VOLTAGE-DEPENDENT CALCIUM-CHANNEL PROMOTER RESTORES BAROREFLEX SENSITIVITY IN CONSCIOUS DOGS WITH HEART-FAILURE

Background-The aim of this study was to determine the mechanism by whi ch the calcium channel promoter BAY y 5959 affects the control of hear t rate and baroreflex sensitivity in conscious dogs with pading-induce d heart failure (HF). Methods and Results-We compared responses to BAY y 5959, which increases inotropy and decreases chronotropy, with thos e to norepinephrine (NE), which coincidentally exerts the same directi onal effects on inotropy and chronotropy, albeit through different mec hanisms, in the presence and absence of ganglionic blockade both in co ntrol and in HF. Both BAY y 5959 and NE elicit direct effects on the h eart and indirect effects through activation of reflexes, primarily th e sinoaortic baroreceptor reflex. BAY y 5959 still reduced heart rate in dogs with arterial baroreceptor denervation, but not after ganglion ic blockade. HF induced classic catecholamine desensitization to the i notropic effects of NE and blunted reflex bradycardia. In contrast, in otropic responses to BAY y 5959 were preserved in HF. Surprisingly, th e autonomically mediated bradycardia induced by BAY y 5959 was also pr eserved in HF. Baroreflex sensitivity was assessed in control and in H F by pulse interval-systolic arterial blood pressure (PI/SAP) slopes c onstructed in response to pharmacological alterations in arterial pres sure. 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 restor ed 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 perfus ion at a low dose, which acted centrally but did not have an effect pe ripherally. Under these conditions, it still decreased heart rate and restored baroreflex sensitivity (PI/SAP slope, 12.7+/-2.8 ms/mm Hg). C onclusions-Thus, the calcium promoter restores arterial baroreflex sen sitivity in HF. Based on intra-carotid artery experiments, this occurs through a central nervous system and vagal mechanism.