Blockade of ATP-dependent K+ channels in myocardium and coronary artery smooth muscle: a possible cause of increased cardiovascular mortality in sulfonylurea-treated patients.
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Biomedical subjects
Publications and source records attributed to R Gasser.
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We herein present the first case in the literature of enucleation of an aldosterone-producing adenoma by laparoscopy. The indication for adrenal-sparing surgery was bilateral adrenal adenoma. The operation turned out to be easier than laparoscopic adrenalectomy. The postoperative course was uneventful, and the patient was cured; split adrenal function tests showed normal function of both adrenal glands.
The purpose of this investigation was to study myocardial function at rest, during three phases of energy supply, and during recovery. Radionuclide angiography was performed during the aerobic phase (phase I, rest-first lactate increase), the aerobic-anaerobic transition phase (phase II, first lactate increase-second lactate increase), the anaerobic phase (phase III, second lactate increase-maximal work performance (Pmax)), and during recovery. Thirty-eight male patients (59 +/- 7 d after myocardial infarction) were compared with 19 healthy control subjects and 21 sport students of comparable age. Left ventricular ejection fraction (LVEF) increased from rest to phase I and from phase I to phase II in sports students and control subjects. During phase III, LVEF did not change significantly in sports students, but it decreased significantly in control subjects. This is in contrast to the patients, who showed an increase of LVEF from resting values (47 +/- 3%) to phase I (50 +/- 1%), no change during phase II (51 +/- 2%), and a decrease to resting values (45 +/- 2) during phase III. All subjects showed an increase in stroke volume (SV) during phase I and II, reaching a maximum at phase II. This was evidenced by an improvement of the systolic function with a constant left ventricular end-diastolic volume (EDV) in control subjects and sports students. In contrast, an improved SV in patients was achieved through an increase in EDV and a less distinct increase in the left ventricular end-systolic volume (ESV). Maximal LVEF values were measured during the first 90 s of recovery in all subjects. Values during recovery are not representative of load dependent myocardial function. This increase in LVEF does not cause an increase in cardiac output but is a consequence of changes in the EDV and ESV, which decrease again immediately after the end of exercise performance.
In early myocardial ischemia we find several characteristic electrical and ionic alterations, like action potential shortening K(+)-accumulation or contractile failure. Trautwein and Dudel were 1954 the first to discuss action potential shortening as an important characteristic of myocardial ischemia. They already demonstrated that the action potential shortening is due to an enhanced outward current, while recently KATP-channels have been found to play an important role in the context. It has been suggested that contractile failure due to myocardial ischemia is caused by the shortening of action potential duration, reduced cytoplasmic free calcium levels, intracellular acidification, and a rise in inorganic phosphate and Mg. All of these phenomena may be related to the opening of KATP-channels. The different ionic and molecular mechanisms of contractile failure in myocardial ischemia will be discussed in this paper.
Purified simian virus (SV40) minichromosomes were photoreacted with psoralen under various conditions that moderately destabilize nucleosomes. This assay allows indirect distinction between stable nucleosomes, partially unravelled nucleosomes and nucleosomes containing (or lacking) histone H1. In replicating molecules the passage of the replication machinery destabilizes the nucleosomal organization of the chromatin fiber over a distance of 650 to 1100 bp. In front of the fork, an average of two nucleosomes are destabilized presumably by the dissociation of histone H1 and the advancing replication machinery. On daughter strands, the first nucleosome is detected at a distance of about 260 nucleotides from the elongation point. This nucleosome is interpreted to contain no histone H1, while no stepwise association of (H3-H4)2 tetramers with H2A/H2B dimers on nascent DNA can be detected in vivo. The second nucleosome after the replication fork appears to contain histone H1. The prolonged nuclease sensitivity of newly replicated chromatin described in the literature therefore may not be due to a slow reassociation of histone H1.
Although there is a tendency for rDNA genes within a species to maintain sequence homogeneity, there can be significant levels of variation among rDNA repeat sequences within populations or individuals of a species as a consequence of mutation mechanisms. To date, there have been no practical techniques available in molecular parasitology that allow the extent of sequence variation among the repeats (i.e., number of sequence types) to be displayed visually. In this report, we describe the use of the denaturing gradient gel electrophoresis (DGGE) technique for the rapid screening of parasite rDNA for sequence variation without the need for exhaustive cloning or DNA sequencing. The resolution of this variation by DGGE provides a diagnostic fingerprint for a species.
