Research Articles¶Naturally occurring 2′-O-methylpurine nucleosides with hypotensive properties

2′-O-Methylinosine (1) has been isolated for the first time and shown to be an intrinsic hypotensive principle. Its probable in vivo precursor, 2′-O-methyladenosine (3), showed stronger and even orally potent hypotensive activity. Resistance of the methyladenosine (3) against adenosine deaminase is thought to contribute to its long-lasting activity. The effect of both nucleosides (1 and 3) was not accompanied with any significant change in heart rate, which is often observed with adenosine. Received 2 October 1997; accepted 28 October 1997     

Plasma adenosine concentrations are elevated in Dahl salt-sensitive rats

We measured plasma levels of adenosine in Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) to examine the potential role of adenosine in cardiovascular regulation in this type of hypertension. Plasma adenosine concentrations were significantly higher in DS than in DR. The NaCl content in the diet did not affect plasma adenosine concentration in either DS or DR. Significant positive correlation was found between adenosine concentrations and systolic blood pressure when the data for DS and DR were analyzed together. These results suggest that adenosine may play an important role in the pathophysiology of hypertension in DS.     

Dosis-Wirkungs-Beziehungen zwischen Koronardurchfluss und Herzfrequenz für Adenosin

Summary In the isolated guinea-pig heart, it has been found that the amount of adenosine which slows the heart rate is about 100 times greater than the amount which increases coronary flow.     

Transmural pressure as a determinant of basic intrinsic heart rate

Summary It was observed the heart rate was minimum at zero transmural pressure. The mean heart rate at zero transmural pressure was 23±5/min. This mean heart rate increased from 23±5/min to a peak value of 40±6/min (74% acceleratin) when the transmural pressure was raised from 0 to +4 mm Hg and to a similar peak value of 36±8/min (56% acceleration) when the transmural pressure was lowered from 0 to –4 mm Hg. The peak values attained at ±4 mm Hg were higly significant (p<0.001). It is concluded that the heart rate at zero transmural pressure represents the basic intrinsic pacemaker frequency independent of neural, humoral, thermal and haemodynamically induced mechanical influences.     

Oxygen consumption in human placental lobules in vitro (survival maintained by perfusion)]

The average oxygen utilization coefficient of 26% is calculated from PO2 determinations during the perfusion of the fetal circulation of isolated human term placental lobules. The oxygen consumption approximates 0.4 ml/min/kg placenta when Earle's salt solution is used as a perfusion medium and is equilibrated with a gas mixture containing 5% O2. The oxygen consumption reaches 2 ml/min/kg when the same Earle's solution is equilibrated with a gas mixture containing 95% O2.     

Zur Pharmakologie von Psilocybin,einem Wirkstoff ausPsilocybe mexicana Heim

Summary The active principle ofPsilocybe mexicana Heim, Psilocybin, is without marked effects on the isolated organs (seminal vesicle, intestine and auricle of the guinea pig; rat uterus) but exerts an actionin vivo which resembles a slight sympathetic stimulation. In unanaesthetized rabbits it produces mydriasis, tachycardia, tachypnea, hyperthermia and hyperglycemia, in unanaesthetized mice mydriasis and piloerection. The EEG (curarized rabbits) after 1–2 mg/kg Psilocybin shows an alerting pattern (disappearance of spindle activity and of slow waves). Spinal reflexes of the cat are predominantly enhanced. However, the motor activity of mice, rabbits and monkeys is unaffected or even slightly depressed. In anaesthetized cats and dogs Psilocybin affects blood pressure and heart rate, the effect depending on dosage and species.     

Phoenixin-14: detection and novel physiological implications in cardiac modulation and cardioprotection

Phoenixin-14 (PNX) is a newly identified peptide co-expressed in the hypothalamus with the anorexic and cardioactive Nesfatin-1. Like Nesfatin-1, PNX is able to cross the blood–brain barrier and this suggests a role in peripheral modulation. Preliminary mass spectrography data indicate that, in addition to the hypothalamus, PNX is present in the mammalian heart. This study aimed to quantify PNX expression in the rat heart, and to evaluate whether the peptide influences the myocardial function under basal condition and in the presence of ischemia/reperfusion (I/R). By ELISA the presence of PNX was detected in both hypothalamus and heart. In plasma of normal, but not of obese rats, the peptide concentrations increased after meal. Exposure of the isolated and Langendorff perfused rat heart to exogenous PNX induces a reduction of contractility and relaxation, without effects on coronary pressure and heart rate. As revealed by immunoblotting, these effects were accompanied by an increase of Erk1/2, Akt and eNOS phosphorylation. PNX (EC₅₀ dose), administered after ischemia, induced post-conditioning-like cardioprotection. This was revealed by a smaller infarct size and a better systolic recovery with respect to those detected on hearts exposed to I/R alone. The peptide also activates the cardioprotective RISK and SAFE cascades and inhibits apoptosis. These effects were also observed in the heart of obese rats. Our data provide a first evidence on the peripheral activity of PNX and on its direct cardiomodulatory and cardioprotective role under both normal conditions and in the presence of metabolic disorders.     

