Cardiac Reflexes in Normotensive and Spontaneously Hypertensive Rats
PETER THOREN, MD EDDY NORESSON, MD SVEN-ERIK Giiteborg,
RICKSTEN,
MD
Sweden
From the Department of Physiology, University of Goteborg, Gdteborg, Sweden. This work was supported by Project no. 14X-04764 and 14X00016, from the Swedish Medical Research Council, Stockholm, Sweden. Address for reprints: Peter Thoren, MD, Department of Physiology, University of Gdteborg, Fack, S-40033 Goteborg 33, Sweden.
884
October 22, 1979
Characteristics of lefl atrial receptors were studied in normotensive control (Wistar) and spontaneously hypertensive rats. The left atrial pressure was chronically elevated in spontaneously hypertensive rats and at the end of the expiratory phase was 10.3 mm Hg as compared with 4.6 mm Hg in normotensive control rats. The thresholds of the receptor endings were twice as high in the hypertensive as in the normotensive rats (10.2 and 4.6 mm Hg, respectively). In other experiments the reflex inhibition of renal sympathetic outflow was studied during plasma infusion in baroreceptor denervated normotensive and hypertensive rats and was inhibited at a lower left atrial pressure in the former. These differences are attributed to decreased ,distensibility of the left atrium in spontaneously hypertensive rats. The reflex splanchnic nerve inhibition with volume load also was recorded in awake rats. At a 10 percent increase in blood volume, splanchnic outflow was more significantly decreased in spontaneously hypertensive than in normotensive rats. The mechanism underlying such a hyperreactive volume receptor response is unknown, but a less distensible venous system, centrally or peripherally, might be a contributing factor.
The role of cardiac reflexes in cardiovascular control has in recent years been the subject of a great number of studies.‘-5 There are two types of endings in the heart of dogs and cats. One type, connected to medullated axons, is located in the atrium at the venous-atria1 junction.3 The bursting discharge in these endings corresponds to atria1 contraction (A type) or atrial filling (B type). When these endings are activated, there is reflex tachycardia and an increase in urinary flo~.~,~ There are also many receptors with nonmedullated vagal afferent fibers (C fibers) in the heart.5-8 They seem to be located throughout the entire heart and respond mainly to changes in cardiac filling.g,10 When activated, these receptors induce powerful depressor reflexes with marked reflex bradycardia and sympathetic inhibition especially in the kidney.5 Cardiopulmonary receptors inhibit the medullary vasomotor centers tonically because interruption of the afferent vagal traffic can induce pressor reflexes, especially if the buffering influences from the arterial baroreceptors are controlled.5J-13 There is also a tonic restraint in renin release from vagal afferent fibers 5~14that is mediated by way of the C fibers.5J5J6 Also found in man is evidence of a tonic vasomotor inhibition from low pressure receptors in the cardiopulmonary area. Thus, moderate degrees of lower body negative pressure can decrease central blood volume and cause vasocontriction in the skeletal muscle without any changes in blood pressure.17 The aim of this study is to describe how these cardiac receptors arc reset during primary hypertension. The characteristics of cardiac endings in normotensive and spontaneously hypertensive rats were compared and the reflex effects of volume loading examined.
The American Journal of CARDIOLOGY
Volume 44
CARDIAC RECEPTORS AND HYPERTENSION-THOREN
Cardiac
Receptors
in Normotensive
Rats
Left atria1 receptors: There are no data on the characteristics of cardiac receptors with vagal afferent fibers in rats. A series of experiments were therefore performed on adult normotensive Wistar rats to examine the characteristics of these receptors.ls A great number of left atria1 receptors were examined, many of which behaved similarly to the medullated atria1 B receptors in dogs and cats, discharging with a high frequency burst of activity with each cardiac cycle (Fig. 1C). Other receptors discharged with low frequency (Fig. 1, A and B), most often without any relation to the cardiac cycle (Fig. 1A). The peculiar finding was that all receptors examined had slowly conducting afferent C fibers. Suprisingly, no left ventricular receptors could be located. High versus low frequency receptors: An attempt was made to analyze separately the characteristics of high and low frequency receptors. Arbitrarily, receptors with a maximal discharge frequency above 25 hertz were called high frequency receptors, and receptors whose discharge frequency was below 25 hertz were called low frequency receptors. The threshold for high frequency receptors was significantly lower than that for low fre-
ET AL.
