Relaxation of tracheal smooth muscle is impaired in innate airway hyperresponsiveness.

The current study was designed to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain is associated with impaired spontaneous relaxation of airway smooth muscle. Strips of the posterior portion of the trachea from 10 adult Fisher and 10 adult Lewis rats were electrically stimulated at pH 7.4, 2.5 mM Ca(2+)concentration, at 37 degrees C. Both isotonic and isometric relaxations of tracheal smooth muscle (TSM) were investigated. Half time for isotonic relaxation at preload was markedly prolonged in Fisher rats (8.33+/-3.21 s) compared with Lewis rats (3.53+/-0.54 s; p<0.001). Maximum lengthening velocity at preload and peak rate of isometric tension decline were significantly decreased in Fisher rats compared with Lewis rats. The ratio of shortening velocity to lengthening velocity at preload, as well as the ratio of the isometric peak rates of tension development to tension decline were higher in Fisher rat TSM than in Lewis rat TSM. These differences were associated with a six-fold higher expression of myosin light chain kinase in Fisher rats than in Lewis rats. In Fisher rats, these results suggest that innate airway hyperresponsiveness is associated with both a reduced level and a slower rate of TSM spontaneous relaxation, promoting maintenance of airway constriction.

Growth hormone excess and sternohyoid muscle mechanics in rats.

In vitro isotonic and isometric mechanical properties of the sternohyoid (SH) muscle, an upper airway dilator muscle, were studied in rats with a growth hormone (GH)-secreting tumour (GH tumour group; n = 10). The effects of muscle fatigue were also studied. Stress and shortening were measured in muscles contracting from zero load up to isometric load under tetanic conditions. Isometric stress and maximum unloaded shortening velocity were determined and compared with values obtained from control rats (n = 10). Crossbridge kinetics and energetics and mechanical efficiency were calculated from Huxley's equations. Compared with controls, isometric stress, mechanical efficiency, crossbridge number and crossbridge single force were lower in the GH tumour group. The probability of crossbridge being in the power stroke configuration was lower in the GH tumour group than in controls. Muscle fatigue significantly impaired maximal muscle efficiency and crossbridge single force in the GH tumour group but not in controls. In conclusion, mechanical and energetic properties of the SH muscle and crossbridge properties were worse in the GH tumour group than in controls. This may partly account for impairment of the upper airway dilator muscle function and the increased occurrence of obstructive sleep apnoea in acromegaly.

Recipients with blood group A associated with longer survival rates in cardiac valvular bioprostheses.

BACKGROUND: Pigs/bovines share with humans some of the antigens present on cardiac valves. Two such antigens are: the major xenogenic Ag, "Gal" present in all pig/bovine very close to human B-antigen of ABO-blood-group system; the minor Ag, pig histo-blood-group AH-antigen identical to human AH-antigen and present by some animals. We hypothesize that these antigens may modify the immunogenicity of the bioprosthesis and also its longevity. ABO distribution may vary between patients with low (<6 years) and high (≥15 years) bioprostheses longevity. METHODS: Single-centre registry study (Paris, France) including all degenerative porcine bioprostheses (mostly Carpentier-Edwards 2nd/3rd generation heart valves) explanted between 1985 and 1998 and some bovine bioprostheses. For period 1998-2014, all porcine bioprostheses with longevity ≥13 years (follow-up ≥29 years). Important predictive factors for bioprosthesis longevity: number, site of implantation, age were collected. Blood group and other variables were entered into an ordinal logistic regression analysis model predicting valve longevity, categorized as low (<6 years), medium (6-14.9 years), and high (≥15 years). FINDINGS: Longevity and ABO-blood group were obtained for 483 explanted porcine bioprostheses. Mean longevity was 10.2 ±â€¯3.9 years [0-28] and significantly higher for A-patients than others (P = 0.009). Using multivariate analysis, group A was a strong predictive factor of longevity (OR 2.09; P < 0.001). For the 64 explanted bovine bioprosthesis with low/medium longevity, the association, with A-group was even more significant. INTERPRETATION: Patients of A-group but not B have a higher longevity of their bioprostheses. Future graft-host phenotyping and matching may give rise to a new generation of long-lasting bioprosthesis for implantation in humans, especially for the younger population. FUND: None.

Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and myosin adenosine triphosphatase activity of rat left ventricle.

We studied papillary muscle mechanics and energetics, myosin phenotype, and ATPase activities in left ventricles from rats bearing a growth hormone (GH)--secreting tumor. 18 wk after tumor induction, animals exhibited a dramatic increase in body weight (+101% vs. controls) but no change in the ventricular weight/body weight ratio. The maximum isometric force of papillary muscles normalized per cross-sectional area rose markedly (+42%, P less than 0.05 vs. controls), whereas the maximum unloaded shortening velocity did not change. This was observed despite a marked isomyosin shift towards V3 (32 +/- 5% vs. 8 +/- 2% in controls, P less than 0.001). Increased curvature of the force-velocity relationship (+64%, P less than 0.05 vs. controls) indicated that the muscles contracted more economically, suggesting the involvement of V3 myosin. Total calcium- and actin-activated myosin ATPase activities assayed on quickly frozen left ventricular sections were similar in tumor-bearing rats and in controls. After alkaline preincubation, these activities only decreased in tumor-bearing rats, demonstrating that V3 enzymatic sites were involved in total ATPase activity. These data demonstrate that chronic GH hypersecretion in the rat leads to a unique pattern of myocardial adaptation which allows the muscle to improve its contractile performance and economy simultaneously, thanks to myosin phenoconversion and an increase in the number of active enzymatic sites.

Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension.

OBJECTIVES: The purpose of this time-domain study was to compare pulmonary artery (PA) pulse pressure and wave reflection in chronic pulmonary thromboembolism (CPTE) and primary pulmonary hypertension (PPH). BACKGROUND: Pulmonary artery pressure waveform analysis provides a simple and accurate estimation of right ventricular afterload in the time-domain. Chronic pulmonary thromboembolism and PPH are both responsible for severe pulmonary hypertension. Chronic pulmonary thromboembolism and PPH predominantly involve proximal and distal arteries, respectively, and may lead to differences in PA pressure waveform. METHODS: High-fidelity PA pressure was recorded in 14 patients (7 men/7 women, 46 +/- 14 years) with CPTE (n = 7) and PPH (n = 7). We measured thermodilution cardiac output, mean PA pressure (MPAP), PA pulse pressure (PAPP = systolic - diastolic PAP) and normalized PAPP (nPAPP = PPAP/MPAP). Wave reflection was quantified by measuring Ti, that is, the time between pressure upstroke and the systolic inflection point (Pi), deltaP, that is, the systolic PAP minus Pi difference, and the augmentation index (deltaP/PPAP). RESULTS: At baseline, CPTE and PPH had similar cardiac index (2.4 +/- 0.4 vs. 2.5 +/- 0.5 l/min/m2), mean PAP (59 +/- 9 vs. 59 +/- 10 mm Hg), PPAP (57 +/- 13 vs. 53 +/- 13 mm Hg) and nPPAP (0.97 +/- 0.16 vs. 0.89 +/- 0.13). Chronic pulmonary thromboembolism had shorter Ti (90 +/- 17 vs. 126 +/- 16 ms, p < 0.01) and higher deltaP/PPAP (0.26 +/- 0.01 vs. 0.09 +/- 0.07, p < 0.01). CONCLUSIONS: Our study indicated that: 1) CPTE and PPH with severe pulmonary hypertension had similar PA pulse pressure, and 2) wave reflection is elevated in both groups, and CPTE had increased and anticipated wave reflection as compared with PPH, thus suggesting differences in the pulsatile component of right ventricular afterload.

Load sensitivity of relaxation in the foetal and newborn rabbit heart.

