Increase in myocardial interstitial adenosine and net lactate production in brain-dead pigs: an in vivo microdialysis study

BACKGROUND: Brain death-related cardiovascular dysfunction has been documented; however, its mechanisms remain poorly understood. We investigated changes in myocardial function and metabolism in brain-dead and control pigs. METHODS: Heart rate, systolic (SAP) and mean (MAP) arterial pressure, left ventricular (LV) dP/dtmax, rate-pressure product, cardiac output (CO), left anterior descending coronary artery blood flow, lactate metabolism, and interstitial myocardial purine metabolite concentrations, monitored by cardiac microdialysis, were studied. A volume expansion protocol was performed at the end of the study. RESULTS: After brain death, a transient increase in heart rate (from 90 [67-120] to 158 [120-200] beats/min) (median, with range in brackets), MAP (82 [74-103] to 117 [85-142] mmHg), LV dP/dtmax (1750 [1100-2100] to 5150 [4000-62,000] mmHg x sec(-1), rate-pressure product (9100 [7700-9700] beats mmHg/min to 22,750 [20,000-26,000] beats mmHg/min), CO (2.2 [2.0-4.0] to 3.3 [3.0-6.0] L/min), and a limited increase in left anterior descending coronary artery blood flow (40 [30-60] to 72 [50-85] ml/min) were observed. Net myocardial lactate production occurred (27 [4-40] to -22 [-28, -11] mg/L, P<0.05) and persisted for 2 hr. A 6-7-fold increase in adenosine dialysate concentration was observed after brain death induction (2.9 [1.0-5.8] to 15.8 [7.0-50.7] micromol/L), followed by a slow decline. Volume expansion significantly increased MAP, CO, and LV dP/dtmax in control animals, but decreased LV dP/dtmax and slightly increased CO in brain-dead animals. A significant increase in adenosine concentration was observed in both groups, with higher levels (P<0.05) in brain-dead animals. CONCLUSIONS: Brain death increased oxygen demand in the presence of a limited increase in coronary blood flow, resulting in net myocardial lactate production and increased interstitial adenosine concentration consistent with an imbalance between myocardial oxygen demand and supply. This may have contributed to the early impairment of cardiac function in brain-dead animals revealed by rapid volume infusion.     

Direct myocardial effects of OPC-18790 in human heart failure: beneficial effects on contractile and diastolic function demonstrated by intracoronary infusion with pressure-volume analysis

OBJECTIVES: We sought to determine the precise myocardial effects of OPC-18790 as demonstrated by intracoronary administration. BACKGROUND: Although previous studies have determined the cardiovascular effects of a novel intravenous inotrope, OPC-18790, the observed benefits on contractile and diastolic function may have been confounded by the marked changes in peripheral loading associated with this drug when given intravenously. METHODS: Eight heart failure patients received intracoronary OPC-18790 at 31.25 microg/min for 20 min, and then at 62.5 microg/min for another 20 min. Hemodynamic variables and pressure-volume indexes using the conductance catheter method were determined at baseline and then after the two doses. RESULTS: There were no significant effects on heart rate, cardiac output or loading conditions, including afterload as determined by systemic vascular resistance and arterial elastance (Ea) and preload as determined by end-diastolic volume (EDV). There were significant increases in end-systolic elastance (Ees) from 0.74+/-0.11 to 0.90+/-0.16 mm Hg/ml at 31.25 microg/min and to 137+/-0.33 mm Hg/ml at 62.5 microg/min (p < 0.05 by analysis of variance [ANOVA]). Diastolic function improved, as determined by the time constant for isovolumetric relaxation tau, which decreased significantly from baseline to 31.25 microg/min (94+/-9 to 79+/-9 ms, p < 0.05), and did not shorten further at 62.5 microg/min (78+/-8 ms, p=NS). There were significant decreases in right atrial pressure (9+/-1 to 7+/-1 mm Hg, p < 0.01 by ANOVA) and mean pulmonary artery wedge pressure (21+/-3 to 16+/-2 mm Hg, p < 0.05 by ANOVA). This fall in filling pressures was not accompanied by any change in EDV. Inspection of the diastolic portion of the pressure-volume curve confirmed a downward shift consistent with pericardial release in five of the eight patients. CONCLUSIONS: Intracoronary administration of OPC-18790 demonstrates that the direct myocardial effects of this agent include a modest increase in inotropy and improvement in diastolic function, both of which occur without increases in heart rate, indicating that this agent may be beneficial for the intravenous treatment of congestive heart failure.     