quency receptors. Furthermore, all high frequency receptors displayed an irregular firing pattern. Therefore, this arbitrary grouping of atria1 C fibers might represent two functionally different types of receptors. In preliminary experiments the characteristics of left atria1 receptors in adult rats of the Wistar-Kyoto strain of normotensive rats (WKR) were studied. Three high frequency receptors had thresholds and pressure response curves within the range of normal Wistar rats. Spontaneously
Hypertensive
Rats
Resetting of left atria1 receptors in spontaneously hypertensive rats: The characteristics of left atrial receptors in adult spontaneously hypertensive rats were examined, and a high frequency bursting discharge pattern was found.lg These receptor endings had higher thresholds than those in normotensive control rats. Mean left atria1 pressure at threshold was 10.2 mm Hg in the hypertensive 4.6 mm Hg in the normotensive rats. The pressure response curves were also significantly displaced to the right in the spontaneously hypertensive rat (Fig. 2). Thus, these receptor endings operate at a higher pressure level in spontaneously hypertensive rats, but there is no difference in maximal discharge frequencies between the two strains of rats.
Aortic occlusion
LEFT ATRIAL PRESSURE, mmHg
ECG NEUROGRAM
LEFT ATRIAL PRESSURE,mmlig
NEUROGRAM
FIGURE 1. Left atrialpressure, electrocardiogram (ECG) and activity in three lefl atrial C fiber endings in three rats. The receptor in panel A has a low frequent irregular discharge on activation and is included with the low frequency receptors. The receptor in the neurogram in panel B is a low frequency redeptor showing cardiac rhythmic@ on elevation of left atrial pressure. The receptor in panel C is in the control situation, activated altern’titively in the a and Y wave, but on elevation of left atrial pressure the receptor shows a progressive discharge in relation to the v wave. (The asterisks indicate the corrected position in the cardiac cycle of the receptor activation). (Reproduced from Thoren et al.‘* by permission.)
ECG
LEFT ATRIAL PRESSURE,mmHg
NEUROGRAh.4 ECG
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
885
CARDIAC RECEPTORS AND HYPERTENSION-THOREN
Receptor
ET AL.
Per cent of
activity,
mox.octivity
spIkesA
75
“‘-
~
0
!i
IO
i5 Mean left otm
2’0 pressure,
mm
No receptors with low frequency discharge were found in spontaneously hypertensive rats. Perhaps, their threshold values were too high to be found with the technique used. Left atria1 pressure in normotensive and spontaneously hypertensive rats: The left atria1 pressure was measured in adult rats of the two strains.20 Thin catheters were placed in the left atrium by means of a small thoracotomy. The animals were allowed to recover about 1 week, and the left atria1 pressure was measured when the animals were awake. The mean pressure at the end of the expiratory phase was twice as high in spontaneously hypertensive as in normotensive rats (10.3 and 4.6 mm Hg, respectively). Thus, although the atria1 receptors in spontaneously hypertensive rats have a higher threshold, this resetting is offset by an increased left atria1 pressure. The obvious question is whether the atria1 receptor activity at rest is higher or lower in spontaneously hypertensive rats in comparison with normotensiie rats. No conclusion can be drawn at this point because the threshold for receptor activation seems to be reset to about the same extent as the left atria1 pressure, so that the receptor discharge in spontaneously hypertensive rats is not significantly different from that in normotensive control rats (Fig. 2). Reflex control of renal sympathetic outflow during volume load: The reflex inhibition of sympathetic outflow to the kidney during volume load was measured in adult anesthetized normotensive control and spontaneously hypertensive rats.21 The arterial baroreceptors were denervated. The observed renal nerve inhibition was mediated by the vagal nerves a&l was due to activation of receptors in the left side of the heart, presumably the left atria1 endings. The relation between renal nerve inhibition and left atria1 pressure is shown in Figure 3 during volume loading with horse
October 22, 1979
A
Hg
FIGURE 2. The mean activity in 11 left atrial high frequency C fiber endings in a spontaneously hypertensive rat (SHR) and similar data from 8 high frequency receptors in a normotensive control rat (NCR). Also shown is the mean left atrial pressure at end expiration in the normotensive (A) and the hypertensive (B, C) rat. Because of the resetting of the receptors there is no clear change in receptor activity in the hypertensive rat (B) despite an increase in left atrial pressure. C indicates the estimated receptor activity in the hypertensive rat in the absence of receptor resetting.