Differences in the mechanism of cardiac relaxation and the influence of changes in the stimulation frequency were studied in foetal and newborn rabbit hearts. In the foetal rabbit heart which lacks a well developed sarcoplasmic reticulum, load sensitivity of relaxation was investigated and compared with that observed in the newborn. Load sensitivity was studied by measuring force and shortening length in twitches with increasing afterloads and also when load clamp steps were rapidly imposed during the twitch. Quantification of the load sensitivity was achieved by the measurement of the time to relaxation "tRi" which was linearly related to the relative developed force. The slope (S) of this linear relation quantifies the load sensitivity: the higher the slope, the more load sensitive is the relaxation. At a frequency of 24 beats X min-1, S was respectively 0.24 in the foetal heart and 0.36 in the newborn heart showing at both ages the existence of a load sensitivity and its significant increase at birth. No further increase in load sensitivity was observed from 1 day to 21 days after birth. Reducing the stimulation frequency from 24 to 10 beats X min-1 abolished the load sensitivity in foetal hearts (S = 0.05) while, in the newborn, a significant load sensitivity could still be observed (S = 0.25). Thus, in rabbit myocardium, the load sensitivity of cardiac relaxation depended upon the age and the stimulation frequency showing a perinatal development of the structures involved in the control of myocardial relaxation.

Spontaneous arrhythmias in various models of cardiac hypertrophy and senescence of rats. A Holter monitoring study.

OBJECTIVE: The aim was to define experimental models of spontaneous arrhythmias in various models of cardiac hypertrophy in rats. METHODS: Cardiac hypertrophy was induced by several methods and 24 h Holter monitoring was recorded in conscious rats to quantify spontaneous arrhythmias in hypertrophied hearts. Male Wistar rats were studied. A group of young controls 1-2 months old (n = 16) was compared to four groups of animals with cardiac hypertrophy: (1) thyrotoxic rats which received a daily intraperitoneal injection of L-thyroxine for 7 d (n = 6); (2) rats subjected to abdominal suprarenal aortic stenosis (n = 11); (3) senescent rats 22-24 month old (n = 6); and (4) S-DOCA-salt (senescent animals rendered hypertensive by uninephrectomy and DOCA-salt treatment, n = 8). RESULTS: (1) Thyroxine resulted in 20% cardiac hypertrophy, with normal arterial tension, sinus tachycardia, a shorter P wave length and PR interval, and frequent (5/6) atrioventricular block. No premature beats were seen. (2) In aortic stenosis, atria and left ventricle were hypertrophied by 53% and systolic carotid pressure increased by 63%. The incidence of supraventricular premature beats was increased [frequency = 0.70 (SEM 0.3) per 24 h in control v 99(61) in aortic stenosis, p < 0.05]. Ventricular premature beats remained as rare as in control. (3) In senescent and S-DOCA-salt rats all types of spontaneous arrhythmias, but specially supraventricular arrhythmias and atrioventricular block, were frequent. Cardiac hypertrophy produced by DOCA-salt treatment in senescent rats had no effect on the incidence and nature of arrhythmias, but resulted in an increased QTc interval. CONCLUSIONS: Senescent rats and rats with aortic stenosis represent valid models of spontaneous arrhythmias occurring in the absence of ischaemia or toxic insult. Spontaneous arrhythmias in rats are mainly of supraventricular origin. Hyperthyroidism in rats is a model of atrioventricular block probably related to tachycardia. Holter monitoring in rats may have several potential pathophysiological and pharmacological applications.

Post-extrasystolic left ventricular peak pressure with and without left ventricular failure.