Protective effects of API0134 on myocardial ischemia and reperfusion injury

A rare case of gangrenous cystitis is described. The questions of the incidence of this pathology are discussed, considering its rareness after the antibiotics age. The etiology of this disease is probably multifactorial and it is never possible to identify a unique cause. The gangrenous cystitis doesn't present with any typical symptomatology, out with urinary troubles common to many urologic diseases. Surgery is often performed in emergency without a preoperative defined diagnosis. Surgical treatment has changed with time from a simple bladder cavity draining to the resection of the necrotized bladder wall. In our case a total cystectomy with uretero-ileocutaneostomy, in two times, was performed. This procedure allowed the patient a good quality of life (1 year of follow-up).     

Protective effect of hypothermia on contractile force in skeletal muscle

The clinical success of limb replantation and tissue transfer is partly dependent on the duration of ischemia experienced by the amputated part. This study focused primarily on the damage that occurs during this ischemic period. An experimental system was implemented that allowed the observation of contractile function in totally isolated skeletal muscle after ischemia. Contractile function was selected as an indicator of ischemic damage because normal function is the ultimate goal of replantation. All experiments were performed on the rat extensor digitorum longus. The muscles were subjected to ischemic periods of 1.5, 3.0, and 5.0 hours and were stored in either a hypothermic (4 degrees C) or a room-temperature (23 degrees C) environment during the ischemic interval. After the ischemic period, all muscles were transferred to a tissue bath and were subjected to contractility testing, followed by fatigue testing. In both groups, muscle function decreased as the ischemic interval was increased. A significant difference in function between the normal control and the muscles of both ischemic groups implied that ischemic injury had occurred in the hypothermic and room-temperature muscles, even with the relatively short 1.5-hour ischemic interval. After each ischemic interval however, the hypothermic muscles produced significantly greater contractile force than the room-temperature muscles in both the contractility and the fatigue tests. After 1.5 hours of ischemia, the contractile force in the hypothermic group was about three times as great as that observed in the room-temperature group. These results indicated that muscle function after a period of totally isolated ischemia is protected by hypothermic preservation. They also support the advisability of storage of amputated parts and free muscle flaps in hypothermic environments before replantation even after relatively brief intervals of ischemia.     

Exercise-induced T-wave normalization predicts recovery of regional contractile function after anterior myocardial infarction

AIMS: We investigated the ability of T-wave pseudonormalization and ST-segment elevation, which are demonstrated in infarct-related leads during submaximal exercise testing, to predict late recovery of contractile function. METHODS: We studied 88 consecutive patients (73 males, mean age 59 +/- 8 years) with anterior infarction, persistent T-wave inversion and a documented lesion of the proximal segment of the left anterior descending coronary artery. They all underwent 2D-echocardiography on admission, 4 weeks as well as 6 months after myocardial infarction to evaluate the dysfunction score and the ejection fraction. Submaximal (75% of maximal predicted heart rate) exercise testing was performed in 80 patients 2 weeks after myocardial infarction following discontinuation of treatment. RESULTS: During exercise testing, 59 of the 88 patients showing negative T-waves on the resting electrocardiogram exhibited pseudonormalization (group A) in at least three adjacent precordial leads, whilst 29 (group B) did not. Patients of group A more frequently exhibited an early creatine kinase peak (41% vs 24%, P < 0.05) and residual angiographic perfusion (97% vs 69%, P < 0.05). The dysfunction score did not change in group B (from 19 +/- 7 to 22 +/- 4), but decreased in group A (from 18 +/- 4 to 11 +/- 6 P < 0.05). The ejection fraction was similar in the two groups on admission (group A: 48 +/- 7%, group B: 45 +/- 10%), but was significantly different at 4-week (52 +/- 99 vs 42 +/- 11%, P < 0.05) and 6-month follow-up (58 +/- 9 vs 44 +/- 10%, P < 0.01). The concomitant presence of ST-segment elevation and T-wave normalization showed the highest positive predictive value for left ventricular function recovery (100%). CONCLUSIONS: T-wave normalization induced by submaximal exercise test is frequently associated with residual perfusion to the infarct area and predicts progressive improvement in regional wall motion, especially if associated with ST-segment elevation. Therefore, these electrocardiographic findings may be used as easily obtainable markers of residual viability that predict late recovery in contractile function.     