3-Hydroxy-4-methoxyphenethylamine,the cardioactive constituent of a soft coral

Summary Intravenous administration to rats of the aqueous extract of the soft coralNephthea sp. caused an increase in heart rate and blood pressure. The cardioactive constituent was isolated and shown to be 3-hydroxy-4-methoxyphenethylamine.     

Über die Steuerung des Ionengleichgewichtes zwischen Zellen und umgebender Flüssigkeit beim isolierten Froschherzen

Summary (1) The isolated frog's heart, repeatedly washed with Ca-free Ringer's solution, stops and, after discontinuing washing, begins to move again in spite of Ca lack. The heart adapts in the same way to the common lack of Ca and K, furthermore to Ringer's solution containing 10–20 times more K than normal.(2) Adaptation was not observed on isolated ventricle driven with electrical current.(3) It is concluded that the isolated frog's heart adapts to the ion composition of the surrounding fluid as a whole, and that the auricle plays an essential role in this process.     

Baroreceptors capable of inducing the biosynthesis and release of prostaglandins (PG) and of modulating adrenergic neurotransmission in the myocardium

In the isolated Rabbit heart, high pressure, on the one hand, inhibits the noradrenaline release, and on the other hand, induces both the biosynthesis and release of PGs(PGE2,PGF2 alpha) from the auricles and mainly from the right auricle i.e. where the sympathetic nerve endings are the most numerous. Therefore, high pressure, by a negative feedback process, plays a great part in moderating the adrenergic neurotransmission responsible for the hypertension. These effects result from a supplementary pressure which acts on the walls of coronary arteries and arterioles and modifies their distensibility. It thus appears that in the walls of arteries and arterioles there are baroreceptors which are sensitive to the pressure variations in order to regulate adrenergic neurotransmission, by means of a reflex path still unknown.     

Cardiac activation and inhibition involved in molting behavior of a spiny lobster

To study the molting behavior of the spiny lobster, electrical activity of the heart, stomach and skeletal muscles was recorded using in-dwelling electrodes. For 1–2 h before molting the heart rate gradually increases. At the same time shorter trains of stomach burst discharges frequently occur. The heart rate then declines and burst discharges of skeletal muscles begin. The skeletal bursts are regularly spaced (10–15 s intervals). A peristalsis pattern of short and long bursts continues for 10–20 min and is terminated by a few bursts corresponding to abdominal flips. The short skeletal burst is followed by a drop in heart rate. Bioassay using the isolated heart suggests that at the final stage of molting the blood contains some substance(s) which inhibit heart beat.     

Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors

Caffeine is the most widely used drug in the world and acts mainly through antagonism of the effects mediated by the adenosine receptor subtypes A1, A2A, A2B and A3. We determined whether repeated caffeine administration at different doses and for different periods of time (400 or 600 mg/day for 1 week and 400 mg/day for 2 weeks) alters human neutrophil A2A adenosine receptor density and function. Saturation binding assays showed an increase in affinity (K(D)) and density (B(max)) of A2A adenosine receptors after caffeine intake. These changes were accompanied by increases in cAMP accumulation and decreases in superoxide anion production after stimulation of the A2A receptor subtype using the agonist 5'-N-ethylcarboxamidoadenosine (NECA). Binding and functional changes of A2A receptors returned to baseline after 48 h of caffeine withdrawal. The findings are consistent with a potential anti-inflammatory effect of caffeine mediated by neutrophil A2A receptors.     

Role of adenosine A1 and A2 receptors in the regulation of aldosterone production in rat adrenal glands

To investigate the roles of adenosine A1 and A2 receptors in the regulation of aldosterone production, we examined the effects of adenosine and adenosine agonists (N6-cyclohexyl adenosine; selective adenosine A1 receptor agonist and 5'-N-ethylcarboxamine adenosine; selective adenosine A2 receptor agonist) on aldosterone and cyclic AMP production in rat adrenal capsular cells. Neither adenosine nor 5'-N-ethylcarboxamine adenosine caused significant effects on basal aldosterone or cyclic AMP production. Also, adenosine (10(-3) M) showed no consistent effects on aldosterone and cyclic AMP production induced by ACTH. On the other hand, N6-cyclohexyl adenosine exhibited a significant inhibition of basal aldosterone and cyclic AMP production at doses of 10(-4) M and 10(-3) M; furthermore, 10(-3) M N6-cyclohexyl adenosine inhibited aldosterone and cyclic AMP production stimulated by ACTH. These results suggest that adenosine A1 receptors are coupled to and inhibit adenylate cyclase and may be involved in the inhibition of aldosterone production.     