18 patients without valvular pathology, coronary artery disease, or idiopathic hypertrophic subaortic stenosis were haemodynamically and angiographically investigated in order to analyse the effects of a ventricular extrasystolic beat upon the post-extrasystolic left ventricular peak pressure. In eight normal patients (group I), the post-extrasystolic peak pressure (P.ES.P.P.) was lower than that of the pre-extrasystolic beat; in 10 patients with symptoms of left ventricular failure (group II) the P.ES.P.P. significantly increased. The reasons are: 1) cardiac origin: stroke volume increased more in group II; 2) arterial origin. a) aortic compliance was lower in group II (this is probably related to the older age of patients in group II), and by decrease in end-diastolic aortic pressure was smaller in group II. Part of this arterial effect (2b) may probably be explained from the fact that post-extrasystolic compensatory pauses are equal in both groups, but the decay time of arterial pressure during diastole (assuming an exponential decay) is larger in group II. At the same age and with the identical aortic compliance only the two factors 1 and 2b play a part in the changes in P.ES.P.P.

Myocardial effects of early therapy with perindopril during experimental cardiomyopathy.

The effects of chronic angiotensin-converting enzyme (ACE) inhibition on intrinsic myocardial contractility of the failing myocardium have been poorly documented. In the present study, inotropy, lusitropy, and economy of force generation were studied in vitro in papillary muscles from cardiomyopathic Syrian hamster (CSH) under early perindopril therapy, i.e., therapy begun at a stage when experimental heart failure was not yet observed. One-month-old CSH from the dilated strain Bio 53.58 were randomly treated over a 5-month period with either the ACE inhibitor perindopril 1 mg/kg/day (n = 11) or placebo (n = 11), and 7 age-matched controls were given placebo. Compared with control, placebo had a lower maximum shortening velocity (Vmax) (p < 0.01) and normalized total force (p < 0.05), and a lower curvature of the force-velocity relationship (p < 0.01). It has been shown that the higher the value of the curvature, the better the myothermal economy of force generation. Compared with placebo, perindopril had a 68% inhibition of plasma ACE activity and a greater Vmax (p < 0.05), whereas total force/mm2 was similar. This resulted in a lesser decrease of the curvature compared to control (p < 0.05). Placebo had a decreased peak lengthening velocity and rate of force decline. However, compared to control, no intrinsic abnormalities of the relaxation phase were observed in either placebo or perindopril when relaxation parameters were corrected for the lower systolic performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between aortic dicrotic notch pressure and mean aortic pressure in adults.

It has recently been suggested that mean arterial pressure provides a reliable estimate of dicrotic notch pressure in infants and children. The aim of the present study was twofold: (1) to investigate the relation existing between aortic dicrotic notch pressure and both the steady and pulsed component of aortic pressure in adults (i.e., mean and pulse aortic pressures, respectively); and (2) to evaluate mean aortic pressure as an estimate of aortic dicrotic notch pressure. High-fidelity pressure recordings were obtained at the aortic root level in 17 men (52 +/- 13 years). Pressure data were analyzed at rest over 10 consecutive beats in each patient, and, in 6 patients, during the Valsalva maneuver (over 22 to 50 consecutive beats). At rest, dicrotic notch pressure was greater than mean pressure (109.0 +/- 17.9 vs 99.6 +/- 12.5 mm Hg, p = 0.0001). Dicrotic notch pressure was positively related to mean pressure (r = 0.93) and to pulse pressure (r' = 0.77), but not to patient's heart rate, cardiac output, or total estimated arterial compliance. There was a spontaneous beat-to-beat relation between dicrotic notch and mean pressures (1) at rest in 16 of 17 patients (mean r = 0.85), and (2) in all patients undergoing the Valsalva maneuver (mean r = 0.97). During the maneuver, intravascular mean pressure ranged from 59 to 171 mm Hg. Dicrotic notch pressure was positively related to mean pressure (r = 0.98) and to pulse pressure (r' = 0.44). Both at rest and during the Valsalva maneuver, mean pressure underestimated dicrotic notch pressure, and the higher the dicrotic notch pressure, the more negative the percent error (each p = 0.0001). In conclusion, aortic dicrotic notch pressure was mainly related to the steady component of aortic pressure. The mean aortic pressure slightly but significantly underestimated aortic dicrotic notch pressure, and thus should be used with greater caution in adults than in young patients as an estimate of end-systolic pressure.

