Rate and Extent of Adaptive Cardiovascular Changes in Rats during Experimental Renal Hypertension

To study the extent and exact time course of cardiovascular structural adaptation to increases in pressure load, renal hypertension was induced in normotensive male Wistar rats by renal artery constriction. At different intervals after operation the hemodynamic characteristics of the hypertensive rats and normotensive control rats were explored in paired hindquarter perfusions, from maximal dilatation up to maximal constriction (cf, Folkow et al, 1970 b). At the same time intervals the extent of left ventricular hypertrophy and of water content of the aortic wall were examined. The results reveal the presence of left ventricular hypertrophy in the hypertensive rats already after one week, soon followed by adaptive structural changes of the resistance vessels, in the form mainly of media hypertrophy, these processes being largely completed 2–3 weeks after operation. In these animals, lacking genetic predisposition for hypertension, the extent of the structural vascular changes seems large enough to explain a considerable part, but not all, of the pressure rise. An increased water content of the hypertensive aortic wall is found first 4.5 months after operation, indicating that some water logging of arterial and maybe also arteriolar walls might occur in late phases of chronic renal hypertension.     

The baroreceptor reflex and the cardiovascular changes associated with sustained muscular contraction in the cat

Summary In decerebrate unanaesthetised cats the cardiovascular effects of raising the pressure in a blind sac preparation of a carotid sinus on one side were examined at rest and during sustained contractions of hind-limb muscles. During a tetanic contraction the absolute value of the blood pressure and heart-rate components of the baroreceptor reflex response were not significantly changed from those at rest. The curve relating heart-rate and mean blood pressure, during carotid sinus distension, was similar at rest and when the muscles of the hind-limb were contracting tetanically, although each value of heart-rate was greater, suggesting a resetting of the baroreceptor reflex. By contrast, in the same experiments, suppression of the baroreceptor reflex changes in heart-rate and blood pressure could be demonstrated during the increases of blood pressure and heart-rate elicited by electrical stimulation of limb nerve. It was concluded that the increases in blood pressure and heart-rate elicited by the afferent discharge from muscles during sustained contraction are buffered to some extent by the baroreceptors, though their inhibitory effect is incomplete under these conditions.     

The influence of aortic baroreceptors on venous tone in the perfused hind limb of the dog.

1. The aortic arch and both carotid sinuses were vascularly isolated and perfused. A hind limb was vascularly isolated and blood was pumped at constant flows into the femoral artery and the central end of a superficial metatarsal vein. 2. Large increases in aortic arch pressure resulted in decreases in arterial blood pressure, heart rate and femoral arterial perfusion pressure. The average response of the vein was a decrease of 11% in the pressure gradient between the perfused vein and the femoral vein. Similar responses were obtained when carotid sinus pressure was increased. 3. Crushing or cooling the lumbar sympathetic trunk caused responsed similar to those induced by increasing baroreceptor perfusion pressure. Stimulation at 1 HZ resulted in venous responses four times as great as the average reflex response, whereas frequencies of 2-5 Hz were required to produce changes in arterial resistance as great as those induced reflexly. 4. These experiments indicate, that although the large superficial veins of the dog's hind limb participate in the baroreceptor reflexes, the activities in the nerves supplying arterioles and veins must have been different.     

Morphology of the carotid sinus wall in normotensive and spontaneously hypertensive rats

The morphology of the carotid sinus region of the internal carotid artery was studied in spontaneously hypertensive rats (SHR) at 5, 8, 16, and 24 weeks of age. The carotid sinus region occupied the proximal millimeter of the internal carotid artery, and was easily recognizable by the presence of an extensive adventitial capillary plexus, which was absent on adjacent arteries (e.g., common and external carotid arteries). Methylene blue-stained whole-mount preparations showed the extent of baroreceptor nerves over the sinus. Baroreceptor fibers terminated in distinctive bulbous-like endings, which, at the ultrastructural level, were filled with mitochondria. No differences were noted in the sinus adventitial capillary network or baroreceptor distribution between SHR and age-matched Wistar-Kyoto (WKY) normotensive control animals. With the onset of a significant rise in SHR blood pressure, the carotid sinus wall increased in thickness and total vessel size. The wall/lumen ratios were significantly larger in the SHR than in age-matched WKY ratios in all age groups. SHR carotid sinus vessel enlargement was uniform throughout the vessel tunics, with no significant change in the proportion of the tunica media occupied by smooth muscle cells. The increase in the carotid sinus wall thickness associated with increasing hypertension could affect the ability of the sinus to distend and may play a secondary role in the maintenance of hypertension by compromising baroreceptor nerve ending sensitivity.     

Influence of carotid baroreceptors on different components of the vascular system

1. Reflex changes in wall tension of the lateral saphenous vein of one hind limb, the splenic veins and capsule, and the resistance vessels of the other hind limb caused by changes in baroreceptor activity were measured in vagotomized dogs under thiopentone-chloralose anaesthesia.2. Three different methods were used to alter pressure in one or both carotid sinuses. (1) Both carotid sinuses were vascularly isolated and filled with fully oxygenated Krebs-Ringer bicarbonate solution (pH 7.4) from a reservoir in which the pressure could be altered at will. (2) One sinus was denervated, and the contralateral sinus was perfused with arterial blood at different flow rates. (3) One sinus was denervated, and the innervated sinus was perfused with arterial blood at constant flow, the pressure being altered by changing the outflow resistance.3. The left saphenous vein was perfused at constant flow with autologous blood; changes in perfusion pressure were used as a measure of changes in veno-motor activity. The right common iliac artery was perfused at constant flow to measure changes in resistance vessel activity. Blood flow through the spleen was temporarily arrested, trapping a fixed volume of blood in the organ. Under these conditions, changes in splenic vein pressure were a measure of changes in smooth-muscle tension in the splenic capsule and veins.4. In order to assess the responses to baroreceptor stimulation in terms of alterations in sympathetic nerve traffic to different components of the peripheral vascular system, ;frequency-response curves' were constructed for spleen, saphenous vein, and limb resistance vessels by electrical stimulation of the splenic nerves and lumbar sympathetic chains.5. The saphenous vein showed no consistent response to changes in baroreceptor activity. Reduction in carotid sinus pressure from 180 to 100 mm Hg caused an increase in venous pressure in the isovolumetric spleen and in the iliac artery perfusion pressure. These results were confirmed by electrical stimulation of the carotid sinus nerve. Whereas the peak responses of the limb resistance vessels corresponded to an increase in lumbar sympathetic nerve traffic of 6-10 c/s, the maximal splenic responses were equivalent to an increase in splenic nerve traffic of 1-4 c/s. These results are consistent with selective autonomic nervous control of different components of the peripheral vascular system.     

Baroreflex “resetting” by arterial hypoxia in the renal and cardiac sympathetic nerves of the rabbit

1. Renal and cardiac sympathetic baroreflex functions were studied in sodium pentobarbitone anaesthetized rabbits given succinylcholine, during constant artificial ventilation with air and with hypoxic gas mixtures. Mean arterial pressure (MAP) was raised and lowered between values of 40 and 140 mm Hg by means of aortic and vena caval periovascular balloons and integrated sympathetic nerve activity (SNA) was recordered. 2. The relationship between MAP and SNA was sigmoid, with upper and lower plateau levels. The curves were defined by calculating median blood pressure, SNA Range and reflex gain. In both renal and cardiac sympathetics section of the carotid sinus and aortic nerves completely abolished the MAP-related changes in SNA. 3. The renal baroreflex curves were reset from control levels during hypoxia. Median blood pressure increased, as did SNA Range and gain. These effects were due to central interactions between arterial baroreceptor, arterial chemoreceptor and vagal afferent activity. 4. The cardiac sympathetic baroreflex curves were shifted in the opposite direction from control with reduction in median blood pressure, SNA Range and reflex gain. These changes were due to chemoreceptor-arterial baroreceptor interactions. 5. Arterial hypoxia thus evokes a differentiated pattern of baroreflex resetting in the renal and cardiac sympathetic montoneuron pools with differing changes in neural response range and sensitivity to arterial pressure changes.     

Role of receptor elements in baroceptor resetting.

Spontaneously hypertensive rats (SHR), 4 wk of age, were treated with antihypertensive agents for 40 wk. The treatment was withdrawn for 2 wk so that the animals experienced hypertension for about 1 wk. The aortic arch was then perfused and aortic nerve activity was recorded. The threshold pressure was 140 mmHg in these SHR. This threshold pressure was less than that observed in age-matched untreated SHR (160--180 mmHg) but greater than that observed in age-matched Kyoto-Wistar rats (80--120 mmHg), indicating partial baroceptor resetting. No significant changes were observed in the vascular wall in these SHR, and partial baroceptor resetting was completely reversed when short duration of hypertension was reversed. On the other hand, baroceptor resetting in untreated SHR was always accompanied by significant changes in vascular wall, and reversal of baroceptor resetting was contingent upon regression of vascular wall hypertrophy. Partial baroceptor resetting in absence of significant changes in vascular wall may be explained by adaptation of baroceptors to persistent high blood pressure.     

