Multifocal leukoencephalopathy and polyneuropathy after 18 years on interferon alpha.

Multifocal leukoencephalopathy and sensory-motor polyneuropathy have not been reported as side-effects of long-lasting interferon alpha therapy in a single patient. In a 77-year-old man interferon alpha2b and interferon alpha2a were administered subsequently but continuously since 1984 for hairy cell leukemia. Since early 2000, left-sided hemi-hypesthesia occurred and the patient developed gait disturbance, proximal weakness of the lower limbs, bilateral stocking-type sensory disturbances, and restless leg syndrome. Repeated cerebral magnetic resonance images showed multifocal T2-hyperintense white matter lesions supratentorially. The nerve conduction velocity of the peroneal and sural nerve was reduced. After exclusion of various differential diagnoses of leukoencephalopathy and application of a screening program for polyneuropathy, central and peripheral nervous system abnormalities were attributed to the long-lasting interferon alpha therapy. In single patients abnormally long-lasting interferon alpha therapy may cause multifocal white matter lesions supratentorially and sensory-motor polyneuropathy.

Long term increases in coronary arterial conductance during five day infusion of low dose nicorandil.

OBJECTIVE: The aim was to test the effects of nicorandil on coronary arterial conductance and on a possible development of tolerance or cross tolerance with glyceryl trinitrate during a 5 d continuous intravenous infusion of this hybrid molecule (consisting of a combination of potassium channel activation and simultaneous nitro-ester induced soluble guanylyl-cyclase activation). METHODS: Continuous intravenous infusions of nicorandil at 2.5 micrograms.kg-1.min-1 and 10 micrograms.kg-1.min-1 into conscious chronically instrumented dogs were carried out for 5 d using a special portable infusion system. Employing additional short term infusions, dose-response curves were obtained by giving nicorandil or glyceryl trinitrate at increasing dosages both in the preinfusion control state and 4 h after terminating the nicorandil infusion. RESULTS: The 5 d infusion of 2.5 or 10.0 micrograms.kg-1.min-1 nicorandil resulted in a significant increase in large coronary artery diameter by 4.21 (SEM 0.14)% or 9.20(0.28)%, respectively. At the lower dose no significant tolerance or cross tolerance with glyceryl trinitrate was observed. However, at the higher dose there was a shift of the dose-response curve of both nicorandil and glyceryl trinitrate to the right, indicating some tolerance. The smaller dose did not induce hypotension or reflex increase in heart rate, whereas the larger resulted in a 42(2.5)% increase in heart rate. CONCLUSIONS: A dose regimen of 2.5 micrograms.kg-1.min-1 continuously administered for 5 d is capable of inducing a significant increase in coronary arterial conductance which was well maintained over the whole infusion period. Thus nicorandil can exert a selective large coronary artery dilatation and may bring about a well maintained increase in epicardial coronary conductance, especially when applied as a low dose slow release preparation which circumvents hypotension and increase in heart rate.

Inhibition of sympathoadrenal activity by atrial natriuretic factor in dogs.

In six conscious, trained dogs, maintained on a normal sodium intake of 2 to 4 mEq/kg/day, sympathetic activity was assessed as the release rate of norepinephrine and epinephrine during 15-minute i.v. infusions of human alpha-atrial natriuretic factor. Mean arterial pressure (as a percentage of control +/- SEM) during randomized infusions of 0.03, 0.1, 0.3, or 1.0 microgram/kg/min was 99 +/- 1, 95 +/- 1 (p less than 0.05), 93 +/- 1 (p less than 0.01), or 79 +/- 6% (p less than 0.001), respectively, but no tachycardia and no augmentation of the norepinephrine release rate (up to 0.3 microgram/kg/min) were observed, which is in contrast to comparable hypotension induced by hydralazine or nitroglycerin. The release rate of epinephrine (control, 6.7 +/- 0.6 ng/kg/min) declined immediately during infusions of atrial natriuretic factor to a minimum of 49 +/- 5% of control (p less than 0.001) during 0.1 microgram/kg/min and to 63 +/- 5% (0.1 greater than p greater than 0.05) or 95 +/- 13% (not significant) during 0.3 or 1.0 microgram/kg/min. Steady state arterial plasma concentrations of atrial natriuretic factor were 39 +/- 10 pg/ml (n = 6) during infusions of saline and 284 +/- 24 pg/ml (n = 6) and 1520 +/- 300 pg/ml (n = 9) during 0.03 and 0.1 microgram/kg/min infusions of the factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Postsynaptic alpha 1- and alpha 2-adrenergic receptors in adrenergic control of capacitance vessel tone in vivo.

