Bainbridge Reflex and Renal Sympathetic Tone

Just as moment-to-moment blood pressure control is maintained through baroreceptor-mediated cardiovascular sympathetic tone, long-term blood pressure homeostasis is controlled through renal extension of the same process. It is one of the most fascinating aspects of the neurohormonal system that even though sympathetic tone for the entire body is processed in the same brain centers, sympathetic output can be customized to each organ for precise control. 

If each organ can have a customized sympathetic output, it makes sense that each should also have a customized afferent input. Whereas the cardiovascular autonomic tone relies primarily on the baroreceptor reflex, the renal autonomic tone relies on a mechanoreceptor reflex located at the cavoatrial and pulmonary-atrial junctions.

Figure 1: Illustration of the antagonistic relationship between the baroreceptor

and Bainbridge reflexes.

The presence of mechanoreceptors in the atria has been known for some time. Early studies revealed that inflation of a balloon in the cavoatrial junction was able to decrease thirst in instrumented animals, presumably by communicating an elevated CVP to hypothalamic centers. Further studies revealed that these mechanoreceptors sent processes to the NTS, CVLM, and paraventricular nucleus, similar to the baroreceptor afferents. Unlike the baroreceptor reflex, however, which detects increased arterial pressures and stimulates a decrease in heart rate, the cavoatrial reflex detects increased central venous pressures and stimulates an increase in heart rate (termed the Bainbridge reflex). The overall purpose appears to be to clear right-sided venous congestion by increasing cardiac output.

Figure 2: Cardiac distension results in release of ANP and BNP

along with activation of the Bainbridge reflex and renal 

sympathetic inhibition. The result of these combined 

neurohormonal reflexes is inhibition in the renin-angiotensin-

aldosterone-ADH system and appropriate sodium and volume 

wasting

The relationship between the bainbridge and baroreceptor reflexes is quite complex and antagonistic. Infusion of IV saline at a high rate initially results in increased CVP and activation of the cavoatrial receptors. This leads to parasympathetic inhibition and reflex tachycardia. Once this increased venous volume reaches the left ventricle, however, it results in increased stroke volume through the Frank-Starling relationship and enhances cardiac output. The resulting increase in arterial pressures activates the baroreceptors in the carotid bodies and aortic arch, which result in parasympathetic stimulation and reflex bradycardia. Along with the baroreceptor reflex the bainbridge reflex is part of the determinants of resting heart rate in humans, and loss of either reflex results in relative tachycardia or bradycardia, respectively.

Even more interestingly, however, activation of these atrial receptors results in a profound suppression of sympathetic tone to the kidneys. Because sympathetic renal tone results in activation of the renin-angiotensin-aldosterone-ADH system, which all tend towards sodium and fluid retention, inhibition of sympathetic tone through the Bainbridge reflex results in fluid and sodium wasting and volume depletion. This is also congruent with the hormonal effect of atrial/ventricular stretch, which is release of ANP/BNP which both mediate natriuresis and promote volume homeostasis.

One interesting finding related to these reflexes is that in chronic hypertensives, the bainbridge reflex seems specifically dampened. These patients have been found to have elevated renal sympathetic tone measured by serum norepinephrine, which at high levels of activation can leak from within the sympathetic synapses. This renal sympathetic tone, however, does not correlate with the patients heart rate, suggesting that cardiac sympathetic tone is relatively depressed. The end result is the relative volume overload and increased SVR that characterizes essential hypertension.

In the context of chronic hypertension, the baroreceptor reflex is also relatively inactive. This is partly because at increased pressures vascular compliance is low and further blood pressure changes do not result in sufficient arterial stretch for detection. Along with this mechanism, chronically activated baroreceptors do undergo receptor desensitization, which has the net effect of allowing the baroreceptor to reset its basal MAP point to higher pressures for the purpose of maximizing dynamic range. Lastly, hormonal regulation of hypertension results in elevated angiotensin levels, which exert a central suppressive effect on central mediators. 

Because of the complex physiology of excessive renal sympathetic tone and resulting baroreceptor desensitization in chronic uncontrolled hypertension, a large multi-institute study (SYMPLICITY HTN-3) was performed which investigated the effect of selective renal denervation on chronic resistant hypertension in optimally medically managed patients (average of 5.1 medications). Unfortunately the trial did not demonstrate any benefit to this population, despite promising phase I and phase II studies. It's unclear why renal denervation was not more successful, although it may prove to have a more significant impact on a less heavily medicated population, or a population that is unable to tolerate medication due to side effects.

References: 

Coote, PH A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney exp physiology 90.2 pp 169-173 

Klabunde R, Cardiovascular physiology, http://www.cvphysiology.com/

Pocock SJ, Bakris G, Bhatt DL, Brar S, Fahy M, Gersh BJ. Regression to the Mean in SYMPLICITY HTN-3: Implications for Design and Reporting of Future Trials. J Am Coll Cardiol 2016;68:2016-25.

Presented by Dr. George Bakris at the European Society of Cardiology Congress, Barcelona, Spain, September 1, 2014.

Bakris GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3. J Am Coll Cardiol 2014;64:1071-8.

Bhatt DL, Kandzari DE, O’Neill WW, et al., on behalf of the SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-1401.