[Morning hyperglycemia in children and adolescents with type 1 diabetes and different modes of therapy: an evaluation of the DPV data pool]. / Morgenhyperglykämie bei Kindern und Jugendlichen mit Typ-1-Diabetes bei unterschiedlichen Therapieformen: Eine Auswertung des DPV-Datenpools.

Early morning hyperglycemia is frequent among children and adolescents with type 1 diabetes. Reasons are a dawn phenomenon, a Somogyi phenomenon or a lack of insulin in the morning hours. Only few studies are published regarding incidence and relation to different modes of basal insulin treatment in this population.We analyzed all cases recorded in the DPV register from 1995 to 2010. 5 839 patients from 128 centers with at least 3 blood glucose measurements during the last night of a hospital stay were included.24.2% of patients showed a morning hyperglycemia above 200 mg/dl. 8.6% showed a dawn phenomenon, 7.0 % a lack of insulin and 2.0% a Somogyi phenomenon. A dawn phenomenon was significantly less frequent in patients treated with an insulin pump (1.1%) compared to long acting insulin analogs Glargin and Levemir (5.4%) or NPH insulin (8.2%). Lack of insulin was again less frequent during insulin pump treatment compared to other treatments (1.9% vs. 4.9% vs. 5.3%). Median rise of blood glucose levels was 33.4 mg/dl between midnight and 6 a.m. Mode of basal insulin treatment is an important factor: while treatment with an insulin pump led to a blood glucose fall of 28.5 mg/dl between 3 and 6 a.m., treatment with insulin analog or NPH insulin resulted in a rise of 28.5 or 35.9 mg/dl, respectively.This study shows that insulin pump treatment reduces the frequency of morning hyperglycemia caused by the dawn phenomenon or a lack of insulin.

Synaptonemal complex protein SYCP3 exists in two isoforms showing different conservation in mammalian evolution.

Meiosis-specific protein SYCP3 is a major structural component of synaptonemal complex (SC) lateral elements. SYCP3 is rather well conserved in vertebrates. However, some differences in SYCP3 expression have been shown among mammals. To clarifiy these differences, we have investigated SYCP3 expression with the aid of bioinformatic, biochemical and cell biological methods. Here we show that, in contrast to other vertebrates, rat and mouse SYCP3 exist in 2 isoforms. The short isoform is conserved among vertebrates. However, the longer isoform, which represents an N-terminal extension of the shorter one, most likely appeared about 15 million years ago in a common ancestor of rat and mouse and after separation from the hamster branch.

[Left ventricular diastolic dysfunction. Implications for anesthesia and critical care]. / Linksventrikuläre diastolische Dysfunktion. Bedeutung in Anästhesie und Intensivmedizin.

Over the last two decades there has been a growing recognition that cardiac function is not solely determined by systolic but also essentially by diastolic function. Left ventricular diastolic dysfunction is characterized by an impairment of ventricular filling caused either by abnormal relaxation, an active energy consuming process or decreased compliance, which is determined by passive tissue properties of the ventricle. Doppler echocardiography, including tissue Doppler imaging, has emerged as the preferred clinical tool for the assessment of left ventricular diastolic function. Recently the importance of left ventricular diastolic function is increasingly being recognized also during the perioperative period. Newer studies have shown that after cardiopulmonary bypass there is a significant decrease in left ventricular compliance. Experimental studies have demonstrated that sepsis is associated with a decrease in both active relaxation and ventricular compliance. Initial studies are also focusing on therapeutic options for patients with isolated diastolic dysfunction.

Reverse intrinsic activity of antagonists on G protein-coupled receptors.