Changes in myocardial hemodynamics and contractile function in patients under surgical treatment for prostatic adenoma

Hemodynamics and left ventricular myocardial contractility in 170 patients who underwent surgery of prostatic adenoma were examined in preoperative period and 16 days after single-stage transvesical adenomectomy. The age of the patients varied from 52 to 85 years. Echocardiography and the dilution method were used for the evaluation. The increase of end-diastolic and end-systolic volumes, stroke volume, cardiac index, was registered. The combined pharmacological treatment made it possible to decrease the number of operative and postoperative cardiovascular complications.     

Administration of desmopressin in brain-dead donors and renal function in kidney recipients

BACKGROUND: Diabetes insipidus is common among brain-dead donors and may lead to decreased graft function. The use of desmopressin to limit the consequences of diabetes insipidus is controversial. We assessed the effects of desmopressin administered to brain-dead donors on early and long-term graft function in kidney recipients. METHODS: In a randomised controlled study, 97 brain-dead donors received desmopressin as 1 microg bolus every 2 h when diuresis was more than 300 mL/h (desmopressin group n=49) or no desmopressin (control group n=48). In 175 kidney recipients (controls n=89, desmopressin group n=86) we measured serum concentrations of creatinine and haemodialysis requirements to assess early renal function in the first 15 days after transplantation. We assessed long-term results of transplantation (median time 45 months) for a homogeneous subgroup of 95 recipients (48 in the desmopressin group). FINDINGS: We found no significant differences between the two groups of brain-dead donors, except for final diuresis, which was lower in the desmopressin group than among controls. Haemodialysis requirement in controls and the desmopressin group (20 vs 23%, p=0.63) and serum creatinine concentrations (decrease from 903 micromol/L to 206 micromol/L vs 814 micromol/L to 193 micromol/L, p=0.14) did not differ significantly in the first 15 days after transplantation. Long-term graft survival was similar in the two groups (88 vs 87%). INTERPRETATION: Desmopressin can be given to brain-dead donors to limit the harmful effects of diabetes insipidus without any substantial effects to graft function in recipients.     

Adverse neonatal effects of maternal labetalol treatment

Two infants with features of severe beta adrenergic blockade, pericardial effusions, and myocardial hypertrophy were born to mothers receiving long term treatment with oral labetalol for hypertension in pregnancy. Labetalol was implicated in the aetiology of these problems. Pericardial effusion and myocardial hypertrophy have not been associated with labetalol toxicity in neonates.     

Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice

We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct. In contrast to the embryonic lethal phenotype of the homozygous betaARK1 knockout (Jaber, M., Koch, W. J., Rockman, H. A., Smith, B., Bond, R. A., Sulik, K., Ross, J., Jr., Lefkowitz, R. J., Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974-12979), betaARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct animals. Contractile parameters were measured in adult myocytes isolated from both groups of gene-targeted animals. A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of betaARK1 activity. This has important implications in disease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.     

The novel effects of 3,5,3'-triiodo-L-thyronine on myocyte contractile function and beta-adrenergic responsiveness in dilated cardiomyopathy

