Summary
Using isolated canine small (right coronary branch, left coronary branch; o. d. 0.4–0.8 mm) and large (left coronary, circumflex; o. d. 1–2 mm) coronary arteries, thebeta-adrenergic antagonist dl-propranolol (5×10−7 to 5×10−5 m/l) was found to produce concentration-dependent contractions. Interestingly, most of these contractile events take place with concentrations of propranolol (0.1–1 μg/ml) found in the blood of patients who are taking this drug for various therapeutic reasons. These propranolol-induced contractions were enhanced in Krebs-Ringer solution containing slightly elevated (weak contractile) concentrations of potassium (15 mmol/l). Experiments with specific pharmacologic antagonists indicated that propranolol-induced contractions on canine coronary arteries can not be mediated by release (or inhibition) of catecholamines, histamine, sertonin or acetycholine. Propranolol contractions could be relaxed by low concentrations of potassium ions (4 mmol/l), suggesting that thebeta receptor antagonist might inactivate coronary arterial membrane Na+, K+-ATPase. Other experiments demonstrated that propranolol can enhance coronary arterial membrane permeability to calcium ions; these observations suggest that propranolol might sensitize coronary vascular smooth muscle cells to calcium ions. Removal of calcium ions from the Krebs-Ringer solution or addition of the calcium entry blocker, verapamil, prevented completely the propranolol-induced contractions. Catecholamines (i.e., epinephrine, norepinephrine, isoproterenol), which normally induce relaxation on these isolated coronary arteries, always induced contraction after use of dl-propranolol. Overall, these experiments suggest that the so-called “beta-blocker poisoning” sometimes noted with propranolol in patients might be brought about by four actions of this drug acting in concert: 1. direct coronary arterial vasospasm; 2. an unmasking of normally silentalpha-adrenergic receptors, thus allowing circulating and released catecholamines to induce potent coronary constriction; 3. attenuation of membrane Na+, K+-ATPase activity; and 4. an enhancement of coronary vascular smooth muscle membrane permeability to calcium ions.
Zusammenfassung
An isolierten Präparaten verschiedener Abschnitte des Koronararteriensystems vom Hund bewirkte der β-adrenerge Antagonist dl-Propranolol (5×10−7 bis 5×10−5 mmol/l) Kontraktionen der glatten Gefäßmuskulatur. Interessanterweise treten solche Kontraktionen häufig in einem Konzentrationsbereich von Propranolol (0,1–1 μg/ml) auf, wie er bei Patienten verzeichnet wird, die diese Substanz aus therapeutischen Gründen einnehmen. Diese Propranolol-induzierte Kontraktionen wurden in Krebs-Ringer-Lösung durch leichte Steigerung der K+-Konzentration (15 mmol/l) verstärkt. Experimente mit spezifischen pharmakologischen Antagonisten wiesen darauf hin, daß Propranolol-induzierte Kontraktionen an den Koronararterien vom Hund nicht durch Freisetzung (oder Hemmung) von Katecholaminen, Histamin, Serotonin oder Acetylcholin vermittelt werden kann. Bei Propranolol-induzierten Kontraktionen führten geringe K+-Konzentrationen (4 mmol/l) zur Erschlaffung; als mögliche Ursache wird eine Inaktivierung der membranären Na+, K+-ATPase diskutiert. Andere Experimente zeigten, daß Propranolol die Membranpermeabilität bzw. die Empfindlichkeit für Ca2+-Ionen steigern kann. Beseitigung der Ca2+-Ionen aus der Krebs-Ringer-Lösung oder Applikation des Ca2+-Antagonisten Verapamil verhinderten die Propranolol-induzierten Kontraktionen völlig. Katecholamine (Adrenalin, Noradrenalin, Isoproterenol), die normalerweise eine Erschlaffung der isolierten Koronararterien bewirken, induzierten nach Anwendung von dl-Propranolol immer Kontraktionen. Insgesamt lassen diese Experimente vermuten, daß die sog. β-Blockervergiftung, die gelegentlich bei Propranolol-behandelten Patienten verzeichnet wird, auf einem Zusammenwirken von 4 verschiedenen Mechanismen dieser Substanz beruht: 1. direkter arterieller Spasmus, 2. Demaskierung eines alpha-adrenergen Rezeptors, 3. Abschwächung der Aktivität einer membranären Na+, K+-ATPase, 4. Steigerung der Membranpermeabilität des vaskulären glatten Muskels für Ca2+-Ionen.
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This work was supported in part by research grants HL 18015 and DA 02339 from the U.S.P.H.S., D.H.E.W.
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Turlapaty, P.D.M.V., Altura, B.M. Propranolol induces contractions of canine small and large coronary arteries. Basic Res Cardiol 77, 68–81 (1982). https://doi.org/10.1007/BF01908132
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DOI: https://doi.org/10.1007/BF01908132