Biological effects observed with an antagonist are usually interpreted as the result of its ability to block receptor activation produced by an endogenous agonist. In this Principles article, Wolfgang Schütz and Michael Freissmuth show how considerable evidence has now been accumulated for G protein-coupled receptors that antagonists not only bind to the receptor, but also induce a conformational change that favours uncoupling of the receptor from its G protein. The spontaneous activity of the unliganded receptor (i.e. the receptor not occupied by any ligand) is a well-established phenomenon in reconstituted systems with purified components. However, its physiological relevance needs to be verified in a more physiological environment before biological effect of antagonists can be primarily ascribed to negative intrinsic activity.

Effect of aminophylline on coronary reactive hyperaemia following brief and long occlusion periods.

The effects of an intracoronary aminophylline infusion, adjusted to give a constant concentration of 25 microgram.cm-3 coronary blood, on the reactive hyperaemic responses following coronary occlusion for 4, 10, and 25 heart beats were investigated in anaesthetised, open-chest dogs. The vasodilator effect of intracoronarily-administered adenosine and the hyperaemic response after coronary occlusion for 10 and 25 heart beats were both significantly diminished under the influence of aminophylline. However, the decrease in the coronary dilator effect of adenosine amounted to 80%, whereas the hyperaemic response was diminished by only 20%. The hyperaemic response following a coronary occlusion for only 4 heart beats remained unchanged. The present results obtained with aminophylline suggest at least a partial involvement of adenosine in mediating reactive hyperaemia after sufficiently long periods of coronary artery occlusion.

A clinical approach for the identification of peripheral pre- and post-synaptic alpha-adrenergic receptors.

The present study examines the possibility that pre- and post-synaptic alpha-adrenergic receptors can be differentiated by a clinical pharmacological approach. We compared the ability of the alpha 1-selective antagonists, prazosin and urapidil, with the ability of the alpha 2-selective antagonist, yohimbine, to inhibit cardiovascular responses to the non-selective alpha-adrenergic agonist norepinephrine in 26 healthy volunteers. Urapidil (50 mg i.v.) and prazosin (5 mg orally) induced significant shifts to the right in the blood pressure dose-response curve of norepinephrine. Yohimbine (10 mg orally), on the other hand, increased norepinephrine sensitivity, as indicated by a significant shift to the left of the norepinephrine dose-response curve. In addition, urapidil and prazosin decreased norepinephrine potency on heart rate, whereas no effect on norepinephrine-induced heart rate elevation was observed with yohimbine. From the studies in which yohimbine was used it can be assumed that the post-synaptic response to norepinephrine is not counteracted by the drug-induced inhibition of sympathetic neurotransmitter release. Hence, our findings confirm the presence of pre- and post-synaptic alpha-adrenergic receptors in man.

P2-, but not P1-purinoceptors mediate formation of 1, 4, 5-inositol trisphosphate and its metabolites via a pertussis toxin-insensitive pathway in the rat renal cortex.

1. The adenosine receptor (P1-purinoceptor) agonists N6-cyclopentyladenosine and N-5'-ethyl-carboxamidoadenosine at concentrations up to 10 mumols 1(-1) affected neither basal, nor noradrenaline- and angiotensin II-stimulated formation of inositol-1-phosphate, inositol-1,4-bisphosphate, and inositol-1,4,5-trisphosphate in slices of rat renal cortex. 2. In contrast, adenine nucleotides (P2-purinoceptor agonists) markedly stimulated inositol phosphate formation. The observed rank order of potency adenosine-5'-O-(2-thiodiphosphate) (EC50 39 mumols 1(-1] greater than adenosine-5'-O-(3-thiotriphosphate) (587) greater than or equal to 5'-adenylylimidodiphosphate (App(NH)p, 899) greater than adenylyl-(beta, gamma-methylene)-diphosphate (4,181) was consistent with the interaction of the compounds with the P2Y-subtype of P2-purinoceptors. AMP and the ADP analogue (alpha, beta-methylene)-adenosine-5'-diphosphate were ineffective. ATP and ADP (less than or equal to 10 mmol 1(-1] did not produce a consistent increase, owing to their hydrolytic degradation in the incubation medium. 3. Whereas the inositol phosphate response to App(NH)p was linear only up to 5 min incubation, the time-dependent stimulation of noradrenaline declined at a slower rate. Following pre-exposure of the renal cortical slices to App(NH)p, renewed addition of App(NH)p caused no further enhancement in the accumulation of inositol phosphates, whilst noradrenaline was still capable of eliciting a response. This suggests that the apparent loss of responsiveness to App(NH)p is not due to substrate depletion or enzymatic inactivation, but most likely attributable to homologous desensitization of the purinoceptor. 4. Pretreatment of the animals with pertussis toxin caused a substantial reduction of functional Gi-protein, as indicated by the lack of [32P]-NAD incorporation in a membrane preparation of the renal cortex. Nevertheless, the increase in inositol phosphate formation induced by noradrenaline, angiotensin II, and App(NH)p was not significantly impaired. 5. We conclude that P2 gamma-purinoceptors are present in the renal cortex; these receptors stimulate formation of inositol phosphates via a pertussis toxin-insensitive pathway and undergo homologous desensitization. On the other hand, our results suggest that renal A,-adenosine receptors do not use stimulation of phosphoinositide breakdown as a transmembrane signalling system.

Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors.

1. Adenosine is known to stimulate capillary outgrowth and endothelial cell proliferation, but the underlying mechanism has not been identified. In order to identify the receptor subtype involved, the effects of adenosine receptor agonists and antagonists on human umbilical vein endothelial cell (HUVEC) proliferation were investigated. 2. Raising intracellular adenosine levels by use of the adenosine transport inhibitor, 4-nitrobenzylthioinosine (NBMPR) did not affect cell growth. This observation suggests that stimulation of an extracellular adenosine receptor generates the mitogenic signal. 3. In the presence of adenosine deaminase (ADA), which was used to remove adenosine present in the culture medium, the adenosine receptor agonists N-ethylcarboxamidoadenosine (NECA, non-selective) and CGS21680 (A2A-receptor-selective) stimulated [3H]-thymidine incorporation with a half-maximum effect at about 10 nM, while N6-cyclopentyladenosine (CPA, A1-selective) was about 100 fold less potent. The adenosine receptor antagonist, xanthine amine congener (XAC) produced a concentration-dependent decrease in endothelial cell proliferation with a half-maximum effect at about 10 nM. Hence, stimulation of an endothelial A2A-adenosine receptor seems responsible for the mitogenic signal. 4. In the presence of ADA, isoprenaline is also able to stimulate [3H]-thymidine incorporation with a half maximal effect of about 3 nM, an effect, which is reversed by the highly beta 2-selective antagonist, ICI 118,551. In the absence of ADA, isoprenaline exerts only a minor stimulatory effect. Combination of A2A adenosine and beta 2-adrenoceptor agonists did not further enhance [3H]-thymidine incorporation when compared to the sole addition of each agonist. We therefore conclude that both receptors stimulate endothelial cell proliferation via a common signal transduction pathway. 5. Both receptors are coupled to stimulation of adenylyl cyclase via the stimulatory G protein G8.However, direct activation of downstream effectors in the cyclic AMP-signalling cascade (G8 with cholera toxin, adenylyl cyclase with forskolin, protein kinase A with 8Br-cyclic AMP) not only failed to mimic the action of receptor-activation, but even reduced cell proliferation.6. Similarly, pertussis toxin-treatment which inactivated the Gi 2 protein present in HUVEC and thus inhibited cell proliferation per se, did not impair the ability of A2A-receptor agonists to stimulate cell proliferation. This suggests that the A2A-adenosine and beta2-adrenoceptor-mediated stimulation of endothelial cell proliferation occurs via a mechanism that is independent of G8 and Gi.

Effects of exercise on circulating vascular adhesion molecules in healthy men.

