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From the Cardiovascular and Pulmonary Research Institute, Allegheny
University of the Health Sciences, Pittsburgh, Pa.
Correspondence to Stephen F. Vatner, MD, George J. Magovern Professor, Director, Cardiovascular Research Institute, Allegheny University of the Health Sciences, 320 E North Ave, Pittsburgh, PA 15212.
Background—The aim of this study was
to determine the mechanism by which the calcium channel promoter BAY y
5959 affects the control of heart rate and baroreflex sensitivity in
conscious dogs with pacing-induced heart failure (HF).
Methods and Results—We compared responses to BAY y 5959, which
increases inotropy and decreases chronotropy, with those to
norepinephrine (NE), which coincidentally exerts the same
directional effects on inotropy and chronotropy, albeit through
different mechanisms, in the presence and absence of ganglionic
blockade both in control and in HF. Both BAY y 5959 and NE elicit
direct effects on the heart and indirect effects through activation of
reflexes, primarily the sinoaortic baroreceptor reflex. BAY y 5959
still reduced heart rate in dogs with arterial baroreceptor
denervation, but not after ganglionic blockade. HF induced classic
catecholamine desensitization to the inotropic effects of
NE and blunted reflex bradycardia. In contrast, inotropic responses to
BAY y 5959 were preserved in HF. Surprisingly, the autonomically
mediated bradycardia induced by BAY y 5959 was also preserved in HF.
Baroreflex sensitivity was assessed in control and in HF by pulse
interval–systolic arterial blood pressure (PI/SAP)
slopes constructed in response to pharmacological alterations in
arterial pressure. HF depressed the PI/SAP slope from
11.5±1.3 to 4.8±0.9 ms/mm Hg, but during BAY y 5959 infusion in HF,
the PI/SAP slope was restored to 24.1±5.2 ms/mm Hg. To assess central
versus peripheral actions of BAY y 5959, the agent was
infused with intra–carotid artery perfusion at a low dose, which acted
centrally but did not have an effect peripherally. Under
these conditions, it still decreased heart rate and restored baroreflex
sensitivity (PI/SAP slope, 12.7±2.8 ms/mm Hg).
Conclusions—Thus, the calcium promoter restores
arterial baroreflex sensitivity in HF. Based on
intra–carotid artery experiments, this occurs through a central
nervous system and vagal mechanism.
© 1998 American Heart Association, Inc.
Basic Science Reports
Voltage-Dependent Calcium Channel Promoter Restores Baroreflex Sensitivity in Conscious Dogs With Heart Failure
Key Words: dihydropyridine • nervous system • bradycardia
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