The involvement of postsynaptic alpha 2-adrenergic receptors in the adrenergic constriction of the capacitance vessels was studied in anesthetized, spontaneously breathing dogs under ganglionic blockade (hexamethonium, 10 mg/kg + 10 mg/kg/hr; methylatropine, 0.5 mg/kg). Effective vascular compliance was measured as an indicator of venous tone (blood volume was varied by +/- 4 ml/kg in an 11-minute cycle of infusion, withdrawal, withdrawal, and reinfusion) and was calculated from the correlation between the observed changes in central venous pressure and the changes in blood volume. Sympathetic activity and central venous pressure were lower and effective vascular compliance was higher than values in untreated conscious dogs. The alpha 2-agonist UK 14,304 (5-bromo-6-[imidazolin-2-ylamino]-quinoxaline; 0.04 and 0.12 micrograms/kg/min; n = 6) dose-dependently lowered compliance and increased central venous pressure to levels found in conscious dogs, as did the alpha 1-agonist methoxamine (10 and 30 micrograms/kg; n = 6). Rauwolscine (alpha 2-antagonist), 0.3 mg/kg, significantly attenuated the effects of UK 14,304, but not those of methoxamine, while prazosin (alpha 1-antagonist), 0.12 mg/kg, attenuated the effects of methoxamine, but not those of UK 14,304 (n = 6 each). Under beta-blockade (nadolol, 2 mg/kg; n = 12) venous tone was increased to about physiological levels by norepinephrine, 0.15 micrograms/kg/min i.v., or by neuronal norepinephrine release induced by tyramine, 10 micrograms/kg/min i.v. These increases were significantly attenuated by prazosin as well as by rauwolscine and were abolished by a combination of both. These results indicate that postsynaptic alpha 2-adrenergic receptors (in addition to alpha 1-adrenergic receptors) are functional in the venous system in vivo and contribute substantially to adrenergic sympathetic and humoral regulation of venous tone.

Sympathetic vasoconstriction sensitive to alpha 2-adrenergic receptor blockade. No evidence for preferential innervation of alpha 1-adrenergic receptors in the canine femoral bed.

In the canine femoral bed, we studied the involvement of vascular alpha 2-adrenergic receptors in vasoconstriction by stimulating the sympathetic nerve during different degrees of activation of metabolic counterregulation (constant pressure and constant flow perfusion). In chloralose-anesthetized, despinalized dogs under beta-blockade (2 mg/kg nadolol) and under a constant femoral perfusion pressure, cumulative doses of rauwolscine (0.03, 0.3, and 3.0 mg/kg i.v., n = 8) or of prazosin (0.012, 0.12, and 1.2 mg/kg i.v., n = 8) caused dose-dependent shifts to the right of the dose-response curve of intraarterial norepinephrine (NE) infusions. These cumulative doses also caused attenuations of the vasoconstriction initiated by lumbar sympathetic stimulation (0.1, 0.3, 1.0, and 3.0 Hz). Sham treatment (n = 8) had no such results. In experiments with constant flow perfusion (n = 6 for each antagonist), rauwolscine shifted the NE dose-response curve significantly more compared to the experiments with constant pressure perfusion, while prazosin was similarly effective under both conditions. Under constant flow perfusion, both antagonists dose-dependently attenuated the vasoconstrictions caused by sympathetic stimulation. While prazosin and sham treatment did not modify the overflow of NE from the femoral bed during stimulation, this overflow was augmented by rauwolscine during stimulation at 3 Hz, which indicated presynaptic modulation of NE release. Under both experimental conditions, no significant difference could be observed in the attenuation of low-frequency sympathetic vasoconstriction by the two antagonists, when dosages were compared on the basis of their action against infused NE. It is concluded that both a rauwolscine-sensitive component and a prazosin-sensitive component are involved in the competition between sympathetic vasoconstriction and metabolic dilation. The vascular alpha-adrenergic receptors activated by these two components have a similar postsynaptic localization relative to the nerve endings.

