Arterial baroreceptor reflex counteracts long-term blood pressure increase in the rat model of renovascular hypertension.

INTRODUCTION: The present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN). METHODS: Repetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR. RESULTS: The inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls. CONCLUSIONS: Arterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN.

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc.