Blood pressure response to central and/or peripheral inhibition of phenylethanolamine N-methyltransferase in normotensive and hypertensive rats

We studied the effects on blood pressure and heart rate of two different phenylethanolamine N-methyltransferase (PNMT) inhibitors in normotensive, in two-kidney renal hypertensive, and in deoxycorticosterone-salt (DOC-salt) hypertensive rats. One compound (SK&F 64139) blocks the conversion of norepinephrine to epinephrine in both the central and the peripheral nervous system, whereas the other (SK&F 29661) does not cross the blood-brain barrier and therefore is active mostly in the adrenal glands. In the rats given SK&F 29661, practically no acute blood pressure changes were in the adrenal glands. In the rats given SK&F 64139 induced only a minor blood pressure and heart rate response in normotensive and two-kidney renal hypertensive rats. However, in DOC-salt hypertensive rats, it reduced arterial pressure to approximately normal levels and concomitantly slowed pulse rate. There was a close correlation between the magnitude of the blood pressure response observed in all SK&F 64139-treated animals and the control plasma norepinephrine (4 = -0.795, P less than 0.001) and epinephrine (r = -0.789, P less than 0.001) levels. These results suggest an important role for central epinephrine in regulating the peripheral sympathoadrenomedullary and the baroreceptor reflex activity, particularly when the maintenance of the high blood pressure is not renin-dependent.

Predictors of red blood cell transfusion after cardiac surgery: a prospective cohort study

Abstract OBJECTIVE To identify predictors of red blood cell transfusion (RBCT) after cardiac surgery. METHOD A prospective cohort study performed with 323 adults after cardiac surgery, from April to December of 2013. A data collection instrument was constructed by the researchers containing factors associated with excessive bleeding after cardiac surgery, as found in the literature, for investigation in the immediate postoperative period. The relationship between risk factors and the outcome was assessed by univariate analysis and logistic regression. RESULTS The factors associated with RBCT in the immediate postoperative period included lower height and weight, decreased platelet count, lower hemoglobin level, higher prevalence of platelet count <150x10 3/mm3, lower volume of protamine, longer duration of anesthesia, higher prevalence of intraoperative RBCT, lower body temperature, higher heart rate and higher positive end-expiratory pressure. The independent predictor was weight <66.5Kg. CONCLUSION Factors associated with RBCT in the immediate postoperative period of cardiac surgery were found. The independent predictor was weight.

Clinical studies with a vascular vasopressin antagonist.

The effect of circulating arginine vasopressin (AVP) on blood pressure, heart rate, and skin blood flow was assessed in normotensive subjects, mild hypertensive patients, and patients with congestive heart failure, utilizing the specific antagonist of AVP at the vascular receptor level, d(CH2)5Tyr(Me)AVP (5 micrograms/kg i.v.). The renin system of the normal volunteers treated with the AVP antagonist was either intact or acutely blocked with the angiotensin converting-enzyme inhibitor captopril (25 mg p.o.). In some volunteers, the cardiovascular effect of AVP released by Finnish sauna or cigarette smoking was studied. In patients with congestive heart failure, hemodynamic measurements (pressures and cardiac output) were obtained invasively. Acute blockade of AVP vascular receptors produced no cardiovascular effect unless plasma AVP levels were markedly elevated. In our experience, abnormally high circulating AVP appears to be responsible for the decrease in skin blood flow induced by cigarette smoking and to some extent for the maintenance of vascular tone in the rare patients with particularly severe congestive heart failure.

Propranolol as an adjunct therapy for hyperthyroid tremor.

We evaluated the use of propranolol as an adjunct to carbimazole in the treatment of hyperthyroid tremor and tachycardia in a double-blind, cross-over and placebo-controlled study. Seven patients were given carbimazole plus either placebo or propranolol (40 mg) for 1 month and then switched to the alternative adjunct treatment for a further month. All patients showed significant improvements (p < 0.001) of heart rate and tremor amplitude after 1 or 2 months from baseline. One month after the baseline, the mean improvements of heart rate were 23% for the carbimazole + placebo group and 38% for carbimazole + propranolol group. Tremor also improved during the 1st month of the study by 31% in the carbimazole + placebo group versus 59% in the carbimazole + propranolol group. Whereas further improvements were observed in both variables in those receiving propranolol as the second adjunct treatment, this was not the case in those who received placebo during the same period. These findings confirm that the beta-blocker propranolol is a useful adjunct in the early treatment of both the tremor and tachycardia of hyperthyroidism.