Norepinephrine constricts the canine coronary bed via postsynaptic alpha 2-adrenoceptors.

The effect of alpha 2-blockade (0.3 mg/kg i.v. rauwolscine) and alpha 1-blockade (1.2 mg/kg i.v. prazosin) on coronary constrictions induced by intracoronary injections of azepexole (B-HT 933, alpha 2-agonist, 0.1-10 microgram/kg), phenylephrine (0.3-3 microgram/kg) and norepinephrine (0.001-0.1 microgram/kg) were studied in dog hearts perfused in situ under beta-blockade. Constrictions by azepexole (antagonized by rauwolscine, yet resistant to prazosin and methysergide) demonstrated coronary alpha 2-adrenoceptors. Norepinephrine-induced constrictions were more attenuated (22-fold) by alpha 2-blockade than by alpha 1-blockade (2.6-fold) and thus were mediated mainly by activation of postsynaptic alpha 2-receptors.

Contrast-enhanced power Doppler harmonic imaging--influence on visualization of renal vasculature.

To compare contrast-enhanced power Doppler (PD) harmonic imaging (CHI) with contrast-enhanced power Doppler fundamental imaging (CPD) in the depiction of renal cortical vessels, 20 healthy volunteers were subjected to PD imaging and HI assessment of the kidney after bolus injection of Levovist(R) (SH U 508A). System settings were standardized and the pulse-repetition frequencies (PRF) systematically toggled from 750 to 500 and 250. Videotapes were independently reviewed by three readers with regard to the presence of artefacts, the degree of Doppler signal enhancement, demarcation of vessels and the extent of visualization. The assessments were graded separately for each PRF in accordance with a multistage scoring system. In comparison to contrast-enhanced PD, artefacts were significantly lower with CHI for all PRF (p = 0.0001). Vessels were better visualized (p = 0.002) and less blurred (p = 0.006) with CHI than with CPD. There was no significant difference in the extent of Doppler signal increase between CPD and the contrast-enhanced harmonic mode. Combination of the contrast-enhanced harmonic method and PD allows the PRF to be lowered and, by balancing the greater susceptibility of PD to interference from clutter, increases the likelihood of detection of flow in small vessels.

Cardiovascular dysfunction in hypercholesterolemia associated with enhanced formation of AT1-receptor and of eicosanoids.

BACKGROUND: In hypercholesterolemia with or without atherosclerosis cardiovascular dysfunction and altered signalling of angiotensin (Ang II), nitric oxide (NO), or prostanoids are intimately related to enhanced oxidant stress and concomitant changes in gene expression. We analyzed cardiac angiotensin receptor (AT1) expression and metabolism of Ang II, eicosanoids, and NO in hypercholesterolemic animals. METHODS: Guinea pigs were fed a 1% cholesterol diet for 8 weeks (Chol). Hemodynamics were analyzed in Langendorff hearts. Spectrophotometric determination of plasma lipids and radioimmunological detection of eicosanoids/cyclic guanosine monophosphate (cGMP). Activities of NO synthase III (NOS-III) or angiotensin converting enzyme (ACE) were determined by enzymatic assays. AT1 receptor density was assessed by radioligand binding assay. NOS-III mRNAs were quantitated by reverse transcription polymerase chain reaction. RESULTS: Hypercholesterolemia was associated with fatty degeneration of the liver and profound myocardial and coronary (e.g., endothelial) dysfunction. In Chol Langendorff hearts we observed significant increases in coronary flow (26.0 +/- 1.0 vs. 17.5 +/- 0.5 mL/min/g tissue) but diminished coronary responses to bradykinin (Bk, 250 ng bolus) or adenosine (Ado, 250 micrograms bolus) (delta CPPBk/Ado: 5 +/- 0.5 vs. 7.2 +/- 1/0.9 +/- 0.1 vs. 1.9 +/- 0.3 cm2 (area under the curve)). AT1 receptor expression was significantly increased in Chol hearts (72 +/- 6.8 vs. 45 +/- 5.6 fmol/mg protein), whereas marked suppression of cardiac activities of ACE (1.96 +/- 0.34 vs. 4.90 +/- 0.20 nmol/min/mg tissue) and of the entire cardiac nitric oxide-cGMP axis (e.g., NOS-III activity: 1.9 +/- 0.4 vs. 3.1 +/- 0.1 pmol/min/mg tissue; NOS-III mRNA: 0.82 +/- 0.16 vs. 1.20 +/- 0.12 arbitrary units; cGMP release: 0.41 +/- 0.02 vs. 0.54 +/- 0.04 pmol/min/g tissue) were shown in Chol. Finally, cardiac release of eicosanoids prostacyclin (PGI2) and thromboxane (TxA2) were significantly enhanced (0.48 +/- 0.05 vs. 0.38 +/- 0.05 and 0.60 +/- 0.10 vs. 0.24 +/- 0.10 ng/min/g tissue, respectively). Enhanced cardiac PGI2 release and suppression of cGMP synthesis in Chol were even more pronounced on stimulation with Bk (38.2 +/- 3.0 vs. 28.2 +/- 2.0 ng/min/g tissue and 1.9 +/- 0.3 vs. 3.0 +/- 0.3 pmol/min/g tissue, respectively). CONCLUSIONS: Altered angiotensin-mediated signal transduction probably related to augmented eicosanoid formation does not compensate for the limited endogenous NO production and for cardiovascular dysfunction in hypercholesterolemic guinea pigs. In this context, changes in redox-sensitive regulation of gene expression (AT1 receptor, NOS-III--caused by enhanced oxidant stress--could play a pivotal role.