Based on previous studies showing an increase in circulating soluble intercellular adhesion molecule-1 (sICAM-1) after exercise, we hypothesized that exercise may also increase serum levels of the vascular cell adhesion molecule-1 (sVCAM-1) and sE-selection. In a prospective controlled clinical trial, serum levels of sE-selectin, sICAM-1 and sVAM-1 were measured before and after two different exercise protocols in healthy untrained men. Lactate levels increased up to 12.7 mmol/L (95% confidence interval: 10.1-15.9) and 3.6 mmol/L (CI: 2.4-4.7) after ergometry and after an one hour endurance exercise at 60% of the maximal work intensity, respectively (p = 0.028 vs baseline and controls). The maximal increase in lymphocyte counts of 106% (CI: 63-146), which was only of short duration, was higher immediately after ergometry as compared to that observed after endurance exercise (p = 0.028). However, the maximal increase in neutrophil counts of 178% (CI: 120-298) which was seen at 2 hours after endurance exercise was higher than that seen after ergometry (p = 0.028). In contrast, only small changes of circulating adhesion molecules were seen immediately after ergometry: sICAM-1 increased by 11% (CI: 4-25; p = 0.028), and similar tendencies were also observed for sVCAM-1 and sE-selectin. No other consistent and time-dependent changes of circulating adhesion molecules were observed and all differences and changes were < or = 11%. In sum our study provides evidence that recreational sporting activities in untrained healthy subjects at normal altitude have little influence on serum levels of the circulating vascular adhesion molecules sE-selectin, sVCAM-1 or sICAM-1.

Improvement of cardiac preservation by preoperative high insulin supply.

Therapeutic administration of high doses of insulin achieves a shifting of metabolism to glycogenesis and glycolysis. The result is an accumulation of the myocardial glycogen stores and an improvement of glucose utilization as well. If on that basis an increased anaerobic provision of adenosine triphosphate will be maintained in the myocardium during ischemia, the myocardial cell viability during aortic cross-clamping will be saved as well. Thus a preventive insulin supply will preserve the heart from ischemic damage. Twenty patients undergoing mitral valve replacement were investigated in two randomized groups. One group received insulin (1 U/kg/hr) together with a 33% glucose infusion (0.5 gm/kg/h) and potassium (0.25 mEq/kg/hr) from the onset of anesthesia until aortic cross-clamping. The control group received Ringer's lactate at the same infusion rate. After an average ischemic time of 26 minutes, an excised papillary muscle tip was immediately plunged into liquid nitrogen and the content of adenosine triphosphate, adenosine diphosphate, and creatine phosphate was determined. The adenosine triphosphate/diphosphate quotient and the energy charge potential were calculated. The mean adenosine triphosphate content in the insulin group was 7.43 mumol/gm wet weight and was significantly (p less than 0.01) higher than that of the control group (4.28 mumol/gm). The mean ADP content was 1.43 mumol/gm in the insulin group versus 1.81 mumol/gm in the control group. The mean creatine phosphate content was again significantly (p less than 0.05) higher in the insulin group (6.70 mumol/gm) than in the control group (5.30 mumol/gm). Also, the mean adenosine triphosphate/diphosphate quotient (insulin group, 5.19; control group, 2.36) and the mean energy charge potential (insulin group, 0.919; control group, 0.851) were significantly (p less than 0.01) higher in the insulin group. It is concluded that the preventive application of high doses of insulin leads to an augmented myocardial adenosine triphosphate provision and a maintained cellular energy charge during coronary ischemia. As a result, ischemic tolerance is enhanced and myocardial protection is improved.

Is it feasible to monitor total hepatic blood flow by use of transesophageal echography? An experimental study in pigs.

