[The (Belgian) Journal of Medicine]. / Het (Belgisch) tijdschrift voor Geneeskunde.

During the second half of the 19th century, a growing tendency developed in the Flemish intellectual circles to promote the use of their own language for the cultural, social and scientific development of Flanders. The emergence of a Dutch-language medical press formed an integral part of this movement. The attempt to regularly supply physicians in Flanders with scientific information on medical progress in their own language only succeeded in 1910 with the first issue of the "Geneeskundig Tijdschrift voor België" (Belgian Medical Journal). This journal became increasingly successful, but its edition was interrupted in 1914 at the outbreak of World War I. In 1920, the aim of this publication was pursued by the "Vlaamsch Geneeskundig Tijdschrift" (Flemish Medical Journal) which was published without interruption until the end of World War II (1944). These two journals not only accomplished a task of disseminating scientific information; they also played an important role in the struggle for the recognition of the Dutch language in academic education which led to Dutch becoming first partially (1923) and then completely (1930) the instructional language at Ghent University. That same struggle resulted also in the creation of the "Koninklijke Vlaamsche Academie voor Geneeskunde" (Royal Flemish Academy of Medicine) in 1938. The actual "Tijdschrift voor Geneeskunde" (Medical Journal) that was launched shortly (1945) after World War II, took over the assignment of providing scientific information. Throughout its existence, the journal was backed by colleagues of the Faculties of Medicine of the Flemish universities and the various sections of the medical profession. As a result, in the fifty-six years of its existence the journal has grown into a permanent value in the field of medical information and continuing education of physicians in Flanders. On the threshold of the 21st century, the "Tijdschrift voor Geneeskunde" will have to take up the challenge to further closely follow the extremely fast advances in medical science and also in our society. It will have to make sustained efforts to continuously adapt itself to new circumstances in order to contribute in a correct way to a high-quality medicine in our community.

Contribution of nitric oxide to the endothelium-dependent hyperpolarization in rat aorta.

1. The effect of endogenous and exogenous nitric oxide on the membrane potential (Em) of smooth muscle cells of the thoracic aorta of rats was investigated. 2. In tissues with intact endothelium, application of ACh or carbachol generated a change of the membrane potential consisting of an initial hyperpolarization by 10-12 mV, followed by a partial recovery toward a level which was at 10 min still 6-8 mV more negative than in control conditions. 3. Application of NG-nitro-L-arginine methylester (L-NAME), an inhibitor of endogenous NO production, had no significant effect on the resting membrane potential. The initial peak endothelium-dependent hyperpolarization elicited by ACh or carbachol was not significantly diminished. However, the recovery was more accentuated. Similarly, NG-monomethyl-L-arginine (L-NMMA) significantly diminished the second component of the endothelium-dependent hyperpolarization without affecting the magnitude of the first transient peak Em change. 4. Nitroglycerin produced a small sustained hyperpolarization of 1-2 mV, and the NO donor SIN-1, the active metabolite of molsidomine, similarly increased Em by about 1 mV. Infusion of high doses of acidified NaNO2 solution caused a hyperpolarization smaller than that evoked by ACh or carbachol. 5. 8-Bromo-cyclic GMP caused little change of membrane potential. In the presence of 8-Br-cGMP, ACh evoked a membrane electrical response similar to that observed in the absence of the nucleotide. 6. It is concluded that, in the rat aorta, the initial peak endothelium-dependent hyperpolarization observed under the influence of ACh or carbachol is not directly related to the synthesis of NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of converting enzyme inhibition on isoflurane-induced hypotension for cerebral aneurysm surgery.

Twenty-five patients (aged 18 to 72 years), who recovered after the first bleed from a cerebral aneurysm, were operated on under neuroleptanaesthesia. Isoflurane was added to induce hypotension. It was found that the required hypotension (51 (SEM 1) mmHg) could be obtained and maintained at much lower isoflurane concentrations (less than 1%) after blockade of the angiotensin converting enzyme activity by enalaprilat (2.5 mg i.v.) than without such inhibition. During the hypotension which lasted 78 (SEM 10) min, only minor adjustments of the isoflurane concentration (0.70 (0.04%) were needed. The desired level of hypotension was obtained with preservation of the cardiac output and without tachycardia. No resistance to the blood pressure lowering effect of isoflurane was observed. On recovery from anaesthesia, a small increase of blood pressure above control values was seen in 16 patients and was easily reversed by small doses of clonidine (mean total dose: 220 (61) micrograms). The operative conditions were excellent and the postoperative recovery was uneventful and complete in 23 patients.