[Diagnosis and results of treatment in appendicitis]. / Diagnose und Behandlungsergebnisse der Appendicitis.

In a period of 5 years 3455 appendectomies were performed because of appendicitis. Acute appendicitis (i.e. gangrenous appendicitis, appendiceal abscess, perforated appendicitis) was found in 30% of all appendectomies. Histological finding, sex, age, symptoms, duration of illness until operation, technique of operation and postoperative complications were documented in a form suitable for computer input and analyzed. The lethality of appendectomy was 0.38%.

Effects of antipsychotics and vitamin C on the formation of reactive oxygen species.

There is evidence that reactive oxygen species (ROS) are involved in the pathophysiology of psychiatric disorders such as schizophrenia. Indirect biochemical alterations of ROS formation have been shown for patients treated with antipsychotics as well as for untreated patients. Only one study measured directly the ROS formation after treatment with antipsychotics by using electron spin resonance spectroscopy. The aim of the present examination was to demonstrate the effects of haloperidol, clozapine and olanzapine in concentrations of 18, 90 and 180 µg/mL on the formation of ROS in the whole blood of rats by using electron spin resonance spectroscopy after incubation for 30 min. To test the protective capacity of vitamin C we incubated the highest concentration of each drug with vitamin C (1 mM). Under all treatment conditions, olanzapine led to a significantly higher formation of ROS compared with control conditions, whereas in the cases of haloperidol and clozapine the two higher concentrations induced a significantly enhanced formation of ROS. Vitamin C reduced the ROS production of all drugs tested and for haloperidol and clozapine the level of significance was reached. Our study demonstrated that antipsychotics induce the formation of ROS in the whole blood of rats, which can be reduced by the application of vitamin C.

Evaluation of preservation solutions by ESR-spectroscopy: superior effects of University of Wisconsin over Histidine-Tryptophan-Ketoglutarate in reducing renal reactive oxygen species.

Despite the causative role of oxidative stress in renal ischemia-reperfusion (I-R) injury effects of preservation solutions on reactive oxygen species (ROS) release have not been sufficiently evaluated. We compared the effects of most common solutions in kidney transplantation, University of Wisconsin (UW) and Histidine-Tryptophan-Ketoglutarate (HTK). ROS formation in isolated perfused rat kidney was detected by electron spin resonance spectroscopy using spin label 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Donor kidneys from Lewis rats were pretreated with saline (controls), in therapeutic groups, kidneys underwent 18 h of cold storage (CS) preserved by HTK or UW solution. Experimental protocol included a stabilization period followed by additional I-R. Kidneys preserved by HTK produced highest ROS values in the control period after CS, whereas levels in UW and control group did not vary significantly. A peak release induced by additional I-R was also significantly highest in HTK kidneys, and UW did not differ from controls. During reperfusion, levels in HTK exceeded control and UW values. Renal vascular resistance, caspase-3-activity, and tissue hydration were enhanced in HTK compared with UW group, whereas ATP concentration was less reduced in UW-preserved tissue. These data show the greater antioxidative potential of UW solution, which also attenuated organ impairment after CS in the early reperfusion period.

