Physiology of the renal baroreceptor mechanism of renin release and its role in congestive heart failure

Physiology of the Renal Baroreceptor Mechanism of Renin Release and its Role in Congestive Heart Failure Hartmut Kirchheim, MD, Heimo Ehmke, MD, and Pontus Persson, MD

The function of the renal baroreceptor can be quantitatively described by a stimulus-response curve showing a fiat section in the high pressure range, a steep slope in the low pressure range, and a welldefined threshold pressure slightly below resting systemic pressure. This stimulus-response curve shows a close functional relation to autoregulation of renal blood flow, glomerular filtration rate and sodium excretion. Threshold pressure and slope are subject to different physiologic control mechanisms: The slope is increased by a low sodium diet, whereas threshold pressure is elevated by an increased renal sympathetic nerve discharge or by circulating catecholamines. Sympathetic influences also reset renal autoregulation. Recent studies have provided evidence for an important role of the renal baroreceptor in the long-term control of arterial blood pressure. The sympathetic modulation of threshold pressure can induce sodium retention in early heart failure, and the sympathetic effects on autoregulation may help to explain clinical reports on a deterioration of renal function during converting-enzyme therapy. (Am J Cardiol 1988;62:68E-71E)

ore than 20 years ago it was shown that the pressure-dependent or renal baroreceptor mechanism plays an important role in regulating renin release from the kidney) Although it has recently been suggested that the renal baroreceptor may be located at the distal juxtaglomerular portion of the afferent arteriole, which shows the highest density of renincontaining epitheloid cells, 2,3 its nature is unknown. However, the pressure-dependent mechanism can be quantitatively described in conscious dogs or rats by plotting arterial plasma renin activity 4-7 or renin release 2,s-l° as a function of renal perfusion pressure (stimulus-response curve). This was achieved by a controlled stepwise reduction of renal artery pressure independent of systemic blood pressure. The stimulus-response curve reveals a characteristic pattern: a flat section or plateau in the high pressure range, a very steep section in the low pressure range, and a well-defined threshold pressure above the lower limit of renal blood flow autoregulation 2 and slightly below the dogs' normal resting blood pressure 2,4,6,8,1],12 (Fig. 1 and 2). The average difference between threshold pressure and long-term blood pressure in 14 dogs fed a normal sodium diet was reported to be 12 mm Hg (see later).12 The steep slope of the curve implies that a decrease in blood pressure by as little as 1.5 to 2.5 mm Hg below threshold pressure increases resting renin release by 100% of control. 2,9,1°

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STIMULUS-RESPONSE CURVE A N D LONGT E R M BLOOD PRESSURE CONTROL

From the I. Physiologisches Institut der Universit~it Heidelberg, Im Neuenheimer Feld 326,6900 Heidelberg, Federal Republic of Germany. This study was supported by the German Research Foundation within the SFB 320, Heidelberg, and the Forschergruppe Niere, Heidelberg. Address for reprints: Hartmut Kirchheim, MD, I. Physiologisches Institut der Universitfit Heidelberg, Im Neuenheimer Feld 326,6900 Heidelberg, Federal Republic of Germany.

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A physiologic role of pressure-dependent renin release in long-term blood pressure control was suggested in 1964 by Skinner et all; in their classic paper on renin release they wrote: "... under normal resting circumstances the average height of arterial pressure is set in part by the threshold of the baroreceptor, pressure tending to stabilize at a level at which renin secretion is minimal. ''I Recently, the relation between the pressure-dependent renin release and long-term Blood pressure was quantitatively described in 14 conscious dogs by Ehmke et alJ 1,12The investigators made the following observations: (1) The intermittent activation of pressure-dependent renin release due to physiologic variations in arterial blood pressure changed plasma renin activity by 300%. (2) The difference between threshold pressure and long-term blood pressure in the individual animal was highly dependent on the slope (i.e., dogs with steep slopes showed a larger difference). (3) A systemic blockade of the reninangiotensin system by converting-enzyme inhibition resuited in a slope-dependent decrease of long-term blood

pressure, which ranged between 8 and 21 mm Hg. (4) A spontaneous shift of threshold pressure in 3 of their dogs was accompanied by parallel changes in arterial blood pressure. These findings thus provide evidence for a major role of pressure-dependent renin release in the longterm control of blood pressure.