Time course of the enhanced blood pressure response to reinduction of renal artery stenosis in unclipped renal hypertensive rats

Moderate or severe hypertension was induced in rats by application of a clip 0.25 or 0.20 mm internal diameter) to the left renal artery leaving the contralateral kidney intact. Removal of the clip 6, 13 or 24 days after the induction of the hypertension was followed by a rapid decrease in blood pressure. A near normotensive level was reached after 2–6 h. Reapplication of the clip to the unclipped renal artery after 1 day caused an enhanced blood pressure response. The preoperative hypertensive levels were reached within 2 h. This enhanced response was related to the level of blood pressure before the removal of the clip. Lengthening the interval between removal and reapplication of the clip gradually reduced the enhanced response of blood pressure, which had disappeared 8 days after the removal of the clip. Reapplication of the clip to the contralateral renal artery was not followed by an enhanced response in rats with previous moderate or severe hypertension.     

Circulatory effects of carotid sinus stimulation and changes in blood volume distribution in hypertensive man

In 8 patients with moderate hypertension and 8 normotensive subjects an attempt was made to study the circulatory effects of high and low pressure baroreceptor stimulation. Intrathoracic low pressure receptors were stimulated by changes in blood volume distribution using lower body negative pressure (LBNP) and lower body positive pressure (LBPP). The carotid sinus was stimulated by sinusoidal neck suction. Blood pressure, central venous pressure, heart rate, cardiac output and forearm blood flow were recorded. During LBNP and LBPP changes in central blood volume, reflected in changes in central venous pressure, induced significantly greater changes in cardiac output and forearm blood flow in the hypertensive subjects. In both normotensive and hypertensive subjects mean arterial blood pressure was essentially unchanged during LBNP and a slight increase was found during LBPP. Heart rate and blood pressure response to stimulation of the carotid sinus decreased with increasing resting mean arterial pressure. The results suggest impairment of reflex adjustments, via arterial baroreceptors, possibly in particular to dynamic stimuli, rather than via intrathoracic “low pressure” baroreceptors in subjects with moderate hypertension.     

Baroreceptor Stimulation Alters Pain Sensation Depending on Tonic Blood Pressure

It has been hypothesized that activation of the baroreceptor reflex arc, by its central nervous inhibitory effects, is involved in an operant learning mechanism of blood pressure elevation. The present study investigated the effects of mechanical stimulation of the baroreceptors in the carotid sinus on pain threshold and electrical brain activity in two groups of humans with different tonic blood pressure levels. In normotensives, baroreceptor stimulation lowered pain threshold as compared to a control condition, while borderline hypertensives tolerated more intense electric stimulation when baroreceptors were activated. A marked reduction of the contingent negative variation in anticipation of the aversive stimulation accompanied baroreceptor stimulation, probably a consequence of baroreceptor afferent impulses exerted via brainstem centers to cerebral cortex. The distribution of the potential change across the scalp depended on the tonic blood pressure, indicating differences in brain functioning between normotensives and borderline hypertensives. The present results suggest that the hypothesis of an operantly-conditioned blood pressure elevation under stress may be valid only in subjects with a predisposition for essential hypertension.     

Cardiovascular reactivity and design in rats with experimental “neurogenic hypertension”

The arterial baroreceptors were denervated in 20 normotensive Wistar rats. 2 1/2 months after the operation their cardiovascular responses to “mental stress” were compared to those of matched control rats (NCR). At the time of investigation the blood pressure of the baroreceptor denervated rats (BDR) was increased some 15 per cent above that of the control group. There was, however, no difference in response to “mental stress” between groups, if anything the BDR responded with less pronounced tachycardia. Two months subsequent to the stress-test the mean blood pressure of the BDR was still significantly above normal levels, but the BDR did not exhibit structural cardiovascular adaptation, which has been documented in most types of stable hypertension as a response to the increased mean blood pressure. The results imply that hypertension induced by baroreceptor denervation is not of a stable and persistent type in which case structural changes in the cardiovascular system would have developed within the observation period (approximately 4 months). Emotional stimuli, however, do not seem to contribute to periodic blood pressure increases at the time of measurement, as earlier suggested.     