Effect of beta adrenoceptors and thyroid hormones on velocity and acceleration of peripheral arterial flow in hyperthyroidism.

Brachial artery flow patterns were studied in 10 hyperthyroid and 10 normal subjects. Mean blood velocity and flow were evaluated by pulsed Doppler, and peak systolic acceleration was calculated by computer-assisted digitization of the instantaneous velocity curve. Compared to control subjects, hyperthyroid patients had higher velocity and flow (p less than 0.01, p less than 0.02) and higher peak systolic acceleration (p less than 0.01). In hyperthyroid patients, measurements were repeated after (1) mechanical exclusion of the hand from brachial circulation, (2) short-term beta-blocker treatment and (3) inducement of the euthyroid state. Exclusion of the hand reduced velocity and flow (p less than 0.001) but did not change peak systolic acceleration. Beta blockade induced disparate changes of velocity and flow but reduced peak systolic acceleration (p less than 0.05). In the euthyroid state, decreased blood velocity (p less than 0.01), flow (p less than 0.02) and acceleration (p less than 0.02) were observed. A hyperkinetic arterial circulation consisting of an increase in both velocity and acceleration is thus observable in hyperthyroidism. Hand exclusion showed that velocity seems to be influenced by peripheral factors while beta blockade suggests that acceleration is dependent of beta 1 adrenoceptors. Comparison between euthyroidism and hyperthyroidism indicates that both mean blood velocity and peak systolic acceleration are influenced by thyroid hormones.

A comparison between systolic aortic root pressure and finger blood pressure.

BACKGROUND: Digital photoplethysmography is used to assess hemodynamic variability and baroreflex sensitivity. Numerous studies have critically evaluated the accuracy of the photoplethysmographic device against peripheral pressure. The aim of our study was to compare finger blood and aortic root pressure. METHODS: We prospectively compared simultaneous recordings of systolic pressure at the aortic root and finger level over three consecutive respiratory cycles in 15 patients (56+/-11 years) undergoing routine cardiac catheterization. Data were obtained at baseline, during deep breathing maneuver (0.1 Hz), and after left ventricular cineangiography. RESULTS: At baseline, systolic finger pressure overestimated systolic aortic pressure (145.2+/-22.5 vs 115.0+/-20.1 mm Hg; p<0.001). The pressure difference (30.2+/-17.0 mm Hg) was not influenced by systolic aortic pressure. There was no relationship between pressure difference and the main determinants of the pulse wave amplification phenomenon. There was a beat-to-beat relationship between finger and aortic pressure in 14 of 15 subjects (slope ranging from 0.37 to 1.70; ordinate: from -56 to +98 mm Hg). During the deep breathing maneuver and after left ventricular cineangiography, finger pressure still overestimated aortic pressure by 32.3+/-15.0 mm Hg and 38.3 13.9 mm Hg, respectively (each p<0.001). There was a beat-to-beat relationship between systolic aortic root pressure (IAoBP) and systolic finger (FBP) in 13 of 15 patients, with major scattering of both slopes and ordinates. Throughout the study, there was no predictable relationship between the level of IAoBP and pressure bias. CONCLUSIONS: As expected, FBP was almost always higher than IAoBP. Importantly, the differences in systolic pressure did not correlate with known determinants of the pulse wave amplification phenomenon. The device must be used cautiously if one wants to noninvasively track spontaneous or induced changes in IAoBP.

Angiotensin-converting enzyme inhibitor therapy improves respiratory muscle strength in patients with heart failure.