[Arthroplasty of the rheumatoid hand. Pre- and postoperative imaging with special consideration of biomechanical and pathobiomechanical aspects and its radiological evaluation]. / Arthroplastik der rheumatischen Hand. Prä- und postoperative Bildgebung mit besonderer Berücksichtigung der Biomechanik und Pathobiomechanik und ihrer Evaluation am Röntgenbild.

Radiology plays a key role when the indications for arthroplasties of the hand and finger joints are determined and for the postoperative follow-up. On the one hand, the degree of inflammatory changes in all affected compartments is to be evaluated and graded; on the other hand, conventional radiograms allow for a first assessment of possible joint instability and impaired biomechanics. Both aspects influence the choice of the proper surgical therapeutic strategy. Osteolysis, deformity, fracture, prosthesis loosening or failure, heterotopic ossification, and foreign body-associated formation of granulation tissue are complications which can be detected on follow-up radiographs early on.

Angiotensin receptor blocker losartan suppresses platelet activity by interfering with thromboxane signaling.

UNLABELLED: Enhanced platelet activity and platelet endothelial interaction are hallmarks of different vascular and metabolic diseases with subsequent thrombus formation. In atherosclerosis, coronary artery disease, congestive heart failure, nitrate tolerance, chronic inflammation, or diabetic states, platelet activation may in part be due to a stimulation of the renin-angiotensin-aldosteron system, which also contributes to enhanced oxidant stress in these conditions. AIMS: We examined the putative role of the angiotensin receptor (AT1) and of phospholipase A2 (PLA2) in mediating platelet activation under defined in vitro conditions using the AT1 receptor antagonists losartan, EXP 3174, candesartan, and the PLA2 inhibitor arachidonyltrifluoromethyl ketone (AACOCF3), respectively. RESULTS: In washed human or canine platelet suspensions, losartan (10(-4)-10(-6) mol/L) dose-dependently suppressed thrombin-induced calcium transients as well as thromboxane (TxA2) release. In both species, aggregation of washed platelets in response to thrombin or ADP was substantially diminished by different doses of losartan. This inhibition of platelet aggregation was even maintained in ADP-stimulated platelet-rich plasma. While the PLA2 inhibitor AACOCF3 effectively inhibited thrombin-induced TxA2 release from washed human or canine platelets (similar to the effects observed with losartan), the AT1 agonist angiotensin II elicited platelet TxA2 release only at high supra-physiological doses (e.g., at 10(-4) mol/L). The AT1 specific antagonist candesartan did not diminish stimulated platelet aggregation, TxA2 formation, or calcium transients. By contrast, the active losartan metabolite EXP 3174 dose-dependently inhibited stimulated platelet calcium transients as well as TxA2 release at 1-100 micromol/L. CONCLUSIONS: Losartan significantly counteracts ex vivo platelet activation, probably via the blockade of TxA2 receptor-dependent signaling (e.g. implying activation of phospholipase A2) rather than acting at the AT1 receptor itself. This implies that the TxA2 signaling pathway plays a significant role during platelet activation, which may be successfully antagonized in vivo under different pathological states with enhanced thrombus formation or platelet-endothelium interactions.

[Report of experiences of a demoscopic survey of a 5-day therapy group for the cessation of smoking]. / Ergebnisbericht einer demoskopischen Befragung von einer 5-Tage-Gruppentherapie zur Raucherentwöhnung.

A 5 days group therapy (2 hours daily) for smoking cessation is presented. Based on the examination of 221 participants the efficiency of this group therapy was between 70 and 80% at the end of the treatment. The long-term follow-up efficiency was about 40%. Therefore this kind of therapy is effective for smoking cessation.

Blockade of angiotensin signaling improves myocardial function in hypercholesterolemia independent of changes in eicosanoid release.

