Carvedilol increases blood pressure response to phenylephrine infusion in heart failure subjects with systolic dysfunction: evidence of improved vascular alpha1-adrenoreceptor signal transduction.
BACKGROUND
Alpha(1)-adrenergic receptor (alpha(1)-AR) stimulation produces smooth muscle contraction, vasoconstriction, and myocyte hypertrophy, suggesting a potential therapeutic role for alpha(1)-AR antagonists to reduce cardiac workload and myocardial hypertrophy. Preliminary reports suggest that vascular alpha(1)-ARs are desensitized in heart failure (HF) in a manner similar to myocardial beta(1)-ARs. We examined alpha(1)-AR signal transduction by repeat phenylephrine (PE) infusions in patients with HF receiving chronic carvedilol therapy.


METHODS
Twelve subjects with HF not currently receiving beta-blockers were up-titrated to maximum tolerable doses of carvedilol. Subjects underwent alpha(1)-AR stimulation testing at study baseline, 2 weeks after each dose titration, and 6 months after maintenance of maximum carvedilol dose. Phenylephrine infusions began at 0.5 microg kg(-1) min(-1), with dose titrations every 10 minutes, to a maximum of 5 microg kg(-1) min(-1). Phenylephrine dose response was evaluated by the PE rate required to elicit a 20 mm Hg increase in systolic blood pressure (BP), designated PS(20).


RESULTS
All doses of carvedilol significantly reduced preinfusion measures of heart rate, systolic BP, diastolic BP, and mean arterial pressure. However, carvedilol also produced a paradoxical trend toward PS(20) reduction (indicating increased PE response) that reached significance at the completion of carvedilol dose titration (PS(20) ratio vs baseline = 0.78; P < .001). All effects were maintained over a 6-month treatment period with no evidence of tolerance.


CONCLUSIONS
Increasing BP response to PE infusion suggests improvement in vascular alpha(1)-AR signal transduction with chronic carvedilol therapy. This effect is evident despite no detectable tolerance to preinfusion BP reductions. The varying affinities of alpha(1)-AR subtypes for carvedilol and PE may have contributed to this finding.
Van Tassell
Benjamin W
BW
Department of Pharmacotherapy, University of Utah, Salt Lake City, UT 84112, USA. benjamin.vantassell@utah.edu
Rondina
Matthew T
MT
Huggins
Franklin
F
Gilbert
Edward M
EM
Munger
Mark A
MA
D018674:Adrenergic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010656:Phenylephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013599:Systole; D018754:Ventricular Dysfunction / Q000188:drug therapy
D018674:Adrenergic Antagonists; D000316:Adrenergic alpha-Agonists; D002227:Carbazoles; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D000077261:Carvedilol; D010656:Phenylephrine