006
\\
r
The American Journal of CARDIOLOGY
SHR
50
: 0
i0
i0
;0
Mean left atrial pressure, mmtig FIGURE 3. The relation between mean left atrial pressure and mean rectified renal nervous activity in six normotensive control (NCR) and six spontaneously hypertensive rats (SHR) during volume loading with horse plasma. The changes in renal activity are expressed as a percent of maximal (max.) control activity. (*** = P
PETER THOREN, MD EDDY NORESSON, MD SVEN-ERIK Giiteborg,
RICKSTEN,
MD
Sweden
From the Department of Physiology, University of Goteborg, Gdteborg, Sweden. This work was supported by Project no. 14X-04764 and 14X00016, from the Swedish Medical Research Council, Stockholm, Sweden. Address for reprints: Peter Thoren, MD, Department of Physiology, University of Gdteborg, Fack, S-40033 Goteborg 33, Sweden.
884
October 22, 1979
Characteristics of lefl atrial receptors were studied in normotensive control (Wistar) and spontaneously hypertensive rats. The left atrial pressure was chronically elevated in spontaneously hypertensive rats and at the end of the expiratory phase was 10.3 mm Hg as compared with 4.6 mm Hg in normotensive control rats. The thresholds of the receptor endings were twice as high in the hypertensive as in the normotensive rats (10.2 and 4.6 mm Hg, respectively). In other experiments the reflex inhibition of renal sympathetic outflow was studied during plasma infusion in baroreceptor denervated normotensive and hypertensive rats and was inhibited at a lower left atrial pressure in the former. These differences are attributed to decreased ,distensibility of the left atrium in spontaneously hypertensive rats. The reflex splanchnic nerve inhibition with volume load also was recorded in awake rats. At a 10 percent increase in blood volume, splanchnic outflow was more significantly decreased in spontaneously hypertensive than in normotensive rats. The mechanism underlying such a hyperreactive volume receptor response is unknown, but a less distensible venous system, centrally or peripherally, might be a contributing factor.
The role of cardiac reflexes in cardiovascular control has in recent years been the subject of a great number of studies.‘-5 There are two types of endings in the heart of dogs and cats. One type, connected to medullated axons, is located in the atrium at the venous-atria1 junction.3 The bursting discharge in these endings corresponds to atria1 contraction (A type) or atrial filling (B type). When these endings are activated, there is reflex tachycardia and an increase in urinary flo~.~,~ There are also many receptors with nonmedullated vagal afferent fibers (C fibers) in the heart.5-8 They seem to be located throughout the entire heart and respond mainly to changes in cardiac filling.g,10 When activated, these receptors induce powerful depressor reflexes with marked reflex bradycardia and sympathetic inhibition especially in the kidney.5 Cardiopulmonary receptors inhibit the medullary vasomotor centers tonically because interruption of the afferent vagal traffic can induce pressor reflexes, especially if the buffering influences from the arterial baroreceptors are controlled.5J-13 There is also a tonic restraint in renin release from vagal afferent fibers 5~14that is mediated by way of the C fibers.5J5J6 Also found in man is evidence of a tonic vasomotor inhibition from low pressure receptors in the cardiopulmonary area. Thus, moderate degrees of lower body negative pressure can decrease central blood volume and cause vasocontriction in the skeletal muscle without any changes in blood pressure.17 The aim of this study is to describe how these cardiac receptors arc reset during primary hypertension. The characteristics of cardiac endings in normotensive and spontaneously hypertensive rats were compared and the reflex effects of volume loading examined.
The American Journal of CARDIOLOGY
Volume 44
CARDIAC RECEPTORS AND HYPERTENSION-THOREN
Cardiac
Receptors
in Normotensive
Rats
Left atria1 receptors: There are no data on the characteristics of cardiac receptors with vagal afferent fibers in rats. A series of experiments were therefore performed on adult normotensive Wistar rats to examine the characteristics of these receptors.ls A great number of left atria1 receptors were examined, many of which behaved similarly to the medullated atria1 B receptors in dogs and cats, discharging with a high frequency burst of activity with each cardiac cycle (Fig. 1C). Other receptors discharged with low frequency (Fig. 1, A and B), most often without any relation to the cardiac cycle (Fig. 1A). The peculiar finding was that all receptors examined had slowly conducting afferent C fibers. Suprisingly, no left ventricular receptors could be located. High versus low frequency receptors: An attempt was made to analyze separately the characteristics of high and low frequency receptors. Arbitrarily, receptors with a maximal discharge frequency above 25 hertz were called high frequency receptors, and receptors whose discharge frequency was below 25 hertz were called low frequency receptors. The threshold for high frequency receptors was significantly lower than that for low fre-
ET AL.