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Angiotensin-converting enzyme (ACE) inhibitors are widely used in the management of hypertension, heart failure, and nephropathy. It has been suggested that ACE inhibitors containing the sulfhydryl group (SH) have an additional effect on KATP channels. To prove this hypothesis, we studied the effects of the SH-containing ACE inhibitors, captopril and zofenopril, on KATP channel opening of bovine coronary arteries and guinea pig thoracic aortas. Bovine coronary arteries were precontracted with the thromboxane A2 analogue, U46619, and guinea pig thoracic aortas were precontracted with phenylephrine and then relaxed with either captopril or zofenopril (n = 8). Inhibition of KATP channel opening with glibenclamide moderately attenuated the zofenopril-induced relaxation of guinea pig thoracic aorta. However, in the bovine coronary arteries, the relaxing effect of both captopril and zofenopril remained uneffected by glibenclamide. In experiments with enalapril (a non SH-containing ACE inhibitor; n = 6) on guinea pig thoracic aortas, no effect on KATP channels could be seen. From our experiments, we conclude that the postulated opening of KATP channels by SH-group-containing ACE inhibitors contributes little to the vasodilation of guinea pig thoracic aortas caused by ACE inhibitors, and that SH groups have no influence upon KATP channels of bovine coronary arteries.
It is suggested that Borrelia burgdorferi infection could be associated with dilated cardiomyopathy (IDC). Stanek et al. were able to cultivate Borrelia burgdorferi from myocardial biopsy tissue of a patient with longstanding dilated cardiomyopathy. Here we present a study in which we examined the effect of standard antibiotic treatment on the left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy associated with Borrelia burgdorferi infection. In this study we assessed the serum (IgG, IgM Elisa) and history of 46 IDC patients with specific regard to Borrelia burgdorferi infection (mean LVEF 30.4 +/- 1.3%, measured by cardiac catheterization and echocardiography with the length-area-volume method). All 46 patients received standard treatment for dilated cardiomyopathy: ACE inhibitors, digitalis, and diuretics. Eleven (24%) patients showed positive serology and a history of Borrelia burgdorferi infection; nine of these also had a typical history of tick bite and erythema chronicum migrans (ECM) and/or other organ involvement, and two had no recollection of tick bite or ECM but showed other Borrelia burgdorferi-associated disorders (neuropathy, oligoarthritis). These 11 patients with Borrelia burgdorferi infection received standard antibiotic treatment with intravenous ceftriaxone 2 g bid for 14 days. Six (55%) recovered completely and showed a normal LVEF after 6 months, three (27%) improved their LVEF, and two (18%) did not improve at all. This amounts to nine (82%) patients with recovery/improvement in the Borrelia burgdorferi group. The 35 patients who did not show positive serology or a history of Borrelia burgdorferi infection did not receive antibiotic treatment. In this group without Borrelia burgdorferi infection 12 (26%), showed recovery/improvement following the standard treatment of dilated cardiomyopathy (see earlier). Our results indicate that Borrelia burgdorferi infection could play a decisive role in the development of dilated cardiomyopathy, especially in a geographical region such as Graz, where Borrelia burgdorferi is endemic. While we are aware of the small number of Borrelia burgdorferi patients in this study, we nevertheless conclude that in a remarkable number of patients with signs of Borrelia burgdorferi infection, dilated cardiomyopathy could be reversed and LVEF improved.
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OBJECTIVES: Our technique of laparoscopic adrenalectomy as well as the results of this method are presented. METHODS: Transperitoneal laparoscopic adrenalectomy was performed in 18 consecutive patients (10 right side, 8 left side) for Conn's disease (7 patients), pheochromocytoma (6 patients), Cushing's syndrome (1 patient), and large inactive adenoma (4 patients). The tumor size ranged between 1 and 8 cm (mean 4.2). One of the patients, who presented with Conn's disease and bilateral adenoma, underwent enucleation of the larger adenoma on the right side leaving the uninvolved portion of the adrenal gland intact. RESULTS: The mean operative time was below 3 h; blood loss was minimal in all cases except 2. Hypertensive crisis was not encountered in this series. The only postoperative complication seen was transient diabetes insipidus which occurred in 1 patient. Analgesics were required only on the first 2 postoperative days. Oral intake and ambulation were resumed within 24 h. Mean postoperative hospitalization was 4.6 days. CONCLUSIONS: In our hands, laparoscopic adrenalectomy proved to be associated with a low morbidity and few complications. In addition, it is one of the few procedures where laparoscopy can compete with open surgery in terms of operative time.
In 1917, spirochaetal neurosyphilis was treated successfully with malariotherapy in combination with salvarsan or bismuth. Malariotherapy for spirochaetal Lyme disease has been discussed, but the mechanism of an antispirochaetal effect remains unclear. We cultured Borrelia burgdorferi at different temperatures, alone and in combination with antibiotics. Our data demonstrate that growth of the strains PKo and ATCC 35210 (B31) was impaired at temperatures of 37 degrees C and inhibited at 39 degrees C and 40 degrees C, respectively. Strain ATCC 35211, however, grew well up to 39 degrees C but did not multiply at 40 degrees C. A bactericidal effect was seen at 41 degrees C for the strains B31 and PKo and at 42 degrees C for all strains. The susceptibility of all strains to penicillin and ceftriaxone was increased up to 16-fold by an elevation of temperature from 36 degrees C to 38 degrees C. These in vitro data suggest that elevated body temperature may be beneficial during antimicrobial treatment of Lyme disease. This may be particularly important in tissues where high concentrations of antibiotics are difficult to achieve.
