EDRF does not mediate coronary vasodilation secondary to simulated ischemia: a study on KATP channels and N omega-nitro-L-arginine on coronary perfusion pressure in isolated Langendorff-perfused guinea-pig hearts.

Several authors have alluded to the possible involvement of EDRF (NO) in ischemia-induced coronary artery dilation. Alternatively, it has been suggested that opening of ATP-dependent K channels could play a key role in this context. We studied the effects of sulfonylureas and NG-nitro-L-arginine (LNNA), a specific inhibitor of endothelial NO (EDRF) synthesis, on ischemia-induced coronary vasodilation in isolated Langendorff-perfused guinea pig hearts arrested with 15 mM KCl in normal Tyrode, and isolated pig coronary arteries precontracted with 43 mM KCl. In Isolated Langerdorff-perfused guinea pig heart, when hypoxia was simulated by switching 100% O2 in the perfusate to 100% N2, coronary perfusion pressure (CPP) fell from 90 cm H2O by 45 +/- 5 cm H2O. In the presence of LNNA, a specific inhibitor of NO synthetase in endothelial cells, CPP dropped by 44 +/- 6 cm H2O (n = 6; +/- SEM, no statistically significant). On biochemical simulation of ischemia (addition of iodoacetate [IAA]), CPP dropped 40 +/- 6 cm H2O, and in experiments performed under the same conditions but in the presence of LNNA, CPP dropped by 38 +/- 5 cm H2O (n = 6; +/- SEM; not statistically significant). When ischemia was simulated metabolically by equimolar replacement of 10 mM glucose with 2-deoxyglucose (DOG), an inhibitor of glycolysis CPP decreased by 24 +/- 1 cm H2O (n = 6; +/- SEM) after 15 minutes. This fall in CPP was almost prevented by 20 microM glibenclamide, whereas in the presence of 20 microM LNNA the DOG-induced decrease in CPP was not significantly inhibited, and CPP decreased by 22 +/- 2.6 cm H2O (n = 6; +/- SEM). In isolated pig coronary artery rings, maximal tension, achieved by depolarizing the smooth muscle cells by 43 mM KCl, decreased by 37 +/- 7% upon simulated hypoxia by replacing 100% O2 with 100% N2 in the perfusate (n = 6; +/- SEM) in arteries with intact endothelium. In arteries without endothelium, maximal tension also dropped by 35 +/- 6% (not statistically significant). In the same experiments the decrease in tension could be largely inhibited in the presence of 50 microM glibenclamide. Our results clearly show that in isolated perfused guinea pig hearts, as well as in isolated pig coronary arteries, EDRF does not play a decisive role in the coronary dilatory response to hypoxia and ischemia.

First description of the effect of a non-sulfonylurea compound, tetramethylpyrazine, on coronary response to desoxyglucose-induced ischemia.

The compound 2,3,5,6-Tetramethylpyrazine (TMP; Ligustrazine), a flavouring component and sweetness enhancer for beverages constitutes a commonly used food additive. Now we studied the effect of TMP on coronary artery dilation during ischemia: In our experiments we used isolated, Langendorff-perfused guinea pig hearts, arrested with K(+)-rich Normal Tyrode solution (in mM: NaCl 129.5, KCl 15, MgCl2 0.8, CaCl2 1.0, glucose 10), buffered with 10 mM HEPES to pH 7.4 at 37 degrees C, equilibrated with 100% O2. Ischemia was simulated by equimolar replacement of glucose by 2-deoxyglucose (DOG), an inhibitor of oxydative phosphorylation. We found that coronary perfusion pressure (CPP) decreased by 20 +/- 1.2 cm H2O (from initially 90 cm H2O; n = 6, +/- SEM) within 15 min from the onset of DOG. In the presence of 1 mM TMP the decrease in CPP was largely attenuated and CPP declined by 1.4 +/- 1.0 cm H2O (n = 6, +/- SEM; p < 0.01). In 2 out of the 6 TMP experiments even as light increase in CPP (< 2 cm H2O) could be seen. We conclude that TMP, a blocker of ATP-dependent K(+)-channels in pancreatic beta-cells and possibly in arterial smooth muscle cells, prevents coronary dilation in response to ischemia. The possible suppression of this vital mobilization of coronary reserve during ischemia in patients with coronary artery disease certainly merits further attention and may question the use of this compound as a food additive.

[Contractile force and myocardial ischemia--electrical and ionic mechanisms]. / Kontraktile Kraft und Myokardischämie--Elektrische und ionale Mechanismen.

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.

Roxithromycin in the treatment of Lyme disease--update and perspectives.

Spirochaetal infections have been successfully treated with penicillin; more recently, erythromycin has been used in cases with known penicillin allergy. The discovery of the spirochaete Borrelia burgdorferi and the elaboration of a new generation of macrolides with properties that differ from older macrolides have led to new ways of treating spirochaetal disease with these compounds. This paper presents data on the in vitro and in vivo efficacy of a combination of roxithromycin and co-trimoxazole against B. burgdorferi. In vitro (checkerboard technique; B. burgdorferi strain B31; modified BSK II medium) it was found that while roxithromycin showed excellent efficacy against B. burgdorferi (MIC 0.031 mg/l), co-trimoxazole had no effect. However, the combination of both chemotherapeutics led to a minor synergistic effect, decreasing the MIC for roxithromycin by one dilution step at concentrations of co-trimoxazole from 256 to 8 mg/l. In addition, a clearly reduced growth of microorganisms was seen at concentrations of roxithromycin as low as 0.015 mg/l in combination with 256 to 4 mg/l co-trimoxazole, when compared to the positive controls. Most interestingly, however, the motility of B. burgdorferi was markedly reduced even when the two drugs were combined at very low concentrations. In an in vivo, non-randomised, open, prospective pilot study it was found that of 17 patients with confirmed late Lyme borreliosis (stage II/III), treated with combined roxithromycin (300 mg b.i.d.) and co-trimoxazole for 5 weeks, 13 (76%) recovered completely by the end of treatment, and four continued to have symptoms on follow-up at 6 and 12 months. This success rate is similar to that seen with i.v. penicillin and ceftriaxone. It appears that the reduced motility of B. burgdorferi makes the pathogen more accessible to the immune system.