Endothelium-dependent relaxation and hyperpolarization in aorta from control and renal hypertensive rats.

Endothelium-dependent relaxations are depressed in hypertension. In this study we investigated the possible involvement of endothelium-dependent smooth muscle hyperpolarization in this phenomenon. In isolated aortic segments from control rats, acetylcholine (10(-8)-10(-5) M) elicits relaxations after precontraction with norepinephrine (10(-7) M), and acetylcholine or carbachol (10(-5) M) induce smooth muscle hyperpolarization (10.6 +/- 0.9 mV). Both effects disappear after removal of the endothelium and are depressed by tetraethylammonium (3 x 10(-3) M), a rather nonspecific blocker of K+ channels, but not by glibenclamide (10(-5) M), a potent blocker of the ATP-regulated K+ channels, which has a marked effect on the relaxation induced by BRL 38227. The relaxation effect of acetylcholine is impaired in norepinephrine-contracted preparations from hypertensive rats but is not further depressed by tetraethylammonium. In aorta from hypertensive rats, hyperpolarization induced by carbachol was significantly reduced to a mean of only 21.8% of the values obtained in preparations from normotensive rats. From the relaxation-hyperpolarization relation obtained with BRL 38227 (opening K+ channels), it is derived that the endothelium-dependent hyperpolarization (approximately 10 mV) contributes for at least 20-30% of the maximal relaxation effect of acetylcholine on rat aorta. It is concluded that the diminished endothelium-dependent hyperpolarization may contribute to the depression of the endothelium-dependent relaxation in hypertension.

Acidification and intracellular sodium ion activity during stimulated myocardial ischemia.

With the use of microelectrodes, intracellular pH (pHi), surface pH (pHs), and intracellular Na+ activity (aiNa) were measured in isolated guinea pig papillary muscles during normal superfusion and during a reversible condition of simulated ischemia. Acid loading by NH+4 prepulse or by CO2-HCO3- addition during superfusion with pH 7.4 solutions caused internal acidification followed by a recovery of pHi, which could be inhibited by amiloride. pHi recovery was associated with an amiloride-sensitive peak rise of aiNa and membrane hyperpolarization, indicative of Na(+)-H+ exchange. Peak increase of aiNa was absent if the pH of the superfusion solution was concomitantly lowered. Imposed ischemia after control superfusion caused membrane depolarization and acidification of pHi and pHs. The change of pHs consistently was larger than that of pHi. aiNa decreased from 5.5 to 4.6 mM after 10-min ischemia. Enlarging the pHi (and pHs) decrease in ischemia by prior reduction of the tissue buffer capacity (CO2-HCO3(-)-free superfusion) was unable to induce a rise of aiNa during the subsequent ischemic period. Amiloride had no significant effect on aiNa during ischemia. It is concluded that the important acidification of pHs reduces the rate of pHi regulatory Na(+)-H+ exchange and thereby contributes to a longer maintenance of the Na+ electrochemical gradient in ischemic cardiac muscle.

Simulated ischemia and intracellular pH in isolated ventricular muscle.

Isolated guinea pig papillary muscles were subjected to an in vitro model of ischemia, consisting of superfusion arrest and immersion in paraffin oil, which results in restriction of substrate supply and metabolite washout. Intracellular pH (pHi) and surface pH (pHs) were measured with glass microelectrodes. Contractile force declined to 82% of the pre-"ischemic" value after 2 min and to 37% of the control value after 10 min. In addition, a shortening of the time to peak and duration of contraction was noted. The rate of force development decreased later than the rate of relaxation. After 10 min, pHi was acidified on average 0.08 pH unit, which is about one-third of the measured pHs change. Tripling the ischemic pHi change by reduction of the intracellular buffering power only slightly increased the rate of tension decline. Experimental pHi changes of similar magnitude, induced during normal superfusion, had a smaller effect on contractile force and failed to reproduce the characteristic changes in time course of the contraction. It is concluded that, in our condition of simulated ischemia, the intracellular acidification cannot account fully for the rapid decline in contractility.

