Preliminary evidence for the mechanism underlying the development of tolerance to prazosin in congestive heart failure: the alpha-agonistic properties of dobutamine unmasked by prazosin treatment.
The hemodynamic effects of acute and chronic treatment with different vasodilators were assessed in patients with chronic heart failure of New York Heart Association (NYHA) class III-IV. Each of 24 patients was randomly allocated; 6 to each of four groups: isosorbide dinitrate, dihydralazine, captopril, or prazosin. In addition, we evaluated the hemodynamic response to dobutamine by using increasing infusion rates of 2.5, 5.0, and 10.0 micrograms/kg/min at the start and end of a 3-month period of chronic therapy with either vasodilator. Dobutamine caused a dose-dependent increase in cardiac index and a decrease in mean pulmonary artery pressure (PAP) at the start of the vasodilatory treatment and maintained the effects during a 3-month period of chronic treatment with either isosorbide dinitrate, dihydralazine, or captopril. After 3-month therapy with 6 mg/day prazosin, however, mean PAP was increased above pretreatment value and dobutamine caused a further increase in PAP, thus reversing the initial effects. The dobutamine-induced increase in cardiac index remained virtually unchanged. We conclude that the reversal of the effects on PAP after chronic treatment with prazosin may be, at least in part, due to upregulation of alpha 1-adrenoceptors. This appears to be unmasked by the alpha 1-adrenoceptor agonist of the (-)-enantiomer of the racemic mixture of (+/-)-dobutamine.
Kersting
F
F
Department of Internal Medicine-Cardiology, Hospital Evangelisches Stift St. Martin, Koblenz, Germany.
Kupp
M
M
Giesen
G
G
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D004280:Dobutamine / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011224:Prazosin / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D000316:Adrenergic alpha-Agonists; D014665:Vasodilator Agents; D004280:Dobutamine; D011224:Prazosin