In hypercholesterolemia in the presence or absence of atherosclerosis, cardiovascular dysfunction and altered signaling of angiotensin, nitric oxide, or prostanoids are closely related to enhanced oxidant stress. We analyzed the potentially beneficial effects of the specific angiotensin-converting enzyme inhibitor enalapril and the specific angiotensin receptor blocker losartan on cardiac performance, eicosanoid metabolism, and parameters of oxidant stress in hypercholesterolemic animals. Guinea pigs were fed a 1% cholesterol diet for 8 weeks (Chol) with or without equieffective doses of either enalapril (1.5 mg/kg/d; Ena) or losartan (3 mg/kg/d; Los). Hemodynamics were analyzed in Langendorff hearts. Detection of eicosanoids was by enzyme immunoassay. Estimation of plasma xanthine oxidase (XO) activity was determined by spectrophotometry. In hypercholesterolemic guinea pigs, enhanced oxidant stress (e.g., increased plasma XO activities) was associated with profound myocardial and coronary (e.g., endothelial) dysfunction. Both enalapril and losartan lowered plasma cholesterol levels slightly, but only the angiotensin receptor antagonist effectively suppressed the increased plasma XO activities (from 11.4 +/- 0.7 to 7.6 +/- 2.2 U/L), and at the same time decreased the augmented coronary flow (from 26.0 +/- 1.0 to 23.0 +/- 1.0 mL/min/g tissue) observed in hypercholesterolemic animals. Assessment of left ventricular pressure and contractility (e.g., dp/dtmax) as well as the diastolic relaxation parameter (tau) revealed substantial myocardial dysfunction (systolic and diastolic) in Chol that was more substantially (and comparably) improved during administration of losartan (Los) than during enalapril (Ena). Surprisingly, angiotensin signaling blockade by either antagonist further suppressed the diminished coronary dilator responses to bradykinin (BK; not significant for enalapril) or adenosine (Ado) was demonstrated in Chol Langendorff hearts [delta CPPBK/Ado: from 5.0 +/- 0.5/0.9 +/- 0.1 to 4.4 +/- 1.5/0.4 +/- 0.1 (Ena) or to 1.9 +/- 0.5/0.4 +/- 0.1 (Los) cm2 (area under the curve), respectively]. Finally, as expected from control studies using heart preparations from normocholesterolemic guinea pigs, enhanced cardiac release of eicosanoids, prostacyclin, and thromboxane in Chol (0.48 +/- 0.03 and 0.6 +/- 0.1 ng/min/g) was augmented even further by treatment with enalapril (Ena: 1.6 +/- 0.4 and 1.0 +/- 0.1 ng/min/g), but was significantly reduced to or below control levels in losartan-treated animals (Los: 0.4 +/- 0.1 and 0.2 +/- 0.1 ng/min/g). Blockade of angiotensin signaling via angiotensin-converting enzyme inhibition or receptor antagonism--although differentially acting on enhanced cardiac prostanoid metabolism and oxidant stress--efficiently restored proper systolic and diastolic myocardial performance (losartan was more beneficial than enalapril), probably by counterbalancing altered angiotensin II-->angiotensin receptor signaling in the cardiovascular system of hypercholesterolemic animals. Impaired coronary vasodilator capacity seems to be irreversible after 8 weeks of a high-cholesterol diet, as shown by the unexpected lack of a dilator effect with both enalapril and losartan.

Development of specific tolerance to nicotine infusions in dogs on chronic nicotine treatment.

Chronic smoking in humans and continuous nicotine application in animals do not induce hypertension, although the acute effects of nicotine are sympathoadrenal activation and elevation of blood pressure. In conscious dogs with a carotid artery loop preparation, we studied whether chronic nicotine application induced tolerance to the acute effects of nicotine test infusions. Nicotine was applied as salicylate via subcutaneously implanted osmotic minipumps at a dosage of 1 microgram/kg/min = 1.44 mg/kg/day, corresponding to heavy smoking in humans. Chronic treatment in eight dogs for 5-8 weeks did not modify resting heart rate and plasma levels of free catecholamines, but significantly increased plasma levels of conjugated dopamine by 100%. Mean arterial pressure at rest was elevated in the 2nd week by 6mm Hg, but did not increase further. Sham treatment (n = 8, sodium salicylate in equivalent dosage) was without effect. Acute test-infusions of nicotine (3 and 10 micrograms/kg/min i.v.) caused acute rises in mean arterial pressure (by 12 and 28 mm Hg), heart rate (by 9 and 18 bpm), plasma norepinephrine (by 36 and 68%), plasma epinephrine (by 110 and 180%) and led to plasma nicotine levels of 31 and 95 ng/ml. Chronic nicotine treatment attenuated the hemodynamic and partially abolished the hormonal effects without affecting the nicotine plasma levels obtained with these test infusions, but it did not modify the hemodynamic effects of a norepinephrine test infusion. The data demonstrate the development of a specific, reversible tolerance to the acute sympathoadrenal activation by nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by (aminooxy)acetate of the malate-aspartate cycle in the isolated working guinea pig heart.