Effect of tamoxifen on the activity of enzymes of testicular steroidogenesis.

Testicular homogenates of tamoxifen-treated rats were incubated with labeled steroid precursors (progesterone, 17 alpha-hydroxyprogesterone, dehydroepiandrosterone, androstenedione or testosterone) in order to study the effect of tamoxifen on testicular steroidogenesis. The results indicate that a 9 day treatment with a daily dose of 1 mg tamoxifen produces a reduction of the synthesis of testosterone. Inhibition of the 17 alpha-hydroxylase and C17,20-desmolase enzyme systems was observed together with an increased 20 alpha-hydroxysteroid dehydrogenase activity.

Streptokinase treatment versus calcium overload blockade in experimental thromboembolic stroke.

Thromboembolic brain ischemia was produced in dogs using an autologous blood clot model. The effect of postembolic treatment with flunarizine and streptokinase on hemispheric cerebral metabolic rate for oxygen (CMRO2), oxygen extraction ratio (OER), and cerebral blood flow (CBF) was studied by positron emission tomography (oxygen-15 technique) 24 hours after the insult. We studied five groups of experimental dogs and compared them with a control group of nonembolized dogs. Group I received no treatment, Group II was treated locally with 500,000 IU streptokinase starting 30 minutes after the insult, Group III received streptokinase locally 30 minutes after the insult and 0.1 mg/kg i.v. flunarizine immediately after the insult and 2 hours later, Group IV received flunarizine as Group III, and Group V was orally pretreated with 0.5 mg/kg/day flunarizine during 2 weeks preceding embolization. Compared with the contralateral hemisphere, in the embolized hemisphere a significant reduction of CMRO2 (-25% to -40%) and CBF in normocapnia (-35%) and hypercapnia (-50%) was observed in Groups I, II, and V. In Groups III and IV, CMRO2, OER, and CBF of the embolized hemisphere were within the normal range during normocapnia and hypercapnia; the extent of the ischemic lesions was markedly less than in the other groups of experimental dogs. We conclude that flunarizine treatment after experimental thromboembolic stroke had a favorable influence on brain tissue. Chronic preventive flunarizine treatment failed to have a beneficial effect.

Relaxations to endothelium-derived relaxing factor and the metabolite of molsidomine, SIN-1, in the aorta and the hindquarters of the rat.

The effects of SIN-1 were studied on isolated aortic rings and perfused hindquarters of the rat and were compared with the effects of nitroglycerin and endothelium-derived relaxing factor (EDRF) released by acetylcholine or histamine (aorta) and carbachol (hindquarters). SIN-1 relaxes rat aortic rings in a dose-dependent and endothelium-independent way. Aortic rings made tolerant to nitroglycerin in vitro show cross-tolerance to isosorbide dinitrate but no cross-tolerance to EDRF, sodium nitroprusside, or SIN-1. Aortic rings made tolerant to nitroglycerin by in vivo treatment show an important cross-tolerance to isosorbide dinitrate, a small degree of tolerance to sodium nitroprusside, but no significant tolerance to SIN-1 or EDRF. Also, in the nitroglycerin-tolerant hindquarter vasculature, no cross-tolerance is found to EDRF or SIN-1. In the aorta of renal hypertensive rats, in which the relaxation to EDRF-dependent dilators is impaired, no depression of the maximal response to SIN-1 occurs.

Experimental thromboembolic stroke studied by positron emission tomography: immediate versus delayed reperfusion by fibrinolysis.

Acute obstruction of the middle cerebral artery (MCA) was obtained by injecting a single autologous blood clot into the internal carotid artery of dogs. The technique induced very reproducible unilateral ischemic lesions in the MCA territory; hemorrhagic transformation of the lesions was often seen. The hemodynamic and metabolic effects of blood clot embolism were studied in 35 dogs with positron emission tomography (PET) and the 15O steady-state technique, and compared with a control group of seven intact animals. In the acute phase, the involved brain tissue still had a nearly normal oxygen consumption (-11%) despite the lowered tissue perfusion (-20%) caused by the vascular obstruction. The lowered oxygen availability was compensated by an increased oxygen extraction ratio (+11%). Twenty-four hours after the insult, the hemodynamic situation had barely changed, and the ischemic event had evolved into a brain infarct in which oxygen consumption was clearly lowered (-25%) and accompanied by a significant lowering (-22%) of the oxygen extraction ratio compared with the acute situation. Therapeutic thrombolysis by local administration of streptokinase (500,000 IU), starting 30 min after the insult, was not able to salvage any brain tissue or to ameliorate tissue perfusion despite angiographically confirmed clot lysis. However, when fibrinolytic therapy was started within the first 5 min after the insult, hemispheric blood flow was normalized, and most of the threatened brain tissue was salvaged, as was indicated by its normalized oxygen consumption and oxygen extraction ratio. Early fibrinolysis was accompanied by definite clinical improvement and substantial reduction in the severity of the morphological lesions that were never hemorrhagic.

Depressed endothelium-dependent relaxation in hypertension: relation to increased blood pressure and reversibility.

Endothelium-dependent relaxation effects have been reported to be impaired in thoracic aorta from genetic and experimentally induced hypertensive rats. This study extends these observations to carotid artery and abdominal aorta from renovascular hypertensive rats. It was also found that rats with coarctation of aorta show depressed endothelium-dependent relaxation responses in thoracic aorta above the stenosis (high pressure region) while no depressed responses are observed in abdominal aorta below the stenosis (normal pressure region). Reversibility of the depression of endothelium-dependent relaxation was investigated on aorta from renovascular hypertensive rats in which blood pressure was normalized by removal of the stenotic kidney three months after induction of hypertension. Endothelium-dependent responses were restored partially after 1-2 weeks and completely after two months of normalization of blood pressure. These results indicate that the increased blood pressure is indeed the causative factor responsible for the impaired endothelium-dependent relaxations in arteries from experimental hypertensive rats, a phenomenon which is reversible, at least in our experimental conditions.

Influence of local intracellular pH changes on pH and action potentials in adjacent parts of cardiac Purkinje fibers.

Isolated sheep cardiac Purkinje fibers were pulled through a latex membrane and both segments were independently superfused with modified Tyrode solutions. Transmembrane potentials and intracellular pH (pHi) were continuously measured in one segment (test compartment, TC), using double-barreled pH sensitive glass microelectrodes, while the internal H+ activity was altered in the adjacent part of the fiber (experimental compartment, EC). In the latter local pHi changes were produced by removal of CO2/HCO3-, by superfusing acidic (pH 6.8) solution, and by addition and subsequent withdrawal of NH4Cl. Withdrawal of CO2/HCO3- in EC was found to have no influence on pHi in TC at 0.35 to 1.0 mm distance. The action potential first shortened and later on prolonged above control duration after switching to HCO3- -free medium. Perfusing EC with an acidic solution had virtually no effect on pHi in TC while action potential duration (APD) increased. Addition and withdrawal of NH4+ in EC decreased, respectively increased, APD. In TC no change in pHi was observed at 0.8 to 1.0 mm distance. At shorter distance a slow acidification was seen, associated with the presence of NH4+ in EC. The presence of amiloride, a blocker of the pHi regulating mechanism, could not unmask a larger pHi change. It is concluded that, in cardiac muscle, large gradients of pHi are possible over a relatively short distance, while electrotonic interaction can produce changes in the time course of the action potential in neighbouring cells having a normal intracellular pH.

Cerebrovascular reserve in the cat after acute bilateral carotid occlusion.