STUDY OBJECTIVES: Respiratory muscle strength has been shown to be reduced in patients with chronic heart failure. The purpose of this prospective study was to determine whether long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor perindopril improves respiratory muscle strength in patients with chronic heart failure. PATIENTS AND METHODS: Eighteen patients with stable chronic heart failure were administered perindopril, 4 mg/d, in addition to their standard therapy for a period of 6 months. Fourteen patients completed the study. Maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax) expressed in percentage of predicted values, left ventricular ejection fraction (LVEF) determined by means of two-dimensional echocardiography, and pulmonary volumes were obtained before and after therapy. MEASUREMENTS AND RESULTS: As compared to baseline, there was a significant increase in both PImax and PEmax after therapy (57 +/- 27% predicted vs 78 +/- 36% predicted and 62 +/- 20% predicted vs 73 +/- 15% predicted, respectively; each p < 0.05). LVEF increased (34 +/- 5% vs 41 +/- 10%; p < 0.05); functional class improved by > or = 1 New York Heart Association (NYHA) class in five patients. There were no changes in pulmonary volumes. No correlation was found between changes in PImax and PEmax and changes in either LVEF or NYHA functional class. CONCLUSIONS: In patients with chronic heart failure, long-term therapy with the ACE inhibitor perindopril improved respiratory muscle strength, as indicated by significant increases in PImax and PEmax.

Effects of hydroxocobalamin on rat cardiac papillary muscle.

Hydroxocobalamin is a rapid and powerful antidote in acute cyanide poisoning. The effects of hydroxocobalamin (0.1, 0.3, and 1 mM) on intrinsic myocardial contractility were studied on isolated rat cardiac papillary muscles (n = 10). Whatever the concentration, hydroxocobalamin did not modify the active isometric force and a slight increase in maximum unloaded shortening velocity was noted at 1 mM. Only 0.3 mM significantly impaired contraction-relaxation coupling under low load, suggesting a slight decrease in sarcoplasmic reticulum function. No changes in contraction-relaxation coupling under heavy load were noted, suggesting the lack of modification of myofilament calcium sensitivity. These results suggest that hydroxocobalamin does not induce noticeable changes in intrinsic myocardial contractility. An indirect mechanism might be involved in the previously reported decrease in cardiac function at supratherapeutic concentrations of hydroxocobalamin.

Diazepam does not improve the mechanical performance of rat cardiac papillary muscle exposed to chloroquine in vitro.

Diazepam has been reported to decrease the cardiac toxicity of chloroquine but the precise mechanism involved remains unknown. Left ventricular papillary muscles from adult Wistar rats were exposed to 10(-4) M chloroquine and assigned to three groups: group I (n = 10) exposed to chloroquine alone; group II (n = 8) exposed to chloroquine and 10(-5) M diazepam; group III (n = 8) exposed to chloroquine and 10(-4) M diazepam. The main mechanical parameters measured were: maximum unloaded shortening velocity (Vmax), maximum lengthening velocity (maxVr), active force normalized per cross-sectional area (AF/s), contraction-relaxation coupling under low load (R1), load sensitivity of relaxation (Isot.A/Isom.A), and peak power output (Emax) determined from Hill's equation of the force-velocity curve. Data are expressed as mean percent of control values +/- SD, for groups I, II, III respectively. No differences between groups I, II, and III were noted for Vmax (87 +/- 13, 82 +/- 9, 86 +/- 7), maxVr (47 +/- 6, 48 +/- 11, 52 +/- 11), AF/s (87 +/- 16, 91 +/- 10, 83 +/- 11), Isot. A/Isom. A (113 +/- 9, 108 +/- 3, 109 +/- 7), or Emax (75 +/- 10, 81 +/- 12, 72 +/- 16). Chloroquine was shown to be a negative inotropic agent since it decreased Vmax, AF/s and Emax, but diazepam did not restore the intrinsic mechanical performance of rat cardiac papillary muscle exposed to chloroquine, therefore 1) the protective cardiovascular effects of diazepam in chloroquine poisoning are not related to an improvement in intrinsic cardiac mechanical properties; 2) inotropic agents are therefore necessary in combination with diazepam for the treatment of severe chloroquine poisoning.

Cardiotoxicity of colchicine in the rat.