STIMULUS-RESPONSE CURVE AND RENAL AUTOREGULATION Figure 1 shows the relation between the stimulusresponse curve and autoregulation of renal blood flow and glomerular filtration rate from 1 of our recent studies./° The experiments were made in chronically instrumented conscious foxhounds fed normal sodium diet. Renal artery pressure was reduced in steps using an inflatable renal artery cuff and a pressure control system. Renal blood flow was measured by an electromagnetic flowmeter, and glomerular filtration rate by inulin extraction. Plasma renin activity was determined by radioimmunoassay from renal venous and arterial plasma samples, which allowed plotting of the venous arterial plasma renin activity difference; note that this indicates renin release as long as renal blood flow remains unchanged. Since pressure levels above the resting value (107 mm Hg) were achieved by bilateral common carotid occlusion (implanted cuffs), intrarenal a blockade was used to I I 1 1 1

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avoid possible reflex vasomotor influences. Detailed descriptions of the methods are to be found in this report and in previous reports from our laboratory. 2,s-13,15,z2 Figure 1 shows that the average threshold pressure (95 mm Hg), the lower limit of glomerular filtration rate (80 mm Hg) and renal blood flow (65 mm Hg) autoregulation were located at different pressure levels. The stimulus-response curve at rest and the lower limits of autoregulation of renal blood flow and glomerular filtration rate were not influenced by ct blockade.

SYMPATHETIC MODULATION OF THE STIMULUS-RESPONSE CURVE The stimulus response curve is physiologicallymodulated by the renal sympathetic nerves, circulating catecholamines and sodium intake. An intrarenal infusion of epinephrine4 or a low-dose intrarenal infusion of the a agonist, methoxamine, which does not affect total renal 5

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FIGURE Relation between mean renal artery pressure, renal blood flow (R.B.F.), glomerular filtration rate (G.F.R.) and renal venous arterial plasma renin activity d'dference (P.R.A.Diff.) in conscious dogs. Values are mean 4- standard error of the mean. (Modified from Pflngers Arch. 1o)

FIGURE 2. Schematic diagram showing the interrelation between pressure-dopendent ronin release, long-term blood pressure and renal function under resting cond'dions (/eft) and in early congestive heart failure with a sympathetically mediated shift of threshoM pressure (dashed line) and reselling of renal autoregulation (r/ght). The third panel from top shows both ronin release (RR) (/eft sea/e) and the relative (Rel.) lrequency disb'ibution of mean arterial blood pressure from repeated measurements (right scale). The hatched area below threshold pressure depicts the pressure values that cause strong renin release. GFR = glomerular filtration; NaV = sodium excretion; RBF = renal blood flow.

THE AMERICAN JOURNAL OF CARDIOLOGY

SEPTEMBER 9, 1988

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A SYMPOSIUM: REGIONAL BLOOD FLOW IN CONGESTIVE HEART FAILURE

blood flOW, 9'13 as well as a reflex activation of the renal sympathetic nerves by the arterial baroreceptor, s,9,13 increase threshold pressure (Fig. 3), A low sodium intake or a blockade of the short inhibitory feedback loop by converting-enzyme inhibition have been shown to increase the slope of the curve without affecting the threshold pressure. 5,6,14 Figure 3 shows the increase of threshold pressure by bilateral common carotid occlusion and by an intrarenal infusion of 0.68 #g/kg/min of methoxamine in trained conscious dogs. In this context, it should be mentioned that bilateral common carotid occlusion in conscious dogs with intact aortic baroreceptors increases renal sympathetic nerve discharge only moderately, i.e., by 62% of control, without affecting total renal blood flow.~5 Figure 3 shows that the shift of threshold pressure by bilateral common carotid occlusion is not affected by/~ blockades but is completely eliminated by an intrarenal infusion of 0.1 to 0.2 pg/kg/min of prazosin. 9,13 This suggests that the reflex activation of renal sympathetic nerves induces an increase of threshold pressure that is mediated by intrarenal a adrenoceptors.

