracaine are useful ligands for the study of sodium channels. Inhibition of their binding by various anti-anginal drugs was tested on a rat synaptosomal preparation and on a heart membrane preparation. Diphenylalkylamines and structurally related drugs inhibited [3H]-BTX-B binding in both the synaptosomal preparation and heart membrane preparation. They were almost inactive on [3H]-tetracaine binding. These results suggest that activity of arylalkylamines could be mediated by an interaction on the sodium channel.

[3H]-tetracaine binding on rat synaptosomes and sodium channels.

[3H]-tetracaine binding was studied in a rat synaptosomal preparation. [3H]-tetracaine bound to a single class of binding sites with a mean KD of 188 +/- 28 nM and a mean maximal binding capacity of 13 +/- 0.7 pmol mg-1 protein. [3H]-tetracaine binding was inhibited by tetracaine, procaine and by beta-adrenoceptor blocking agents which possess local anaesthetic properties. [3H]-tetracaine binding was not modified by neurotoxins interacting specifically with the sodium channels.