OBJECTIVES: Colchicine poisoning may be lethal and a decrease in cardiac function has been reported in several case reports, but the precise cardiotoxicity of colchicine remains unknown. DESIGN: The experimental in vitro study assessed the intrinsic contractility of left ventricular papillary muscle in rats, 24 h after administration of intraperitoneal colchicine or saline. RESULTS: The administration of colchicine (2 or 4 mg.kg-1) in adult Wistar rats markedly impaired intrinsic myocardial contractility, as shown by a decrease in maximum shortening velocity (-32 and -61%, respectively), active isometric force (-47 and -65%, respectively), and peak power output (-57 and -69%, respectively) of left ventricular papillary muscle. Colchicine impaired isotonic relaxation and load dependence of relaxation, suggesting a decrease in sarcoplasmic reticulum function. Conversely, colchicine significantly accelerated isometric relaxation, suggesting a decrease in calcium myofilament sensitivity. Myothermal economy was markedly impaired only in some rats (3/10 in each group), in which the negative inotropic effect of colchicine appeared to be more particularly pronounced. CONCLUSION: The results indicate that the administration of high doses of colchicine induced intrinsic cardiotoxic effects. Due to its amplitude, such cardiotoxic action may participate in the fatal outcome of acute colchicine poisoning.

Hydroxocobalamin vs cobalt toxicity on rat cardiac and diaphragmatic muscles.

BACKGROUND: Hydroxocobalamin has been shown to be a rapid and powerful antidote in acute cyanide poisoning and to prevent cyanide poisoning during sodium nitroprusside administration. This cobalt-containing compound has been shown to be devoid of significant immediate side effects during acute administration. However, its potential delayed toxicity related to cobalt accumulation in tissue remains unknown. Therefore, we evaluated the toxicity of hydroxocobalamin as compared with that of cobalt salts on rat cardiac and diaphragmatic muscles. METHODS: For a 21-day period, rats were treated intraperitoneally with either hydroxocobalamin (70 mg kg-1 per day, n = 14), cobalt chloride hexahydrate (12 mg kg-1 per day, n = 14) or saline (n = 10). Hydroxocobalamin and cobalt chloride groups received equimolar doses of cobalt. We studied: (1) the mechanical properties of isolated left ventricular papillary muscles and diaphragmatic strips, (2) the cardiac and diaphragmatic cobalt tissue concentrations, and (3) the myocardial histological aspect. RESULTS: During the study period, no significant increase in body weight was noted in the cobalt-treated group (-4 +/- 1%), which was in contrast to the hydroxocobalamin-treated group (+21 +/- 2%) and the saline-treated group (22 +/- 2%). Compared with controls, the mechanical properties of cardiac and diaphragmatic muscles were unchanged after either hydroxocobalamin or cobalt salt treatments, and myocardial histological characteristics were similar in all groups. Conversely, large amounts of cobalt deposit were observed in the cobalt-treated group in both the diaphragm (41.90 +/- 16.30 vs 0.70 +/- 0.40 mu mol mu g-1 in the control group, P < 0.001) and the myocardium (16.90 +/- 6.40 vs 0.14 +/- 0.01 mu mol mu g-1 in the control group, P < 0.001). After hydroxocobalamin administration, cobalt concentrations were significantly lower in the diaphragm (25.10 +/- 16.50 mu mol mu g-1, P < 0.001 vs cobalt-treated group) and the myocardium (4.50 +/- 1.20 mu mol mu g, P < 0.001 vs cobalt-treated group). CONCLUSION: These results indicate that repeated administration of hydroxocobalamin was devoid of significant diaphragmatic and cardiac muscle toxicity and therefore remains a safe antidote for acute cyanide poisoning.

Relation between dicrotic notch and mean pulmonary artery pressure studied by using a Swan-Ganz catheter in critically ill patients.