Zur Entwicklung der Gefässe im Herzmuskel

Summary In the developing rat heart 3 periods may be distinguished with regard to the nutrition of the myocardium: (1) Nutrition by diffusion (up to the 12th embryonic day). (2) Period of venous circulation in which the blood passes from the ventricles through sinusoids, capillaries and veins to the coronary sinus. (3) The coronary circulation, which starts with the formation of coronary arteries. By the end of the first week of life, the cardiac circulating system is fully developed.     

The cytogenetic efficiency of the antitumor agents bleomycin and peplomycin is enhanced by the heart drug verapamil (isoptin)

The induction of 2-break chromosome aberrations (dicentrics and ring chromosomes) in human lymphocytes by the antitumor agents bleomycin and peplomycin is strongly enhanced when those agents are applied together with the heart drug verapamil (isoptin).     

Flying insects: model systems in exercise physiology

Insect flight is the most energy-demanding exercise known. It requires very effective coupling of adenosine triphosphate (ATP) hydrolysis and regeneration in the working flight muscles.³¹P nuclear magnetic resonance (NMR) spectroscopy of locust flight muscle in vivo has shown that flight causes only a small decrease in the content of ATP, whereas the free concentrations of inorganic phosphate (P _i ), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) were estimated to increase by about 3-, 5- and 27-fold, respectively. These metabolites are potent activators of glycogen phosphorylase and phosphofructokinase (PFK). Activation of glycolysis by AMP and P _i is reinforced synergistically by fructose 2,6-bisphosphate (F2,6P₂), a very potent activator of PFK. During prolonged flight locusts gradually change from using carbohydrate to lipids as their main fuel. This requires a decrease in glycolytic flux which is brought about, at least in part, by a marked decrease in the content of F2,6P₂ in flight muscle (by 80% within 15 min of flight). The synthesis of F2,6P₂ in flight muscle can be stimulated by the nervous system via the biogenic amine octopamine. Octopamine and F2,6P₂ seem to be part of a mechanism to control the rate of carbohydrate oxidation in flight muscle and thus function in the metabolic integration of insect flight.Dedicated to Dr. Ernst Zebe, Emeritus Professor of Zoology (University of Münster) on the occasion of his 70th birthday.     

Structure-activity relationship of various ephedrine isomers on noradrenaline uptake by the isolated perfused rabbit heart]

(-)Ephedrine, (+) Ephedrine, (-) psi ephedrine and (+) psi ephedrine inhibit both the neuronal and extraneuronal uptakes of noradrenaline in isolated Rabbit heart. (-) ephedrine is the most active isomer for the inhibition of both neuronal and extraneuronal uptakes. The relative inhibition potential of the three other isomers is not the same when applied to one or other uptake.     

Wiederherstellung des normalen Herzschlages nach elektrisch erzeugtem Kammerflimmern durch Adenosintriphosphorsäure

Summary (1) In the isolated mammalian heart (rabbit, cat, dog) electrically induced ventricular fibrillation is stopped in practically 100% of the cases by adenosin-triphosphoric acid (ATP) in doses of 0.25–20 mg, and the normal rhythm of the heart is permanently restored (as far as the experiment extends).(2) This effect of ATP follows from a primary blocking, which leads to a complete cessation of the activity of the ventricles with diastolic dilatation of the heart.(3) In as much as adenyl acid from yeast and adenosin (in large doses) also stop ventricular fibrillation, the energetic effect of ATP seems to be of no importance in stopping it; it is a specific effect of the adenyl compounds on the bundle ofHis.     

Heilmittelchemische Studien mit Dien-Additionsprodukten V: Über die coronardilatierenden Eigenschaften einer neuen Klasse von Aminen

Summary The addition productsof 2 M N-alkyl substituted maleinimides with 1M asymmetric diphenylethylen and some of its substitution products were reduced with LiAlH₄ to give amines of the structure V. These substances produce coronary dilation on the isolated guinea-pig heart perfused according to the method of Langendorff, a few of them being more active than papaverin. On the barbiturate anaesthetized dog, however, the activity was much less than that of papaverin after intraarterial injection and was entirely absent on intravenous application. High doses caused lowering of the blood pressure. The limited value of the Langendorff heart preparation for screening coronary dilators is emphasized.

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IV. Mitteilung: I.Molnar, Helv. Chim Acta49, 586 (1966).