SYMPATHETIC MODULATION OF RENAL AUTOREGULATION AND SODIUM EXCRETION In anesthetized dogs, electrical stimulation of the renal sympathetic nerves or the intrarenal infusion of methoxamine have been shown to increase the lower limit of renal blood flow autoregulation. ]6,27Very recent observations made in our laboratory confirmed these findings in conscious dogs: A reflex increase of renal sympathetic nerve discharge by bilateral common carotid occlusion and an intrarenal infusion of 0.68 #g/kg/minof methoxamine increased the lower limit of renal blood flow and of glomerular filtration rate autoregulation; the mechanism was a adrenergic in origin since it was abolished by the intrarenal application of 0.1 to 0.2 pg/kg/minof prazosin (Persson Pet al, unpublished data; Fig. 2). In preliminary

experiments measuring urine output with a chronically implanted pelvic catheter, we also found that close to the dogs' resting blood pressure there was little change in sodium excretion (plateau level), while below it the threshold pressure for the pressure-dependent renin release sodium excretion decreased strongly, although autoregulation left glomerular filtration rate unchanged to 80 mm Hg (Fig. 2). We believe that the decrease in sodium excretion below threshold pressure is caused by the tubular antinatriuretic effect of angiotensin II.

ROLE OF PRESSURE-DEPENDENT RENIN RELEASE IN THE PATHOPHYSIOLOGY OF CONGESTIVE HEART FAILURE More than 40 years ago, Merrill et al ]8 reported an increased renal venous renin activity in patients with congestive heart failure (CHF). It is known by now that the renin-angiotensin-aldosterone system plays an essential role in the restoration of cardiac output and arterial blood pressure in CHF.19,2° However, the mechanisms controlling renin release in CHF have not been well defined. In the past, it seemed particularly difficult to explain sodium retention in early CHF when blood volume and renal blood flow are apparently unchanged. Witty et al, 2J using the inferior vena cava constriction model of heart failure in dogs, proposed that the renal baroreceptor mechanism was responsible for the increase in plasma renin activity. Comparing this model with the pulmonary artery constriction model to induce heart failure in dogs, Watkins et a119 found a less pronounced increase in plasma renin activity for a comparable increase in arterial pressure after pulmonary artery constriction, and concluded that some other stimulus in addition to renal artery hypotension was responsible for the greater release of renin after inferior vena cava constriction. Figure 2, which summarizes our own findings, suggests that a threshold shift of the renal baroreceptor by the renal sympathetic nerves is probably the major physiologic mechanism explaining

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FIGURE 3. Average changes of threshold pressure of the pressure-dependent renin release in conscious dogs. BCO = bilateral common carotid occlusion; BCO + Praz. = bilateral c o m m o n carotid occlusion during an intrprenal a blockade by prazosin; BCO + Prop. : bilateral common carotid occlusion during a systemic/~ blockade with propranolol; Methox = inb'arenal ~-adrenocepter stimulation by methoxamine. * p <0.05; * * p <0.01. * * * p <0.001. (ReI~nted with permission hem Pflugers Arch 8 and Clin Exp Hypertens. e)