In this pilot trial, 18 patients participated in an investigation in which the combined therapy of co-trimoxazole and roxithromycin in late Lyme borreliosis was tested. The study has been performed as a result of earlier case reports in "The Lancet" where this combination has been used successfully in order to thwart late Lyme disease. The authors show that 76% of the patients recovered completely. In 2 patients, symptoms could be resolved with i.v. penicillin and 2 did not respond to any antibiotic therapy. These results show that oral therapy of co-trimoxazole and roxithromycin in combination provides similar results as i.v. antibiotics in earlier studies.
From a cardiologist's view there are several established indications for the use of ACE-inhibitors like hypertension, heart failure and acute myocardial infarction. In other forms of coronary artery disease like stable and unstable angina and prevention of arteriosclerotic complications. ACE-inhibitors are under discussion. As antihypertensives ACE-inhibitors are about equally effective as calcium blockers, betablockers and diuretics without the negative effects on lipid metabolism and insulin sensitivity. Vascular and cardial remodelling are prevented with ACE-inhibitors at least to a certain degree. In heart failure ACE-inhibitors reduce morbidity and mortality, if left ventricular ejection fraction is reduced. In acute myocardial infarction ACE-inhibitors are indicated in overt heart failure, depressed left ventricular function and high-risk-patients. In silent ischaemia and secondary prevention ACE-inhibitors are under discussion.
ACE-inhibitors are used in the treatment of hypertension, and ischemic heart disease, chronic heart failure, cardiomyopathy and diabetic nephropathy. The effect of the ACE inhibitors is mainly due to the inhibition of the angiotensin converting-enzyme, but they also potentiate the effect of bradykinine. Sargent et al. have indicated, that SH-containing ACE-inhibitors show an effect on KATP-channel open probability in vascular smooth muscle. In our experiments, we used isolated bovine coronary arteries and guinea pig aortas, which were cut transversally and brought into Normal-Tyrode-solution. The vessels were precontracted with phenylephrine or U 46619, and after that a cumulative dose of the SH-containing ACE-inhibitors Captopril or Zofenopril was added to obtain a relaxation curve. In a second series we blocked the KATP-channels with glibenclamide to see if the relaxation could be attenuated. In bovine coronary arteries the relaxing effect of Captopril could not be attenuated by glibenclamide, a specific blocker of KATP-channels of vascular smooth muscle. In the guinea pig aorta, the relaxing effect of Zofenopril was also not effected by glibenclamide. The concentrations of Zofenopril were between 10(-7) and 10(-4) mol/l; the maximal effect could be seen at a concentration of 10(-5) mol/l. Experiments with the non SH-containing ACE-inhibitor Enalapril did also not show any statistically significant difference between the 2 groups of series. We conclude, that, in contrast to Sargent's conclusions, there is little or no effect on KATP-channels due to the presence of SH-groups.
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The correlation between the behaviour of the heart rate/work performance (fc/W) curve and blood lactate ([la]b) and plasma adrenaline/noradrenaline concentrations ([A]/[NA]) during incremental cycle ergometer exercise was investigated. A group of 21 male sports students was divided into two groups: group I, with a clear deflection of the fc/W curve; group II, without or with an inverse deflection of the fc/W curve. The aerobic threshold (Thaer) and the lactate turn point (LTP) were defined. Between Thaer and maximal work performance (Wmax) the behaviour of the fc/W curve as well as the behaviour of [la-]b and [A]. [NA] were described mathematically. The fc, systolic blood pressure (BPs), W, [la-]b, [A] and [NA] at rest, Thaer, LTP, Wmax, after 3 and 6 min of recovery (Re3/Re6) were calculated. A significant difference between the two groups could only be detected for fc at LTP, Re3 and Re6 (P < 0.05). No significant correlation could be found between individual fc/W-behaviour and individual time course of [la-]b, [A] and [NA]. However, a significant correlation was visible between [la-]b/W-behaviour and individual catecholamine response. These results and the fact that the different flattening at the top of the fc/W curve was related to diminished stress-dependent myocardial function led us to the conclusion that it is possible that sympathetic drive is not directly involved in mechanisms of regulation between load dependent fc and myocardial function. In addition, individual fc/W behaviour was independent of BPs and Wmax, or individual conditions of energy supply.
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