Modulation of baroreflex and baroreceptor function in experimental heart failure

The reflex control of the circulation is clearly abnormal in heart failure. It has been known for many years that the baroreflex control of heart rate is depressed in both humans and animals with heart failure. The mechanisms for these abnormalities have not been well worked out. We have carried out experiments to determine the relative roles of the various components involved in the arterial baroreflex arc which may be abnormal in chronic heart failure. An experimental model of chronic heart failure was used which involved continuous ventricular pacing in dogs for periods of up to 6 weeks. This model is characterized by progressive increases in left atrial and left ventricular enddiastolic pressure with increases in resting heart rate and decreases in mean arterial pressure. The dogs become edematous, showing both pulmonary and peripheral edema and ascites. Exercise tolerance is also reduced. Three sets of experiments are described. In the first study, the activity from arterial baroreceptors was recorded in normal dogs and in dogs with heart failure. Carotid sinus pressure-receptor discharge curves were constructed along with pressure-diameter curves. Increasing carotid sinus pressure using either static or pulsatile pressure steps from below threshold to saturation levels caused an increase in discharge at each step. The curves generated in each group of dogs showed that the baroreceptor discharge sensitivity was significantly depressed in the dogs with heart failure. The peak slope of the curves as well as the threshold were significantly different from the normal dogs. There were no differences in carotid sinus compliance curves between the two groups of dogs. Perfusion of the carotid sinus with a dose of ouabain which did not constrict the carotid sinus (0.01 µg/ml) caused a shift in the pressure-discharge curve back to that seen in normal dogs. This dose of ouabain did not affect discharge sensitivity in normal dogs. These data suggest that an augmentation of Na-K ATPase in baroreceptor nerve endings in heart failure contributes to the poor discharge sensitivity. In the second series of experiments, the baroreflex control of heart rate was evaluated in dogs before and after heart failure had been induced. Both reflex tachycardia (in response to nitroglycerin) and reflex bradycardia (in response to phenylephrine) were depressed in dogs with heart failure. The use of cholinergic and β adrenergic blocking drugs indicated that both arms of the autonomic control of the heart were partly responsible for this depressed chronotropic response. The final series of experiments evaluated the baroreflex control of renal sympathetic nerve activity and mean arterial pressure in dogs with heart failure. The relationship between carotid sinus pressure and mean arterial pressure as well as renal nerve activity was depressed in dogs with heart failure. Electrical stimulation of the carotid sinus nerve reduced arterial pressure less in heart failure than in normal dogs. However, electrical stimulation of the carotid sinus nerve reduced renal sympathetic nerve activity to a similar degree in heart failure and normal dogs. Vagotomy caused an increase in the sensitivity of the baroreflex control of arterial pressure in the heart failure dogs, but not in the normal dogs. These data demonstrate that the abnormal baroreflex is likely to be mediated by alterations in arterial and cardiac receptor discharge, but not in the central regulation of sympathetic outflow. The control of the circulation in heart failure is multifactorial and the abnormal reflex control of peripheral vascular resistance and heart rate contribute to the pathophysiology of this disease.