Adenosine release and the subsequent activation of adenosine receptors are involved in ischaemic preconditioning in dogs and rabbits. In the present study, we investigated whether adenosine also mediates ischaemic preconditioning in swine. Swine were used since, due to the lack of an innate collateral circulation, infarct development in this species most closely resembles that observed in humans. In 36 enflurane-anaesthetized swine the impact of increased adenosine breakdown with exogenous porcine adenosine deaminase (5 IU/ml blood/min) on global and regional myocardial function (sonomicrometry), subendocardial blood flow (ENDO, microspheres) and infarct size (IS, triphenyl tetrazolium chloride staining following 90 min ischaemia and 120 min reperfusion) were analysed. Low-flow ischaemia for 90 min at an ENDO of 0.09 +/- 0.04 (mean +/- SD) ml/min/g caused an IS of 13.2 +/- 9.7% (n = 8) of the area at risk. Ischaemic preconditioning by a cycle of 10 min low-flow ischaemia followed by 15 min reperfusion prior to the 90-min ischaemic period (ENDO = 0.06 +/- 0.03 ml/min/g) reduced IS to 2.6 +/- 3.0% (n = 11, P < 0.05). The interstitial adenosine concentration (microdialysis) increased from 1.60 +/- 0.87 nmol/ml to above 10 microM during ischaemia; with intracoronary adenosine deaminase, the interstitial adenosine concentration fell from 1.65 +/- 0.23 to 0.12 +/- 0.07 nmol/ml and did not increase during ischaemia. Adenosine deaminase per se did not alter IS after 90 min ischaemia (n = 7, ENDO = 0.08 +/- 0.04 ml/min/g, IS = 12.1 +/- 6.9%) but abolished the beneficial effect of ischaemic preconditioning (n = 10, ENDO = 0.06 +/- 0.03 ml/min/g, IS = 8.8 +/- 5.8%). For any given ENDO, IS was significantly reduced in the ischaemic preconditioned group compared with the other three groups. Global and regional myocardial function were comparable among all groups of swine. We conclude that endogenous adenosine mediates ischaemic preconditioning also in swine.

Involvement of endogenous adenosine in ischaemic preconditioning in swine.

Single cardiac Ca channels exhibit three modes of gating, expressed as current records with brief openings occurring in bursts (mode 1), records with long-lasting openings and very brief closings that appear only rarely (mode 2), and records that lack openings because of channel unavailability (mode 0). The dihydropyridine Ca agonist Bay K 8644 enhances Ca channel current by promoting mode 2, while the Ca antagonists nitrendipine and nimodipine reduce the current by favoring mode 0.

Cardiovascular effects of dihydropyridine-type calcium antagonists and agonists

Regulation of intracellular magnesium by Mg2+ efflux.

Ultrastructural alterations during ischemia and reperfusion in human hearts during cardiac surgery.

In vascular smooth muscle (as in myocardial fibers), a transmembrane supply of calcium ions is required for active tension development. In consequence, calcium antagonists possess a wide scope of action against practically all types of vasoconstrictor or spastic responses of arterial smooth muscle cells. Calcium antagonists are the drugs of choice for the treatment of coronary, pulmonary, cerebral or mesenteric artery spasms. Other clinically important targets of calcium antagonists are the systemic resistance vessels that rapidly dilate, which explains why calcium antagonists are increasingly used for the treatment of acute hypertensive crises as well as for antihypertensive long-term therapy. In physiologic experiments, calcium antagonists normalize the blood pressure of spontaneously hypertensive rats, neutralize various vasoconstrictor agents (if they act via promotion of transmembrane calcium influx), and greatly reduce the sensitivity of the systemic arteries and arterioles to mechanical stimuli, which can produce additional vasoconstriction, if a rise in intraluminal pressure stretches the vascular wall (Bayliss effect). Calcium antagonists also prevent noxious arterial calcium overload in animals. In the human arterial walls, at an advanced age, pathogenic degrees of calcium accumulation are reached and probably play an important role in both the development of hypertension and of arteriosclerotic lesions. Hypertensive rats exhibit progressive arterial calcium overload that responds well to the calcium antagonists nifedipine, nimodipine, nisoldipine and nitrendipine, as well as to verapamil.