Evaluation de l'efficacite antihypertensive de l'isradipine SRO par enregistrement tensionnel en ambulatoire. [Evaluation of the antihypertensive efficacy of isradipine SRO as assessed by ambulatory blood pressure determination]

The calcium channel blocker isradipine has become recently available in a form with delayed release (isradipine SRO). The anti-hypertensive efficacy and tolerance of this preparation at a single daily dose of 5 mg was studied in 40 patients with uncomplicated essential hypertension over a period of 6 weeks. Blood pressure during office visits decreased under Isradipine SRO from 164/105 +/- 16/7 to 144/93 +/- 12/7 mmHg (mean +/- 1 standard deviation p < 0.001). Using ambulatory blood pressure recording we could show that antihypertensive efficacy of the new galenic form persisted over 24 hours. During the day the blood pressure dropped from 150/95 +/- 13/7 to 141/91 +/- 13/7 mmHg (p < 0.001), during the night from 131/85 +/- 13/3 to 121/81 +/- 15/9 mmHg (p < 0.001). Heart-rate was not changed by treatment and the drug was well tolerated. Isradipine SRO at a single dose is thus well suited for antihypertensive treatment.

Volume expansion enhances plasma endothelin-1.

We hypothesized that acute volume expansion by saline infusion triggers the release of endothelin-1. Bolus intravenous saline infusion (8 mL/min) in six groups of conscious Wistar rats and spontaneously hypertensive rats did not change mean arterial pressure or heart rate (n = 8 to 12). At 1 min after infusion, the plasma endothelin-1 level was significantly increased in Wistar rats and in spontaneously hypertensive rats by 42% and 61%, respectively (unpaired data). In 12 Wistar rats, the endothelin-1 level increased from 0.68 +/- 0.13 to 1.19 +/- 0.17 fmol/mL (mean +/- SEM, P <.0001, paired data). Thus, acute volume load by rapid saline infusion increases plasma endothelin-1 levels. Vasoconstriction induced by endothelin-1 may counteract enhanced circumferential stretch created by volume expansion.

Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A.

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.

Heritability of left ventricular structure and function in Caucasian families.

AIMS: The aim of this study was to investigate the heritability as well as genetic and environmental correlations of left ventricular (LV) structural and functional traits in complex pedigrees of a Caucasian population. METHODS AND RESULTS: We randomly recruited 459 white European subjects from 52 families (50% women; mean age 45 years). LV structure was measured by M-mode and 2D echocardiography and LV function was measured by conventional Doppler and tissue Doppler imaging (TDI). Other measurements included blood pressure, anthropometric, and biochemical measurements. We estimated the heritability of LV traits while adjusting for covariables, including sex, age, body height and weight, systolic and diastolic blood pressures, and heart rate. With full adjustment, heritability of LV mass was 0.23 (P= 0.025). The TDI-derived mitral annular velocities Ea and Aa showed moderate heritability (h(2)= 0.36 and 0.53, respectively), whereas the mitral inflow A peak had weak heritability (h(2) = 0.25) and the E peak was not heritable (h(2) = 0.11). We partitioned the total phenotypic correlation when it reached significance, into a genetic and an environmental component. The genetic correlations were 0.61 between the E and Ea peaks and 0.90 between the A and Aa peaks. CONCLUSION: Our study demonstrated moderate heritability for LV mass as well as the mitral annular Ea and Aa peaks. We also found significant genetic correlations between the E and Ea peaks and between the A and Aa peaks. Our current findings support the ongoing research to map and detect genetic variants that contribute to the variation in LV mass and other LV structural and functional phenotypes.

Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice.

Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism.