Cerebral blood flow in the cat was studied before and after acute bilateral common carotid occlusion under normocapnic and hypercapnic conditions and after induced hypotension. Regional blood flow to different brain structures was studied with the microsphere method. Local blood flow in the caudate nucleus, the cerebral cortex and medulla oblongata was studied with H2-polarography. Although the blood flow to the anterior brain regions is significantly decreased after bilateral common carotid occlusion, their blood supply is kept above ischaemic levels by re-distribution of the vertebrobasilar flow. Cerebrovascular reserve in anterior brain regions, however, is lost as indicated by the severe impairment of both the flow response to hypercapnia and to blood pressure decrease. After bilateral common carotid occlusion paradoxical CO2-reactions, indicating intracerebral steal, were seen in the caudate nucleus. In posterior brain regions resting blood flow, flow-reaction to hypercapnia and to hypotension are better preserved under these conditions. Measurement of the CBF responses to induced hypercapnia is a dependable test for appreciation of cerebrovascular reserve after cerebrovascular occlusion but may be potentially hazardous where local flow is close to ischaemic levels.

Influence of vascular tolerance to nitroglycerin on endothelium-dependent relaxation.

Many physiological important substances elicit a relaxing effect on blood vessels which is mediated by (a) substance(s) [EDRF(s)] released from the endothelial cells. EDRF(s) stimulate(s) guanylate cyclase, increasing cGMP at the smooth muscle level, resulting in relaxation. Since this mechanism of action is very similar to that of nitrovasodilator substances, we investigated whether EDRF(s) would act via the "organic nitrate receptor", which is thought to be the common site of action for organic nitrovasodilator substances. The relaxation effect of EDRF-mediated substances (histamine and acetylcholine) was investigated on contracted rat aorta preparations in which the affinity of the organic nitrate receptor was lowered by a treatment with high doses of nitroglycerin. The dose-relaxation curve of nitroglycerin on aorta preparations of pre-treated animals showed a highly significant shift to the right compared to preparations of control rats, proving the nitrate-receptor tolerance. However, when the same preparations were tested for their reactivity to acetylcholine or histamine, no differences could be demonstrated. These results indicate that, although it is known that organic nitrates and EDRF relax vascular smooth muscle cells by stimulating guanylate cyclase, this stimulation is mediated by a different mechanism.

Influence of neonatal androgenization on the testicular steroidogenesis in the adult rat.

The in vitro testicular steroidogenesis of male rats, androgenized on the third postnatal day by a single injection of 1 mg testosterone propionate, was investigated when the animals were 100 days old. The neonatal androgenization resulted in a 25% lower testes weight, significantly increased plasma levels of FSH (P less than 0.01) and LH (P less than 0.02), and normal levels of testosterone. Although the testes were hypotrophic, the incubation of the testes pairs yielded the same amounts of testosterone, 7 alpha-hydroxytestosterone and 5 alpha-androstane-(3 alpha + 3 beta), 17 beta-diol as in the control animals. However, the steroidogenic response to an acute hCG stimulation was reduced. From incubations of testes homogenates with various labelled steroid precursors it could be inferred that the activity of the 17 alpha-hydroxylase, the 3 beta-hydroxysteroid dehydrogenase-isomerase and the 17 beta-hydroxysteroid dehydrogenase, expressed per unit of incubated protein, was significantly increased in the testes of the androgenized rats. These data indicate that the basal steroidogenesis in neonatally androgenized male rats is maintained by an increased synthesis per unit of tissue, possibly under influence of an increased gonadotrophic stimulus, but that the maximum steroidogenic capacity is reduced.

Influence of a prolonged tamoxifen administration on steroidogenesis by incubated rat testes.

Tamoxifen was administered i.m. for 9 days to adult male rats in a daily dose of 100 micrograms or 1 mg. The treatment resulted in a significant reduction of the plasma levels of testosterone and LH, without modification of the plasma levels of FSH and of the testes weight. Upon incubation, the testes from the tamoxifen-treated rats produced less testosterone and 7 alpha-hydroxytestosterone, but metabolized [4-14C]testosterone in the same way as the control animals. Small doses of hCG (0.5 i.u. for 9 days) were unable to modify the tamoxifen effect on the testicular function, while tamoxifen significantly inhibited the increase of the plasma levels of testosterone induced by the administration of moderate doses of hCG (1.5 i.u. or 2.5 i.u. for 9 days) to hypophysectomized rats. Tamoxifen treatment, however, did not modify significantly the reactivity of the testes towards high doses of hCG (10 i.u.), administered either 2 h before sacrifice or for 9 days. It is concluded that a prolonged administration of tamoxifen in the rat has, besides an indirect effect resulting from a decrease of the LH levels, a direct inhibitory influence on the testicular testosterone formation, which can be reversed by high doses of hCG.