rcnin activation and sodium retention in the carly phase arterial blood pressure associated with the application of of CHF. a converting-enzyme inhibitor can cause marked deThe normal physiologic situation is shown in Figure 2: creases of glomerular filtration rate and thus may induce Short-term blood pressure, which oscillates around long- a deterioration of renal function. 2° term blood pressure (frequency distribution curve in third Acknowledgment: We thank Dr. Eberhard Hackpanel from the top), intermittently falls below threshold enthal, Pharmakologisches Institut der Universit/it Heipressure, thus powerfully inducing renin release (hatched delberg, for determination of plasma renin activity, and area). Renin, in turn, increases the formation of angiotenInge Keller, Luci¢ Mahl and Renatc Stahl for their skillsin I and finally of angiotensin II. By both its potent ful technical assistance. vasoconstrictor action and the enhancement of sodium retention, angiotensin II will increase blood pressure, thus switching off again the pressure-dependent release of renin. Thus, in the steady-state, long-term blood pressure REFERENCES Skinner SL, McCubbin JW, Page IH. Control ofrenin secretion. Circ Res (mean of the frequency distribution) will stabilize at a I.1964;15:64-76. level above threshold pressure (95 mm Hg) and above the 2. Finke R, Gross R, Haekenthal E, Huber J, Kirchhcim H. Thresholdpressure lower limits of glomerular filtration rate (80 mm Hg) and for the pressure-dependent renin release in the autoregulating kidney of condogs. Pflr~gers Arch 1983;399.'102-110. renal blood flow autoregulation (65 mm Hg). Therefore, scions 3. Taugner R, BfihrleCP, Hackenthal E, Mannek E, Nobiling R. Morphology of under normal resting conditions, the level of long-term the juxtaglomerular apparatus and secretory mechanisms. Contrib Nephrol blood pressure will ensure a normal glomerular filtration 1984;43:76- I01. Farhi ER, Cant JR, Barger AC. Interactions between intrarenal epinephrine rate with a margin of safety of some 25 mm Hg. Note 4. receptors and the renal baroreceptor in the control of PRA in conscious dogs. Circ that the pressure-dependent renin release to 80 mm Hg is Res 1982;50.'477-485. Farhi ER, Cant JR, Barger AC. Alterations of renal baroreceptor by salt associated with a decrease of sodium excretion by approx- 5. intake in control of plasma renin activity in conscious dogs. Am J Physiol imately 40% without affecting glomerular filtration rate. 1983,245:FI 19-F122. In patients with early CHF, a slight decrease in stroke 6. Barger AC, Farhi ER, Cant JR. Modulation of renal baroreceptorfunetion by and salt intake in the conscious dogs. Clin Exp Hypertens volume will be sensed by the high dynamic sensitivity catecholamines 1984;,46.'287-298. (decrease of pulse pressure and rate of change of aortic 7. lmagawa J, Miyauchi T, Satoh S. Direct relationship between renal arterial pressure) of the arterial baroreceptors 22and cause a mod- pressure and plasma renin activity in conscious rats. Jpn J Pharmacol 1984; 35.'481-484. erate reflex increase in renal sympathetic nerve dis- 8. Kirchh¢im H, Finke R, Hackenthal E, L6wc W, Persson P. Baroceflex sympacharge. This increases threshold pressure, which induces thetic activation increases threshold pressure for the pressure-dependent renin in conscious dogs. Pfl~gers Arch 1985;405:127-135. a marked increase in renin release, although blood pres- release 9. Kirchh¢im H, Ehmke H, Fischer S, L6weW, Persson P. Sympathetic modulasure does not change (Fig. 2, right). The moderate reflex tion of the pressure-dependent renin release in conscious dogs. Clin Exp Hyperactivation of the renal sympathetic nerves leaves total tens 1987:A9:suppl:167-180. |@. Kirchheim H, Ehmke H, Hackenthal E, L6we W, Pcrsson P. Autocegulation renal blood flow and glomerular filtration rate un- of renal bloodflow, glomerularfiltration rate and renin