Acute myocardial dysfunction is a typical manifestation of septic shock. Experimentally, the administration of endotoxin [lipopolysacharride (LPS)] to laboratory animals is frequently used to study such dysfunction. However, a majority of studies used load-dependent indexes of cardiac function [including ejection fraction (EF) and maximal systolic pressure increment (dP/dt(max))], which do not directly explore cardiac inotropism. Therefore, we evaluated the direct effects of LPS on myocardial contractility, using left ventricular (LV) pressure-volume catheters in mice. Male BALB/c mice received an intraperitoneal injection of E. coli LPS (1, 5, 10, or 20 mg/kg). After 2, 6, or 20 h, cardiac function was analyzed in anesthetized, mechanically ventilated mice. All doses of LPS induced a significant drop in LV stroke volume and a trend toward reduced cardiac output after 6 h. Concomitantly, there was a significant decrease of LV preload (LV end-diastolic volume), with no apparent change in LV afterload (evaluated by effective arterial elastance and systemic vascular resistance). Load-dependent indexes of LV function were markedly reduced at 6 h, including EF, stroke work, and dP/dt(max). In contrast, there was no reduction of load-independent indexes of LV contractility, including end-systolic elastance (ejection phase measure of contractility) and the ratio dP/dt(max)/end-diastolic volume (isovolumic phase measure of contractility), the latter showing instead a significant increase after 6 h. All changes were transient, returning to baseline values after 20 h. Therefore, the alterations of cardiac function induced by LPS are entirely due to altered loading conditions, but not to reduced contractility, which may instead be slightly increased.

Effect of a novel beta-adrenoceptor agonist (Ro 40-2148) on resting energy expenditure in obese women.

The aim of this single-blind, placebo-controlled study was to investigate the effects of the new beta-adrenergic compound Ro 40-2148 on resting energy expenditure (REE) at rest and after an oral glucose load in non-diabetic obese women before and after two weeks of treatment. After one week of placebo administration and after an overnight fast and one hour rest, REE and glucose and lipid oxidation rates were measured by indirect calorimetry (hood system) before and for 6 h after a single dose of placebo solution. A 75 g oral glucose tolerance test (OGTT) was performed during this period starting 90 min after the placebo administration. During the following two weeks, using a randomization design, six patients received Ro 40-2148 at a dose of 400 mg diluted in 100 ml water twice a day (i.e. 800 mg per day), while six others continued with the placebo administration. The same tests and measurements were repeated after two weeks, except for the treatment group which received the drug instead of the placebo. The 14-day period of drug administration did not increase REE measured in post-absorptive conditions. Similarly, there was no acute effect on REE of a 400 mg dose of Ro 40-2148. In contrast, glucose-induced thermogenesis was significantly increased after two weeks in the treatment group (means +/- s.e.m.: 3.7 +/- 1.3%, P = 0.047), while no change was observed in the placebo group (-0.8 +/- 0.7%, not significant). Since there was no significant change in the respiratory quotient, the increase in energy expenditure observed in the treatment group was due to stimulation of both lipid and glucose oxidation. The drug induced no variations in heart rate, blood pressure, axillary temperature or in plasma glucose, insulin and free fatty acid levels. In conclusion, this study shows that Ro 40-2148 activates glucose-induced thermogenesis in obese non-diabetic patients.

Data-based approach for developing a physical activity frequency questionnaire.

Measurement of total energy expenditure may be crucial to an understanding of the relation between physical activity and disease and in order to frame public health intervention. To devise a self-administered physical activity frequency questionnaire (PAFQ), the following data-based approach was used. A 24-hour recall was administered to a random sample of 919 adult residents of Geneva, Switzerland. The data obtained were used to establish the list of activities (and their median duration) that contributed to 95% of the energy expended, separately for men and women. Activities that were trivial for the whole sample but that contributed to > or = 10% of an individual's energy expenditure were also selected. The final PAFQ lists 70 activities or group of activities with their typical duration. About 20 minutes are required for respondents to indicate the number of days and the number of hours per day that they performed each activity. The PAFQ method was validated against a heart rate monitor, a more objective method. The total energy estimated by the PAFQ in 41 volunteers correlated well (r = 0.76) with estimates using a heart rate monitor. The authors conclude that the design of their self-administered physical activity frequency questionnaire based on data from 24-hour recall appeared to accurately estimate energy expenditure.