Release of endothelium-derived relaxing factor from human umbilical vessels.

The ability of human umbilical endothelial cells to release relaxing substance(s) in response to different agonists was investigated. Endothelium-denuded aortic rings of rats were used for the bioassay and tension recording. After precontraction, this preparation showed no response to histamine, acetylcholine, A 23187, or adenosine triphosphate while serotonin elicited further contraction. Superfusion of the precontracted preparations with the perfusate from umbilical veins and arteries stimulated with histamine (10(-7)-10(-5) M), A23187 (10(-7)-10(-6) M), or adenosine triphosphate (10(-5)-10(-4) M) elicited a relaxation. No relaxation was obtained with acetylcholine (10(-8)-10(-6) M) or serotonin (10(-8)-10(-6) M). The relaxation of bioassay aortic rings under the influence of the perfusate from histamine-stimulated umbilical vessels was inhibited by mepyramine (10(-5) M) but not by cimetidine (10(-4) M) suggesting the involvement of H1-receptors. The relaxation was also inhibited by increasing the transit time between the donor and the detector preparation, by methylene blue (5 X 10(-5) M), and by nordihydroguaiaretic acid (5 X 10(-5) M) but not by indomethacin (5 X 10(-5) M), and which have been reported for endothelium-derived relaxing factor. The involvement of umbilical endothelial cells in the relaxation response was further confirmed by studying precontracted, rubbed rat aortic rings seeded with cultured endothelial cells from human umbilical veins. Such preparations relaxed in response to histamine (10(-7)-10(-4) M) in contrast with the control preparations. No relaxations of these preparations were observed in response to acetylcholine (10(-9)-10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of neonatal androgenization of male rats on testosterone metabolism by the hypothalamus-pituitary-gonadal axis.

Male rats were androgenized on the third postnatal day by a single injection of 1 mg testosterone propionate. The in vitro metabolism of [4-14C]testosterone by pituitary and hypothalamus homogenates was investigated at the age of 90 days. The pituitary and hypothalamus homogenates from control and neonatally androgenized animals converted [4-14C]testosterone to the same metabolites, mainly 5 alpha-reduced derivatives; the quantitative yield of 5 alpha-reduced metabolites was much higher in the pituitary homogenates of androgenized rats. The hypothalamic homogenates showed no differences. In the androgenized rats a very significant increase of the plasma FSH levels was measured while the LH levels were also augmented. The plasma levels of testosterone were not different from the values in control rats, notwithstanding a 25% reduction in testes weight. The present experiments appear to indicate that the neonatal androgenization results in an accentuation of the sexual dimorphism which normally exists in the pituitary of adult rats for the 5 alpha-reductase activity.

Study of the metabolism of steroids in larvae of the fleshfly Sarcophaga bullata.

1. Larvae of the fleshfly Sarcophaga bullata were injected with several 3H C21 and C19 steroids. After different incubation times, the larvae were homogenized and the metabolites were extracted and fractionated by Sephadex LH 20-, paper- and thin-layer chromatography. The chromatographic mobility of the labeled zones was compared with that of standard steroids. 2. Progesterone and 17 alpha-hydroxypregnenolone were metabolized to 17 alpha-hydroxyprogesterone. Androstenedione, 17 alpha-hydroxyprogesterone and dehydroepiandrosterone were converted to testosterone. Transformation of pregnenolone to progesterone or 17 alpha-hydroxypregnenolone was not observed. 3. C21 or C19 steroid formation from cholesterol could not be demonstrated. 4. Sixteen metabolites, different from all our standard substances have been found. Their structure remains to be elucidated.