[Physical activity at intermediate altitude by healthy probands and patients with coronary sclerosis]. / Körperliche Aktivität in mittleren Höhenlagen bei Gesunden und Patienten mit Koronarsklerose.

For the majority of the population, exposure to altitudes higher than 2000 m above sea level constitutes a situation of pronounced stimulation of the organism. The question comes in of the health relevance of physical activity at intermediate altitudes for the healthy subjects, but above all for people with heart problems. At first, there is an acute adaption on the cardiovascular and the respiration system as well as the system of oxygen carriage, until the chronic adaption processes of the same systems are completed. Doubtlessly, these adaption processes at intermediate altitudes and in particular training in such regions considerably improve the endurance capacity under conditions of the kind mentioned. However there is little evidence, for an absolute improvement of the maximal aerobic capacity. As a rule, the effects of adaption to higher altitudes can also be expected in patients with coronary sclerosis. But a lowered level of capacity must be taken into account in these cases. Accordingly, the medication as well as the intensity of stress should be adapted to altered conditions of this kind. Training intensity must be reduced according to altitude, and any treatment for angina, must be intensified. It may be necessary to re-determine the appropriate training intensity as well as the dosage in pharmacotherapy by ergometric methods to match the new requirements. However, when a comparison is tried to kinetotherapy under normal conditions, an immediate therapeutical effect of exposition to higher altitudes appears to be at least doubtful.

[Coronary heart disease as the initial manifestation of primary hyperparathyroidism]. / Koronare Herzkrankheit als Erstmanifestation eines primären Hyperparathyreoidismus.

Due to unstable angina pectoris coronary arteriography was performed in a 57 year-old female, showing diffuse 3-vessel disease; aortocoronary bypass surgery was recommended. During routine pre-operative examination hypercalcemia, as well as an elevated value of parathormone were observed. Ultrasonography of the parathyroid glands showed two enlarged cranial glands. In a simultaneous surgical procedure 4 bypass grafts were performed and 4 hyperplastic parathyroid glands were removed, one of which was re-operated as an autotransplantation in the left musculus adductor magnus. Histological examination showed water clear cell hyperplasia of the parathyroid glands. Though the patient had suffered from stomach and duodenal ulcers and nephrolithiasis over several years, primary hyperparathyroidism was diagnosed only after angiographically proven coronary artery disease.

A physiological oral magnesium supplement does not influence total serum magnesium, left ventricular ejection fraction and prognosis in patients with dilated cardiomyopathy.

It has been postulated that patients with congestive heart failure (CHF) benefit from physiological oral magnesium supplements. In order to study the effect of such supplements upon patients with idiopathic dilated cardiomyopathy (IDC) we studied a group of 23 patients with the salient characteristics of IDC (18 male, 5 female; mean age 51 +/- 13 years [range: 23-72]; Mg group), who received oral magnesium supplements (15 mmol/day). All patients received oral ACE inhibitors and 22 were receiving digitalis and diuretics. A control group of 27 patients, matched for age, sex, symptoms, and additional treatment (22 male, 5 female; mean age 52 +/- 13 years [range 22-71]) were not given oral magnesium supplements. All these patients also received oral ACE inhibitors, 25 were receiving digitalis, and 23 were receiving diuretics. Mean serum magnesium concentration (total serum Mg) in the Mg group was 0.83 +/- 0.06 mmol/litre [mean +/- SD, range 0.69-0.99], while in the control group it was 0.83 +/- 0.07 mmol/litre [range 0.70-0.96], P = NS. Left ventricular ejection fraction (LV-EF) improved from 32 +/- 11 per cent [range 13-51] to 42 +/- 14 per cent [range 15-66] in the Mg group and from 30 +/- 13 per cent [range 10-52] to 42 +/- 11 per cent [range: 25-64] in the control group. We found that physiological oral Mg supplements did not influence serum magnesium, LV-EF, or prognosis. Furthermore, we found that 56 per cent of all patients improved when subjected to strict guidance and therapy with ACE inhibitors, digitalis, and diuretics.

Frequency of magnetic resonance signal abnormalities of the brain in patients aged less than 50 years with idiopathic dilated cardiomyopathy.

Twenty patients with idiopathic dilated cardiomyopathy (IDC) aged less than 50 years (mean 41) and an age-matched group of 20 healthy volunteers were studied. All subjects were free of cerebrovascular symptoms and risk factors for stroke. Magnetic resonance imaging of the brain, extracranial Doppler ultrasonography, heart catheterization and echocardiography were performed. In patients with IDC, a higher frequency of ventricular enlargement (p less than 0.02), cortical atrophy (p less than 0.01) and white matter lesions (p less than 0.05) was observed. Cerebral infarcts were found in 4 patients (p less than 0.05) who showed clinically severe limitation of functional capacity (New York Heart Association class III or IV). The extent of cortical atrophy, and the duration of clinical evidence of IDC showed a significant correlation (p less than 0.04). The data indicate a high incidence of parenchymal abnormalities of the brain in young, neurologically asymptomatic patients with IDC.