Tapering for marathon and cardiac autonomic function.

The purpose of this study was to investigate changes in post-exercise heart rate recovery (HRR) and heart rate variability (HRV) during an overload-tapering paradigm in marathon runners and examine their relationship with running performance. 9 male runners followed a training program composed of 3 weeks of overload followed by 3 weeks of tapering (-33±7%). Before and after overload and during tapering they performed an exhaustive running test (Tlim). At the end of this test, HRR variables (e.g. HRR during the first 60 s; HRR60 s) and vagal-related HRV indices (e.g. RMSSD5-10 min) were examined. Tlim did not change during the overload training phase (603±105 vs. 614±132 s; P=0.992), but increased (727±185 s; P=0.035) during the second week of tapering. Compared with overload, RMSSD5-10 min (7.6±3.3 vs. 8.6±2.9 ms; P=0.045) was reduced after the 2(nd) week of tapering. During tapering, the improvements in Tlim were negatively correlated with the change in HRR60 s (r=-0.84; P=0.005) but not RMSSD5-10 min (r=-0.21; P=0.59). A slower HRR during marathon tapering may be indicative of improved performance. In contrast, the monitoring of changes in HRV as measured in the present study (i.e. after exercise on a single day), may have little or no additive value.

Variability of resting energy expenditure in healthy volunteers during fasting and continuous enteral feeding.

The magnitude of variability in resting energy expenditure (REE) during the day was assessed in nine healthy young subjects under two nutritional conditions: 1) mixed nutrient (53% carbohydrate, 30% fat, 17% protein) enteral feeding at an energy level corresponding to 1.44 REE; and 2) enteral fasting, with only water allowed. In each subject, six 30-min measurements of REE were performed using indirect calorimetry (hood system) at 90-min intervals from 9 AM to 5 PM. The mean REE and respiratory quotient were significantly (p less than .01) greater during feeding than during fasting (1.08 +/- 0.07 [SEM] vs. 1.00 +/- 0.06 kcal/min and 0.874 +/- 0.007 vs. 0.829 +/- 0.008 kcal/min, respectively). Mean postprandial thermogenesis was 4.9 +/- 0.4% of metabolizable energy administered. The intraindividual variability of REE throughout the day, expressed as the coefficient of variation, ranged from 0.7% to 2.0% in the fasting condition and from 1.2% to 4.1% in the feeding condition. There was no significant difference between the REE measured in the morning and that determined in the afternoon.

Effects of adrenergic and cholinergic blockade on insulin-induced stimulation of calf blood flow in humans.

Euglycemic hyperinsulinemia stimulates both sympathetic nerve activity and blood flow to skeletal muscle, but the mechanism is unknown. Possible mechanisms that may stimulate muscle blood flow include neural, humoral, or metabolic effects of insulin. To determine whether such insulin-induced vasodilation is modulated by stimulation of adrenergic or cholinergic mechanisms, we obtained, in eight healthy lean subjects, plethysmographic measurements of calf blood flow during 3 h of hyperinsulinemic (1 mU.kg-1.min-1) euglycemic clamp performed alone or during concomitant beta-adrenergic (propranolol infusion), cholinergic (atropine infusion), or alpha-adrenergic (prazosin administration) blockade. Euglycemic hyperinsulinemia alone increased calf blood flow by 38 +/- 10% (means +/- SE) and decreased vascular resistance by 27 +/- 4% (P < 0.01). The principal new observation is that these insulin-induced vasodilatory responses were not attenuated by concomitant propranolol or atropine infusion, nor were they potentiated by prazosin administration. In conclusion, these findings provide evidence that during euglycemic hyperinsulinemia in lean healthy humans stimulation of muscle blood flow is not mediated primarily by beta-adrenergic or cholinergic mechanisms. Furthermore, alpha-adrenergic mechanisms do not markedly limit insulin-induced stimulation of muscle blood flow.