Antihypertensive and arterial anticalcinotic effects of calcium antagonists

Intracellular overloading with calcium as a decisive causative factor in the pathogenesis of noncoronary myocardial necroses

Uberdosierung von Vitamin D oder Dihydrotachysterol (DHT) fuhrt insbesondere bei kombinierter Verabreichung mit NaH2PO4 bei Ratten nicht nur zu Myokard-Lasionen, sondern auch zu arteriosklerotischen Gefasprozessen (1). Nach unseren vorausgegangenen Studien mit markiertem 45Ca ist die Nekrotisierung durch eine Ca++-Uberladung der Myokardfasern bedingt und dahernach Schwere und Ausdehnung mit der 45Ca-Inkorporation quantitativ korreliert (2,3). Organische Ca++-Antagonisten wie Verapamil, Substanz D 600 oder Prenylamin, die den transmembranaren Ca++-Influx in die Myokardfasern reduzieren, konnten daher die Nekrosebildung verhuten. Ahnlich wirkten K+- und Mg++-Salze als naturliche Ca++-Antagonisten. Ganz analoge Verhaltnisse wurden nunmehr an den Gefasen gefunden: Ratten wurden 10 Tage lang peroral taglich mit 2 mal 10 mM/kg NaH2PO4 und 7 Tage lang peroral taglich mit 1 mal 0, 5 mg/kg DHT vorbehandelt. Am elften Tag wurde intraperitoneal 45Ca (10 /uC/kg) injiziert und die 45Ca-Inkorporation in Aorta und Arteria mesenterica sup. gemessen. Bei den unbehandelten Kontrollratten erreichte der 45Ca-Gehalt in der Aortenwand innerhalb von 6 Stunden nach der 45Ca-Injektion 70% und in der Mesenterial-Arterie etwa 100% (bezogen auf die Plasma-Aktivitat = 100%), wahrend bei den vorbehandelten Tieren der 45Ca-Gehalt der Aorta innerhalb der gleichen Beobachtungszeit auf 5000–8000%y d.h. auf das 70–120-fache und der Mesenterial-Arterie auf 4000–5000%, d.h. auf das 40-50-fache der Norm anstieg.

Hemmung arteriosklerotischer Gefäßprozesse durch prophylaktische Behandlung mit MgCl2, KCl und organischen Ca++-Antagonisten (Quantitative Studien mit Ca45 bei Ratten)

Ca ions are highly cardiotoxic if their influx into the myocardial fibres becomes abundant. The intracellular Ca overload initiates a deleterious high-energy phosphate deficiency by excessive activation of Ca-dependent intracellular ATPases and by impairing the phosphorylating capacity of mitochondria. This Ca-induced high-energy phosphate exhaustion is a crucial point in the etiology of the myocardial fibre necroses produced in rats by large doses of beta-adrenergic catecholamines, particularly isoproterenol, or by a number of other cardiotoxic agents. Accordinly, the myocardium is sensitized to necrotization by factors which favour Ca overload (dihydrotachysterol, 9alpha-flourocortisol acetate, NaH2PO4). Conversely, the structural integrity of the hearts can be protected by any substance or procedure which prevents an excessive intracellular Ca accumulation, particularly by inhibitors of the transmembrane Ca influx, such as verapamil, D 600 or prenylamine.

[Key-role of intracellular calcium overload in acute necrosis of the myocardium. Cardioprotection with verapamil].

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.

[Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations].

In fruheren tier-experimentellen Studien von Fleckenstein, D00f6ring und Kammer,eier (1966, 1967, 1968) wurden 2 Typen von kontraktiler Herz-In-suffizienz herausgearbeitet: 

1.

Das Herzversagen infolge Mangels an energiereichem phosphat nach Hypoxie, Ischamie oder Hemmung des oxydativen Stoffwechsels;




2.

das Herzversagen infolge einer ungen00fcgenden Utilisation von energie-reichem Phosphat. Eine solche Utilisations-Insuffizienz tritt z. B. bei Ca++- Mangel ein, weil dann die Ca++-abhangige Myofibrillen–ATPase in den erregten Myokardfasern nicth mehr gen00fcgend ATP zur Gewinnung der Kontraktionsenergie spalten kann.

Einschränkung der Isoproterenol-induzierten 45Ca++-Netto-Aufnahme und der Utilisation von energiereichem Phosphat im hypertrophierten Rattenmyokard

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