Effects of flestolol, an ultra-short acting beta-adrenoceptor antagonist, on hemodynamic changes produced by treadmill exercise or isoprenaline stimulation in conscious dogs.
The beta-blocking activity of flestolol was established during increasing isoprenaline infusions and during graded physical exercise in conscious, chronically instrumented dogs. After a control cycle, flestolol was infused at three doses (1, 2.67, and 10 micrograms/kg/min). Flestolol has an extremely short half-life, demonstrated by an 83% loss of effect within 25 min. Thus, flestolol allows easy titration of the effect, which might be a valuable property for its use in the treatment of critically ill patients. Due to the difference between pure beta-adrenergic stimulation and the much more complex regulation of circulation during exercise, the hemodynamic response to flestolol elicited marked differences between both set ups. Flestolol shifted the dose-response curves of isoprenaline-induced changes in heart rate, positive left ventricular dp/dtmax, and diastolic arterial pressure dose dependently to the right, while its main effect during exercise was a decrease in positive left ventricular dP/dtmax. Thus, testing of beta-adrenoceptor blockers using isoprenaline-induced tachycardia leads to an overestimation of potency and therefore is not appropriate to predict the clinical efficacy of these drugs to prevent stress- or exercise-induced increases in heart rate and hence myocardial oxygen-demand.
Grohs
J G
JG
Pharmakologisches Institut, Universität Wien, Vienna, Austria.
Fischer
G
G
Raberger
G
G
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010805:Physical Conditioning, Animal; D011412:Propanolamines / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D005464:Fluorobenzenes; D011412:Propanolamines; D007545:Isoproterenol; C047847:flestolol