OBJECTIVES: Total hepatic venous blood flow is determined by the common hepatic arterial blood flow and the venous outflow from stomach, spleen, pancreas, small intestine, and bowel, collected by the portal vein, and thus represents overall splanchnic perfusion. We investigated whether transesophageal echography (TEE) can provide a method for bedside assessment of hepatic venous blood flow useful as a noninvasive method for measuring splanchnic perfusion in clinical practice. DESIGN AND SETTING: Experimental study in 15 anesthetized and ventilated pigs in an animal research laboratory. INTERVENTIONS: TEE-derived calculations of hepatic venous blood flow were compared with liver blood flow measurements using perivascular ultrasound flow probes surgically positioned on portal vein and common hepatic artery. Parameters were determined at baseline and after modulating splanchnic perfusion by either PEEP maneuver (15 cmH2O) or intravenous epinephrine (0.1 microgram kg-1 min-1). MEASUREMENTS AND RESULTS: Diameter (d) and velocity time integral (VTI) of all three hepatic veins were determined by TEE, heart rate (HR) was derived from electrocardiography and flow subsequently calculated as Q = pi.(d/2)(2).0.57.VTI.HR. Regression analysis of matched TEE and flow probe values showed a significant linear relationship (r2 = 0.698). Bias analysis revealed a systematic underestimation of liver blood flow by TEE, possibly due to use of 0.57 as correction factor for mean velocity, while changes in liver blood flow were reliably detected. CONCLUSION: TEE offers a noninvasive approach for monitoring hepatic perfusion and may be used in patients.

Evidence against adenylate cyclase-coupled adenosine receptors in the guinea pig heart.

(--)-N6-(Phenylisopropyl)adenosine (PIA, 10 microM) and 5'-N-(ethylcarboxamide)adenosine (NECA, 50 microM), potent agonists at the adenylate cyclase-coupled R-site adenosine receptor, were investigated for adenylate cyclase inhibition in a guinea pig ventricular membrane preparation by means of the dATP assay method. Neither compound influenced basal or isoproterenol-stimulated cyclase activity, irrespective of whether Na ions were present or not. These data suggest that R-site receptors may not be involved in the cardiac adenylate cyclase system of the guinea pig.

Functional identification of adenylate cyclase-coupled adenosine receptors in rat brain microvessels.

It was investigated whether adenosine affects the adenylate cyclase system of microvessels, isolated from the rat cerebral cortex, via an external receptor recently classified as R-site receptor. Several adenosine analogs caused GTP-dependent stimulation of adenylate cyclase. The rank order of potency: NECA (5'-(N-ethylcarboxamido)-adenosine, EC50 0.2 microM) greater than adenosine (0.71 microM) = 2-chloroadenosine (0.72 microM) greater than L-PIA (N6-(L-phenylisopropyl)-adenosine, 1.03 microM) greater than D-PIA (N6-(D-phenylisopropyl)-adenosine, 5.27 microM) is consistent with that for agonism at activatory (Ra-site) adenosine receptors in other tissues. Adenylate cyclase stimulation by PIA displayed stereoselectivity. The action of NECA was competitively antagonized by 8-phenyltheophylline. These findings provide functional evidence for Ra-site adenosine receptors in rat brain microvessels. However, direct identification of these receptors by binding studies was not possible. Binding of [3H]NECA to rat brain microvessels displayed rapid on-off kinetics and saturability, but equivocal specificity.

Interaction of the antihypertensive drug urapidil with cardiac beta-adrenoceptors in vitro.

A possible interaction of the antihypertensive drug, urapidil with beta-adrenoceptors was investigated in a guinea-pig ventricular membrane preparation. Urapidil at concentrations above 1 microM antagonized the isoproterenol-induced stimulation of adenylate cyclase activity. Urapidil 10 microM shifted the concentration-response curve for isoproterenol in a parallel manner to the right by a factor of 16. Urapidil competed with specific beta-adrenoceptor binding of [125I]iodocyanopindolol with an IC50 of 12 microM. Since the affinity of urapidil to beta-adrenoceptors appeared rather low, any beta-adrenoceptor blocking property may be of relevance in vivo at high dosages only.

Prolongation of the QT interval by dofetilide modulates rate-dependent effects of mexiletine on intraventricular conduction.