Medical management of patients with chronic left ventricular dysfunction continues to be a difficult problem. Recent clinical and experimental studies have suggested that 3,5,3'-triiodo-L-thyronine improves left ventricular pump function. However, whether 3,5,3'-triiodo-L-thyronine directly improves myocyte contractile function in cardiomyopathic states is unknown. Accordingly, this study examined the direct effects of 3,5,3'-triiodo-L-thyronine on isolated myocyte contractile function in cardiocytes obtained from control (n = 6) pigs and pigs with tachycardia-induced dilated cardiomyopathy (atrial pacing at 240 beats/min for 3 weeks; n = 6). Myocyte percent shortening and velocity of shortening were obtained at baseline and in the presence of 3,5,3'-triiodo-L-thyronine doses of 80 and 100 pmol/L. For both control and dilated cardiomyopathy groups, 3,5,3'-triiodo-L-thyronine caused a significant increase in myocyte contractile function. For example, a 100 pmol/L dose of 3,5,3'-triiodo-L-thyronine increased myocyte velocity of shortening by 51% in control myocytes and by 54% in dilated cardiomyopathy myocytes compared with baseline. A second series of experiments was performed to determine whether 3,5,3'-triiodo-L-thyronine altered the responsiveness of the beta-adrenergic receptor system in control and dilated cardiomyopathy myocytes. Myocyte contractile function was examined during beta-adrenergic stimulation with isoproterenol alone and in myocytes preincubated with 3,5,3'-triiodo-L-thyronine doses of 80 and 100 pmol/L to which isoproterenol was added. Isoproterenol alone increased velocity of shortening by 139% in control and by 233% in dilated cardiomyopathy myocytes compared with baseline. This was significantly greater than the increase with 3,5,3'-triiodo-L-thyronine alone. 3,5,3'-triiodo-L-thyronine followed by isoproterenol increased velocity of shortening by 245% in control and 313% in dilated cardiomyopathy myocytes compared with baseline. This was significantly greater than the response with 3,5,3'-triiodo-L-thyronine or isoproterenol alone and appeared to be greater than an additive response. The results from this study clearly demonstrated that 3,5,3'-triiodo-L-thyronine directly augmented myocyte contractile function in both control and dilated cardiomyopathy myocytes. In addition, 3,5,3'-triiodo-L-thyronine enhanced the contractile response to beta-adrenergic stimulation in dilated cardiomyopathy. This study provides unique evidence to suggest that 3,5,3'-triiodo-L-thyronine may be a useful adjunct to conventional inotropic support in the setting of advanced left ventricular dysfunction.     

Right atrial contractile performance in patients with myocardial infarction

To evaluate right atrial (RA) contractile performance in patients with myocardial infarction, we validated a cineangiographic method of RA volume measurement, and investigated RA volume change in 'normal' individuals and patients with a previous myocardial infarction. Sixteen silicone rubber RA casts made from human cadavers were filmed in the postero-anterior and left lateral projections. The cast volumes calculated following Simpson's rule were in good agreement with those measured by water replacement (r = 0.992, P < 0.01). At cardiac catheterization, biplane RA cineangiography was performed in 19 'normal' individuals (N group), in 14 patients with a previous antero-septal infarction (AMI group) and in seven patients with a previous inferior infarction (IMI group). The RA volume-time curve was constructed at 20-40 ms intervals for one cardiac cycle. RA volume at the beginning of the atrial contraction (RAVd), which was defined as the 'preload' of the RA, tended to be larger in both the AMI and IMI groups compared with 'normal' individuals. The RA ejection volume was significantly larger in both the AMI (18.4 +/- 2.1 ml.m-2, P < 0.01) and IMI groups (19.4 +/- 2.8, P < 0.01) than in the N group (14.5 +/- 1.9), even for a comparable level of RAVd (range from 26 to 36 ml.m-2) (18.6 +/- 2.1, P < 0.01, 18.2 +/- 2.0, P < 0.01, 14.7 +/- 1.9, respectively). These results suggest that RA contraction increases in patients with myocardial infarction by increasing both the 'preload' and 'contractility' of the RA.     

An experimental study of cardiac contractile force in myocardial infarction

The host-parasite relationship of HeLa M cells artificially infected with a bovine species of Mycoplasma was studied by light microscopy, transmission electron microscopy and scanning electron microscopy. The use of morphometry to quantitate some of the findings was explored. The parasites were seen in locations extracellular to the cell surface. The detection of small numbers of organisms by light microscopy was well demonstrated by use of the flurescent antibody technique. Scanning electron microscopy proved to be an excellent method for revealing the surface details of cell-parasite morphology. Ultra-thin sections showed that the parasites are aligned mostly parallel to the plasma membrane of the host cell but separated by a gap of 10nm. Morphometry indicated an average of 69 organisms per cell surface occupying 1.7% of the surface area. An increase of 26% in diameter of the HeLa cells, possibly as a result of infection, was observed.     