release in conscious dogs. changed but will reset the lower limits of renal blood flow Pflf~gers Arch 1987,410:441-449. and glomerular filtration rate autoregulation. The acti- 1 | . Ehmke H, Pcrsson P, Kirchheim H. Pressure-dependent renin release: the kidney factor in long-term control of arterial blood pressure in conscious dogs. vated renin-angiotensin system leads to sodium retention Clin Exp Hypertens 1987;A9:suppl:181-195. (Fig. 2, bottom), increased water intake and plasma vol- 12. Ehmke H, Persson P, Kirchheim H. A physiological role for pressurerenin release in long-term blood pressure control. Pfl~gers Arch ume expansionJ 9 The volume expansion stimulates the dependent 1987,410:450-456. low pressure system receptors that, because of their pow- 13. Ehmk¢ H, Persson P, Fischer S, Hackenthal E, Kirehheim H. Resetting of erful inhibitory influence on the renal sympathetic pressure-dependent renin release by intrarenal alpha-l-adrenoceptocs in condogs. Pflugers Arch 1988; in press. nerves, will bring back threshold pressure to normal and scious 14. Farhi ER, Cant JR, Paganelli WC, Dzau VJ, Barger AC. Stimulus-response also eliminate the resetting of renal autoregulation. A curve of the renal baroreceptor: effect of converting enzyme inhibition and new steady state (compensation) will be attained, which changes in salt intake. Cirv Res 1987,'61:670-677. 15. Gross R, Kirchheim H. Effects of bilateral carotid occlusion and auditory is characterized by an increase plasma volume, normal stimulation on renal bloodflow and sympathetic nerve activity in conscious dogs. plasma renin levels, normal blood pressure, and (depend- Pflflgers Arch 1980;383:233-239. 16. Langaard O, Holdaas H, Eide I, Kill F. Conditions for humoral alphaing on the severity of heart failure) even a normal cardiac adrvnoceptoc stimulation of renin release in anaesthetized dogs. Scand J Clin output. However, the new steady state may also be associ- Lab Invest 1981;41:527-534. ated with a reduced cardiac output; under these circum- 17. Holdaas H, Langaard O, Eide I, Kill F. Mechanism ofrenin release during nerve stimulation in dogs. Scand J Clin Lab Invest 1981;41:617-625. stances, the contribution of the renin-angiotensin system renal | 8 . Merrill AJ, Morrison JL, Brannon ES. Concentration ofrenin in renal venous to the resting level of blood pressure is correspondingly blood in patients with chronic heart failure. Am J Med 1946;1:468-472. greater. Consequently, in decompensation there is an in- 19. Watkins L, Burton JA, Habcr E, Cant JR, Smith FW, Barger AC. The reninangiotensin-aldosterone system in congestive failure in conscious dogs. J Clin verse correlation between mean blood pressure and plas- Invest 1976;57.'1606-1617. ~'9. Dzau VJ, Pratt RE. Renin-angiotensin system: biology, physiology, and ma renin activity. 23 In."Fozzard HA, Hober Eo Jennings RB, Katz AM, Morgan HE, Our results are consistent with a number of experi- pharmacology. eds. The Heart and Cardiovascular System. New York: Raven Press, 1986:163Imental and clinical studies on C H F , 19,20,23 and may also 1662. explain several clinical findings after therapy with con- 21. Witty RT, Davis JO, Shade RE, Johnson JA, Prcwitt RL. Mechanisms renin release in dogs with thoracic cars/ constriction. Cirv Res verting-enzyme inhibitors. When the renin-angiotensin regulating 1972:3L'339-347. system is stimulated owing to an increased threshold pres- ~.° Kirchheim HR. Systematic arterial baroreceptor reflexes. Physiol Rev 1976:56:100-176. sure, the resetting of autoregulation has correspondingly 23. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the reninreduced the margin of safety for glomerular filtration angiotensin-aldosterone system to clinical state in congestive heartfailure. Cirautoregulation (Fig. 2). Thus, even small reductions in culation 1981,63.'645-651. THE AMERICANJOURNALOF CARDIOLOGY SEPTEMBER9, 1988 7111=