Prolongation of action potential duration during treatment with agents that possess class I antiarrhythmic activity may result in a clinically relevant increase in Na+ channel block. In order to test this hypothesis in vivo, the effect of QT prolongation on intraventricular conduction was assessed during administration of mexiletine. Epicardial His bundle recordings were made in anesthetized guinea pigs. After abolition of spontaneous sinus node activity by application of high-frequency current to the sinus node area, the hearts were paced via the left atrium. Administration of the class III antiarrhythmic agent dofetilide (10 micrograms/kg i.v.; n = 6) significantly prolonged QT intervals without a significant effect on HV intervals. Infusion of mexiletine (bolus 2 mg/kg + 0.18 mg/kg per min i.v.; n = 6) produced significant increases in HV intervals at cycle lengths of 200 and 300 ms. Subsequent addition of dofetilide (20 micrograms/kg i.v.) to mexiletine induced similar increases in QT intervals as single treatment with 10 micrograms/kg dofetilide and significantly enhanced the rate-dependent conduction slowing. Upon abruptly decreasing the pacing cycle length from 500 ms to 300 ms, conduction slowing developed with a rate constant of 1.0 +/- 0.2 beat-1 after mexiletine and with a rate constant of 1.1 +/- 0.2 beat-1 after subsequent addition of dofetilide (P = n.s.). After rapid stimulation at a cycle length of 250 ms the conduction slowing produced by mexiletine recovered with a time constant of 174 +/- 24 ms. No further change of this recovery time constant was observed after subsequent addition of dofetilide to mexiletine (160 +/- 19 ms, P = n.s.). Thus action potential duration, as reflected by the QT interval, is an important modulator of the magnitude Na+ channel block in vivo. The kinetic parameters of Na+ channel block produced by mexiletine, however, remain unchanged by prolongation of action potential duration after addition of dofetilide.

Efficacy and safety of sultamicillin (750 mg bid) compared with amoxycillin/clavulanate (625 mg tid) in patients with umcomplicated urinary tract infections.

In an open, randomized, multicentre study, two aminopenicillin/beta-lactamase inhibitor combinations for oral administration were compared in 132 out-patients with umcomplicated urinary tract infections. Two groups of 66 patients each received a dose of 750 mg sultamicillin (STM) bid or 625 mg amoxycillin/clavulanic (AMX/CLA) acid tid. The evaluation of efficacy was performed on a total of 126 patients (STM: 64, AMX/CLA: 62) in whom bacteria were isolated before the start of treatment. In the STM group, 61 patients (95.3%) were treated successfully (cure and elimination of the organism), versus 56 patients in the AMX/CLA group (90.3%). Both combinations were well tolerated; troublesome adverse effects were not seen. Sultamicillin is an efficacious treatment for acute urinary tract infections, like AMX/CLA. Moreover, whereas STM is as efficacious as AMX/CLA, and is as well tolerated, it has the advantage of requiring only twice-daily dosing.

Bioequivalence between two furosemide-spironolactone formulations: a pharmacokinetic and pharmacodynamic approach.

Two formulations of the drug combination furosemide (20 mg)-spironolactone (100 mg) were tested for bioequivalence in a randomized crossover trial in 12 healthy volunteers. By comparing the AUC values derived from drug serum concentrations, bioequivalence was only achieved for canrenone, the main metabolite of spironolactone, but not for furosemide. A significant difference in the tmax values indicates sustained release of furosemide from one of the formulations. By contrast, bioequivalence was achieved if pharmacodynamic criteria, such as urine volume and Na+ and Cl- excretion over a period of 12 hours, were used. Fractional measurements of urinary volume and electrolyte excretion (0 to 3 h, 3 to 6 h, 6 to 12 h) correlated with the different tmax values for both formulations. These data indicate that bioequivalence is more conclusively verified on the basis of pharmacodynamic parameters than on the basis of pharmacokinetic parameters. These considerations are applicable in particular to drugs displaying large inter-individual variations in serum levels and/or a poor correlation between serum levels and effect.