Insulin improves cardiac contractile function and oxygen utilization efficiency during moderate ischemia without compromising myocardial energetics

Insulin improves myocardial contractile function during moderate ischemia, but the mechanism is unknown. To determine effects of insulin on myocardial oxygen utilization efficiency (O2UE) and energetics, regional left coronary perfusion pressure (CPP) was lowered sequentially from 100 to 60, 50, and 40 mmHg in 24 anesthetized, open-chest dogs. Regional power index (PI), myocardial oxygen consumption (MVO2), and O2UE index (PI/MVO2) were determined in untreated and insulin treated (4 U/min, i.v.) hearts. Biopsies were obtained from six untreated and six insulin-treated hearts at CPP=40 mmHg for determining high energy phosphates and the cytosolic phosphorylation potential. Measurements were compared with data from normal, untreated myocardium (n=11). MVO2 fell (P<0.05) in all hearts as CPP was lowered to 40 mmHg, and was unaffected by insulin treatment. PI decreased 32 and 75% in untreated hearts at CPP=50 and 40 mmHg, respectively (P<0.05). In insulin treated hearts, PI was not significantly depressed at CPP>40 mmHg, and fell only 26% at CPP=40 mmHg. O2UE increased (P<0.05) in all hearts at CPP=60 mmHg. In insulin treated hearts, O2UE was greater (P<0.05) at CPP=50 and 40 mmHg than at CPP=100 mmHg, and greater (P<0.05) than in untreated hearts at CPP=40 mmHg. Reducing CPP to 40 mmHg produced similar metabolic changes in all hearts. Compared to normal myocardium, ATP content of untreated and treated hearts was unchanged, creatine phosphate content decreased 21 and 14%, creatine content increased 24 and 30%, inorganic phosphate concentration increased 108 and 140%, and phosphorylation potential decreased 80 and 77%. We conclude that insulin markedly improves PI and O2UE without altering cytosolic energetics during moderate myocardial ischemia.     

Disparate effects of adhesion and degranulation of platelets on myocardial and coronary function in postischaemic hearts

Pre-mRNA splicing is an important regulatory step in the expression of most eukaryotic genes. In vitro studies have shown splicing to occur within 50-60 S multi-component ribonucleoprotein (RNP) complexes termed spliceosomes. Studies of mammalian cell nuclei have revealed larger complexes that sediment at 200 S in sucrose gradients, termed large nuclear RNP (lnRNP) particles. These particles contain all factors required for pre-mRNA splicing, including the spliceosomal U snRNPs and protein splicing factors. Electron microscopy has shown them to consist of four apparently similar substructures. In this study, mass measurements by scanning transmission electron microscopy of freeze-dried mammalian lnRNP preparations, both confirm the similarity between the lnRNP particles and reveal the mass uniformity of their subunits. Thus, the tetrameric lnRNP particle has a mass of 21.1(+/-1.6) MDa, while each repeating subunit has a mass of 4.8(+/-0.5) MDa, which is close to the estimated mass of the fully assembled 60 S spliceosome. The 1.9 MDa discrepancy between the lnRNP particle's mass and the cumulative masses of its four subunits may be attributed to an additional domain frequently observed in the micrographs. Notably, strands and loops of RNA were often seen emanating from lnRNP particles positively stained with uranyl formate. Our results support the idea that the nuclear splicing machine is a supraspliceosome complex. For clarity, we define spliceosomes devoid of pre-mRNA as spliceosome cores, and propose that the supraspliceosome is constructed from one pre-mRNA, four spliceosome cores, each composed mainly of U snRNPs, and additional proteins. In this way a frame is provided to juxtapose exons about to be spliced.     

Exposure to chlorine gas: effects on pulmonary function and morphology in anaesthetised and mechanically ventilated pigs

We report on a child with a 'new' syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, bilateral symmetrical digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism of digits I-III. Because he had a similarly affected brother and his parents were cousins we suggest autosomal recessive inheritance, X-linked recessive inheritance cannot be excluded. Differential diagnosis from other syndromes with preaxial brachydactyly and hyperphalangism is presented.