The quantitative importance of the malate-aspartate cycle and the sn-glycerol 3-phosphate cycle, with respect to the flux of cytosolic reducing equivalents across the mitochondrial membrane, was studied in isolated perfused guinea pig hearts. The heart preparations performed pressure-volume work and metabolized glucose, lactate, pyruvate or 3-hydroxybutyrate. With glucose or lactate as the substrate, (aminooxy)acetate, an inhibitor of the malate-aspartate cycle, caused left ventricular failure, manifested by reduced aortic pressure and cardiac output, in association with a decrease in myocardial oxygen consumption and a depletion of high energy phosphate stores; lactate and particularly sn glycerol 3-phosphate accumulated in the myocardium. Moreover, lactate release rates increased more than 10-fold in presence of glucose and (aminooxy)acetate. Pretreatment of the animals with high doses of triiodothyronine did not prevent the hemodynamic and metabolic alterations caused by (aminooxy)acetate. In contrast, (aminooxy)acetate did not affect performance and energy-yielding metabolism when hearts metabolized pyruvate or 3-hydroxybutyrate as the substrate. From the findings it is concluded that the malate-aspartate cycle preponderates over the sn-glycerol 3-phosphate cycle in the working guinea pig heart, even when sn-glycerol 3-phosphate accumulates.

Dilation of epicardial arteries in conscious dogs induced by angiotensin-converting enzyme inhibition with enalaprilat.

Vasodilators may provoke myocardial ischemia in patients with coronary heart disease. Therefore, we analyzed in conscious dogs the effect of angiotensin-converting enzyme (ACE) inhibition by enalaprilat on parameters potentially important to provocation of myocardial ischemia, such as sympathetic activity, myocardial oxygen consumption, and vascular tone in coronary conduit and resistance vessels. Under normal sodium intake (2-4 mEq/kg/day), enalaprilat (0.03 and 0.3 mg/kg i.v. during 5-min infusion with 30-min intervals, n = 8) did not modify the norepinephrine release rate into plasma (a parameter of overall sympathetic activity). The higher dosage reduced myocardial oxygen consumption (to 87 +/- 2% of control), mean arterial pressure (MAP) (to 90 +/- 1%) and coronary conduit artery tone (normalized delta diameter: +3.2 +/- 0.7%) without dilating coronary resistance vessels. Following renin-angiotensin activation by sodium deprivation (3 X 1 mg/kg furosemide plus 7 days sodium intake less than 0.2 mEq/day), enalaprilat similarly lowered myocardial oxygen consumption and reduced vascular tone both in coronary conduit (normalized delta diameter: +4.0 +/- 0.9%) and resistance vessels (delta coronary flow: +45 +/- 12%). Although MAP declined to 76 +/- 6%, heart rate and norepinephrine release rate were not modified significantly. We propose that the dilation of epicardial arteries results from a direct intramural action. Enalaprilat seems unlikely to provoke myocardial ischemia even in states with a strongly activated renin-angiotensin system.

Fructose, a substrate for energy-yielding metabolism in the heart?

Effects of fructose and glucose on cardiac function and 14CO2 production from radioactive hexoses were studied in isolated working guinea pig hearts perfused at constant filling pressure via the left atrium. When hearts were perfused without exogenous substrates external work declined, indicating exhaustion of endogenous energy sources. It was possible to restore left ventricular function with concentrations of glucose in the physiological range; in order to achieve a similar restoration with fructose as the only exogenous substrate concentrations higher than 40mM were necessary. 14CO2 necessary. 14CO2 production from [U-14C]glucose was half-maximal at about 2mM glucose. On the other hand, 14CO2 production from [U-14C]fructose did not show saturation kinetics and, at concentrations around 2mM, was less than 5% of the rates observed with [U-14C]glucose. Moreover, fructose oxidation was suppressed in the presence of 5mM glucose. The data suggest that fructose cannot serve as a major substrate in the heart under in vivo conditions.