title: In vivo cardiovascular responses to isoproterenol, dopamine and tyramine after prolonged infusion of isoproterenol.
abstract: Effects of prolonged in vivo infusion of isoproterenol on acute cardiovascular responses to isoproterenol, dopamine and tyramine were studied in pithed rats. Isoproterenol infusion resulted in a significant decrease in control values for maximum left ventricular dP/dt; heart rate and left ventricular systolic blood pressure were not altered. This treatment also depleted both atrial and ventricular stores of norepinephrine and caused cardiac hypertrophy. Isoproterenol infusion resulted in a desensitization of drug-induced cardiovascular responses. The acute in vivo effects of isoproterenol on maximum left ventricular dP/dt, heart rate and left ventricular systolic blood pressure responses to isoproterenol were severely attenuated. The ED50 for maximum left ventricular dP/dt was increased 36-fold and maximal responses were reduced by half; changes in heart rate occurred in a parallel fashion. By contrast, ED50 values for inotropic responses to tyramine and dopamine were increased 14- and 4-fold, respectively, whereas increases in heart rate were blunted. Tyramine and dopamine-mediated increases in heart rate were completely attenuated by desensitization; chronotropic effects were again evident after pretreatment with the selective alpha-1 blocker prazosin. In addition, prazosin blocked the inotropic responses to tyramine and dopamine after desensitization and this antagonism was only slightly enhanced by addition of propranolol (prazosin + propranolol); propranolol alone was ineffective. These results are consistent with the down-regulation of beta adrenoceptors after prolonged exposure to catecholamines and indicate that under such conditions the alpha-mediated cardiovascular responses may be unmasked. Compared to pure beta agonists, agents with a degree of alpha-1 activity might be superior inotropes in heart failure patients who characteristically present with depleted stores of myocardial norepinephrine and minimal beta adrenoceptor reserve.
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002395:Catecholamines / Q000032:analysis; D004298:Dopamine / Q000494:pharmacology*; D007545:Isoproterenol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D014439:Tyramine / Q000494:pharmacology*
chemical_list: D002395:Catecholamines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D004298:Dopamine; D014439:Tyramine