The role of a low beta 1-adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands.

On the basis of saturation binding studies on rat cardiac microsomes, which contained a mixed population of beta-adrenoceptor subtypes, [3H]CGP-12177 is presumed to be a non-selective beta-adrenergic radioligand. However, saturation binding studies carried out in the presence of subtype-saturating concentrations of the beta 2-selective antagonist ICI 118,551 and the beta 1-selective antagonist ICI 89,406, respectively, revealed a KD for beta 1-adrenoceptors of 0.33 +/- 0.02 nmol/l and a KD for beta 2-adrenoceptors of 0.90 +/- 0.14 nmol/l. Competition experiments with the highly selective antagonists revealed greatly different competition binding curves in the presence of either [3H]CGP-12177 or (-)[125I]iodocyanopindolol (ICYP), a beta-adrenergic radioligand considered to be as non-selective as [3H]CGP-12177. The following results are further suggestive for a selectivity of [3H]CGP-12177 for beta 1-adrenoceptors: (1) Using non-linear regression analysis, a significantly lower selectivity (expressed as the ratio of the IC50 for beta 2-adrenoceptors to the IC50 for beta 1-adrenoceptors) as well as a larger proportion of beta 1-adrenoceptors were calculated by competition of the beta 1-selective antagonist ICI 89,406 with [3H]CGP-12177 binding than by competition of ICI 89,406 with ICYP binding; (2) reducing the [3H]CGP-12177 concentration from 2 to 0.4 nmol/l, competition experiments with ICI 89,406 led to an increase in the estimated selectivity of the competitor and in the estimated proportion of beta 1-adrenoceptors; (3) reverse findings were obtained with ICI 118,551, a beta 2-selective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for glucagon-releasing activity of vasoactive adenosine analogues in the conscious dog.

An investigation was carried out in conscious dogs concerning the effects of three adenosine derivatives substituted at the 5'-(744-96) or 2'-, 3'-, and 5'-positions (744-98, 744-99), with pronounced and long-lasting coronary dilator activity, on glucagon release. All three compounds (10 microgram/kg i.v.) induced a sustained increase in plasma glucose and a decrease in plasma FFA concentration; concomitantly, plasma glucagon levels rose 2--3 fold. Changes in plasma insulin concentration were relatively small and of no statistical significance. A simultaneous fall in arterial blood pressure was also observed. A lowering of blood pressure of similar magnitude by sodium nitroprusside infusion in control experiments failed to show any significant effect on plasma glucagon level. These results point to a specific effect of vasoactive adenosine derivatives on glucagon release.

Haemodynamic and coronary actions of ouabain during coronary infusion.

The investigations were carried out on 24 mongrel dogs which were anaesthetized with chloralose or sodium pentobarbital. Ouabain was added to the coronary blood (50, 100 and 200 ng/ml coronary blood or 0.7, 1.4 and 2.8 X 10(-7) M) over periods of 30 or 60 min by intracoronary infusion of the glycoside. Under chloralose anaesthesia, ouabain at concentrations of 100 and 200 ng/ml coronary blood augmented left ventricular dp/dt significantly. No significant changes were observed in coronary resting flow and flow per beat at the same time. Likewise, the maximum reactive hyperaemic blood flow remained constant, indicating the absence of any changes in the tone of the large extramural arteries. Under sodium pentobarbital anaesthesia small decreases in heart rate and increases in left ventricular dp/dt were seen only at the highest ouabain concentration (200 ng/ml). All flow parameters remained unchanged. These experiments provide evidence that concentrations of ouabain which 100- and 200-fold exceed therapeutic maintenance levels and 10- and 20-fold exceed the concentrations that produce constriction of helically cut pig and rabbit coronary arteries in vitro, do not diminish the coronary blood supply of the anaesthetized dog in vivo.