quency receptors. Furthermore, all high frequency receptors displayed an irregular firing pattern. Therefore, this arbitrary grouping of atria1 C fibers might represent two functionally different types of receptors. In preliminary experiments the characteristics of left atria1 receptors in adult rats of the Wistar-Kyoto strain of normotensive rats (WKR) were studied. Three high frequency receptors had thresholds and pressure response curves within the range of normal Wistar rats. Spontaneously
Hypertensive
Rats
Resetting of left atria1 receptors in spontaneously hypertensive rats: The characteristics of left atrial receptors in adult spontaneously hypertensive rats were examined, and a high frequency bursting discharge pattern was found.lg These receptor endings had higher thresholds than those in normotensive control rats. Mean left atria1 pressure at threshold was 10.2 mm Hg in the hypertensive 4.6 mm Hg in the normotensive rats. The pressure response curves were also significantly displaced to the right in the spontaneously hypertensive rat (Fig. 2). Thus, these receptor endings operate at a higher pressure level in spontaneously hypertensive rats, but there is no difference in maximal discharge frequencies between the two strains of rats.
Aortic occlusion
LEFT ATRIAL PRESSURE, mmHg
ECG NEUROGRAM
LEFT ATRIAL PRESSURE,mmlig
NEUROGRAM
FIGURE 1. Left atrialpressure, electrocardiogram (ECG) and activity in three lefl atrial C fiber endings in three rats. The receptor in panel A has a low frequent irregular discharge on activation and is included with the low frequency receptors. The receptor in the neurogram in panel B is a low frequency redeptor showing cardiac rhythmic@ on elevation of left atrial pressure. The receptor in panel C is in the control situation, activated altern’titively in the a and Y wave, but on elevation of left atrial pressure the receptor shows a progressive discharge in relation to the v wave. (The asterisks indicate the corrected position in the cardiac cycle of the receptor activation). (Reproduced from Thoren et al.‘* by permission.)
ECG
LEFT ATRIAL PRESSURE,mmHg
NEUROGRAh.4 ECG
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
885
CARDIAC RECEPTORS AND HYPERTENSION-THOREN
Receptor
ET AL.
Per cent of
activity,
mox.octivity
spIkesA
75
“‘-
~
0
!i
IO
i5 Mean left otm
2’0 pressure,
mm
No receptors with low frequency discharge were found in spontaneously hypertensive rats. Perhaps, their threshold values were too high to be found with the technique used. Left atria1 pressure in normotensive and spontaneously hypertensive rats: The left atria1 pressure was measured in adult rats of the two strains.20 Thin catheters were placed in the left atrium by means of a small thoracotomy. The animals were allowed to recover about 1 week, and the left atria1 pressure was measured when the animals were awake. The mean pressure at the end of the expiratory phase was twice as high in spontaneously hypertensive as in normotensive rats (10.3 and 4.6 mm Hg, respectively). Thus, although the atria1 receptors in spontaneously hypertensive rats have a higher threshold, this resetting is offset by an increased left atria1 pressure. The obvious question is whether the atria1 receptor activity at rest is higher or lower in spontaneously hypertensive rats in comparison with normotensiie rats. No conclusion can be drawn at this point because the threshold for receptor activation seems to be reset to about the same extent as the left atria1 pressure, so that the receptor discharge in spontaneously hypertensive rats is not significantly different from that in normotensive control rats (Fig. 2). Reflex control of renal sympathetic outflow during volume load: The reflex inhibition of sympathetic outflow to the kidney during volume load was measured in adult anesthetized normotensive control and spontaneously hypertensive rats.21 The arterial baroreceptors were denervated. The observed renal nerve inhibition was mediated by the vagal nerves a&l was due to activation of receptors in the left side of the heart, presumably the left atria1 endings. The relation between renal nerve inhibition and left atria1 pressure is shown in Figure 3 during volume loading with horse
October 22, 1979
A
Hg
FIGURE 2. The mean activity in 11 left atrial high frequency C fiber endings in a spontaneously hypertensive rat (SHR) and similar data from 8 high frequency receptors in a normotensive control rat (NCR). Also shown is the mean left atrial pressure at end expiration in the normotensive (A) and the hypertensive (B, C) rat. Because of the resetting of the receptors there is no clear change in receptor activity in the hypertensive rat (B) despite an increase in left atrial pressure. C indicates the estimated receptor activity in the hypertensive rat in the absence of receptor resetting.
006
\\
r
The American Journal of CARDIOLOGY
SHR
50
: 0
i0
i0
;0
Mean left atrial pressure, mmtig FIGURE 3. The relation between mean left atrial pressure and mean rectified renal nervous activity in six normotensive control (NCR) and six spontaneously hypertensive rats (SHR) during volume loading with horse plasma. The changes in renal activity are expressed as a percent of maximal (max.) control activity. (*** = P
