Carvedilol increases blood pressure response to phenylephrine infusion in heart failure subjects with systolic dysfunction: Evidence of improved vascular α₁-adrenoreceptor signal transduction

Introduction

α₁-Adrenergic receptor (α₁-AR) stimulation produces smooth muscle contraction, vasoconstriction, and myocyte hypertrophy, suggesting a potential therapeutic role for α₁-AR antagonists to reduce cardiac workload and myocardial hypertrophy. Preliminary reports suggest that vascular α₁-ARs are desensitized in heart failure (HF) in a manner similar to myocardial β₁-ARs. We examined α₁-AR signal transduction by repeat phenylephrine (PE) infusions in patients with HF receiving chronic carvedilol therapy.

Methods

Twelve subjects with HF not currently receiving β-blockers were up-titrated to maximum tolerable doses of carvedilol. Subjects underwent α₁-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 μg kg⁻¹ min⁻¹, with dose titrations every 10 minutes, to a maximum of 5 μg 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 PS₂₀.

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 PS₂₀ reduction (indicating increased PE response) that reached significance at the completion of carvedilol dose titration (PS₂₀ 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 α₁-AR signal transduction with chronic carvedilol therapy. This effect is evident despite no detectable tolerance to preinfusion BP reductions. The varying affinities of α₁-AR subtypes for carvedilol and PE may have contributed to this finding.