OBJECTIVE: It has been recently shown that there is a match between dicrotic notch and mean pulmonary artery (PA) pressures in spontaneously breathing patients studied by means of high-fidelity pressure catheters. The aim of the study was to analyze the relation between mean PA pressure and PA pressure at the incisura by using a Swan-Ganz catheter in critically ill, mechanically ventilated patients. MEASUREMENTS AND RESULTS: Fluid-filled PA pressures were obtained over four ventilatory cycles in 32 consecutive, mechanically ventilated patients in the intensive care unit. We measured mean PA pressure and dicrotic notch pressure. We also calculated the widely used approximation of mean PA pressure (mean PAPapprox = diastolic + 1/3 pulse pressure). Cardiac output was measured in triplicate by using the thermodilution technique. Dicrotic notch was clearly identified in 30 of 32 patients. Mean PA pressure (32.1 +/- 10.2 mm Hg) and PA dicrotic notch pressure (31.8 +/- 10.4 mm Hg) were linearly related (r = 0.989, p < 0.001). Agreement between dicrotic notch and mean PA pressures was suggested (mean difference +/- SD = -0.3 +/- 1.5 mm Hg). Similar agreement was found between mean PAPapprox and mean PA pressure (mean difference +/- SD = -0.7 +/- 0.8 mm Hg; p = 0.20). CONCLUSION: By using a Swan-Ganz catheter we found that dicrotic notch pressure equalled mean PA pressure in the critically ill, mechanically ventilated patients studied. This indicated that right-sided ejection was completed at a PA pressure equal to mean PA pressure in these patients.

Relaxation of diaphragm muscle.

Relaxation is the process by which, after contraction, the muscle actively returns to its initial conditions of length and load. In rhythmically active muscles such as diaphragm, relaxation is of physiological importance because diaphragm must return to a relatively constant resting position at the end of each contraction-relaxation cycle. Rapid and complete relaxation of the diaphragm is likely to play an important role in adaptation to changes in respiratory load and breathing frequency. Regulation of diaphragm relaxation at the molecular and cellular levels involves Ca(2+) removal from the myofilaments, active Ca(2+) pumping by the sarcoplasmic reticulum (SR), and decrease in the number of working cross bridges. The relative contribution of these mechanisms mainly depends on sarcomere length, muscle tension, and the intrinsic contractile function. Increased capacity of SR to take up Ca(2+) can arise from increased density of active SR pumping sites or in slow-twitch fibers from phosphorylation of phospholamban, whereas impaired coupling between ATP hydrolysis and Ca(2+) transport into the SR or intracellular acidosis reduces SR Ca(2+) pump activity. In experimental conditions of decreased contractile performance, slowed, enhanced, or unchanged relaxation rates have been reported in vitro. In vivo, a slowing in the rate of decline of the respiratory pressure is generally considered an early reliable index of respiratory muscle fatigue. Impaired relaxation rate may, in turn, favor mismatch between blood flow and metabolic demand, especially at high breathing frequencies.

Mechanics of human quadriceps muscle.

Mechanics of human quadriceps muscle strips (vastus lateralis; n = 10) were investigated over the whole load continuum. Mechanical experiments were performed at 29 degrees C and in both twitch and tetanus modes. For a given level of isotonic total load (P) and over a large part of the contraction phase, instantaneous velocity (V) was shown to be a unique function of instantaneous length (L), regardless of time and initial length. By considering this time- and initial length-independent mechanical property between instantaneous L and instantaneous V over the whole P continuum, a three-dimensional P-V-L relationship was constructed. Any variations in stimulation conditions modified the time-independent P-V-L diagram. Such modifications in the P-V-L relationship were characteristics of changes in contractile performance. Moreover, characteristics of the P-V relationship were investigated in both twitch and tetanus modes. The curvature of the P-V hyperbola was significantly higher in tetanus at 30 Hz than in twitch mode (P < 0.001). In conclusion, our study indicates that, in human quadriceps muscles, contractility can be defined as the time- and initial length-invariant part of a three-dimensional P-V-L relationship. Moreover, our data are consistent with an increase in economy of force generation in tetanus contractions compared with that in twitches.