Static and dynamic changes in carotid artery diameter in humans during and after strenuous exercise

Arterial baroreflex function is altered by dynamic exercise, but it is not clear to what extent baroreflex changes are due to altered transduction of pressure into deformation of the barosensory vessel wall. In this study we measured changes in mean common carotid artery diameter and the pulsatile pressure: diameter ratio (PDR) during and after dynamic exercise. Ten young, healthy subjects performed a graded exercise protocol to exhaustion on a bicycle ergometer. Carotid dimensions were measured with an ultrasound wall-tracking system; central arterial pressure was measured with the use of radial tonometry and the generalized transfer function; baroreflex sensitivity (BRS) was assessed in the post-exercise period by spectral analysis and the sequence method. Data are given as means ± s.e.m . Mean carotid artery diameter increased during exercise as compared with control levels, but carotid distension amplitude did not change. PDR was reduced from 27.3 ± 2.7 to 13.7 ± 1.0 μm mmHg⁻¹. Immediately after stopping exercise, the carotid artery constricted and PDR remained reduced. At 60 min post-exercise, the carotid artery dilated and the PDR increased above control levels (33.9 ± 1.4 μm mmHg⁻¹). The post-exercise changes in PDR were closely paralleled by those in BRS (0.74 ≤ r ≤ 0.83, P < 0.05). These changes in mean carotid diameter and PDR suggest that the mean baroreceptor activity level increases during exercise, with reduced dynamic sensitivity; at the end of exercise baroreceptors are suddenly unloaded, then at 1 h post-exercise, baroreceptor activity increases again with increasing dynamic sensitivity. The close correlation between PDR and BRS observed at post-exercise underlies the significance of mechanical factors in arterial baroreflex control.     

Hemodynamic characteristics of conscious deoxycorticosterone acetate hypertensive rats

An electromagnetic flow probe was chronically implanted around the common carotid, superior mesenteric, or renal artery or the terminal aorta in deoxycorticosterone acetate (DOCA) hypertensive rats (prepared with DOCA and saline after uninephrectomy) and uninephrectomized control rats. A catheter for pressure measurement was inserted into the terminal aorta through a femoral artery. At rest the carotid and hindquarter (measured at the terminal aorta) blood flows in DOCA hypertensive rats were similar to the respective, corresponding values in normal rats with intact bilateral kidneys. The group mean of superior mesenteric flow was about 70% and that of renal flow about 40% larger than in normal rats. Cardiac output was estimated to be greater in DOCA hypertensive rats than in normal rats. In uninephrectomized control rats, superior mesenteric flow was larger than in normal rats to such an extent that an increase in cardiac output was assumed as in DOCA hypertensive rats, but renal flow was normal (about twice the unilateral renal flow in normal rats). Estimation of regional sympathetic vasoconstrictor tone from the decrease in peripheral resistance with hexamethonium and vasopressin antagonist revealed a substantial tone also in the superior mesenteric and hindquarter areas, where the tone was estimated to be almost absent in normal rats and uninephrectomized rats. It is suggested that hypertension in DOCA hypertensive rats is sustained by an increase in cardiac output and an elevation of vasoconstrictor tone in resistance vessels. Since increase in cardiac output appears to be similarly present in uninephrectomized control rats, the elevation of sympathetic tone due to administration of DOCA and salt seems to be indispensable for DOCA hypertension.     

Cardiovascular reactivity and design in rats with experimental "neurogenic hypertension"

The arterial barorecptors were denervated in 20 normotensive Wistar rats. 2 1/2 months after the operation their cardiovascular responses to "mental stress" were compared to those of matched control rats (NCR). At the time of investigation the blood pressure of the baroreceptor denervated rats (BDR) was increased some 15 per cent above that of the control group. There was, however, no difference in response to "mental stress" between groups, if anything the BDR reponded with less pronounced tachycardia. Two months subsequent to the stress-test the men blood pressure of the BDR was still significantly above normal levels, but the BDR did not exhibit structural cardiovascular adaptation, which has been documented in most types of stable hypertension as a response to the increased mean blood pressure. The results imply that hypertension induced by baroreceptor denervation is not of a stable and persistent type in which case structural changes in the cardiovascular system would have developed within the observation period (approximately 4 months). Emotional stimuli, however, do not seem to contribute to periodic blood pressure increase at the time of measurement, as earlier suggested.     

Relationship between the baroreceptor reflex and the variability of arterial pressure and of the heart beat period in rats with arterial hypertension

The relationship between depression of the cardiochronotropic component of the baroreceptor reflex and arterial pressure and heart beat variabilities was investigated in normotensive rats and rats with renal hypertension (one kidney — one clamp). In the hypertensive rats, the arterial pressure and heart rate were both increased and more variable, while the cardiochronotropic component of the baroreceptor reflex was depressed. No cause-effect relationship between baroreceptor reflex attenuation and increased variability of hemodynamic parameters was found in this rat model of arterial hypertension. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, No. 5, pp. 474–476, May, 1995 Presented by B. I. Tkachenko, Member of the Russian Academy of Medical Sciences     

Structural “Resetting” of the Renal Vascular Bed in Spontaneously Hypertensive Rats (SHR)

Studies in both man and rats (cf. Folkow et al. 1973, 1974) show that a rapid structural adaptation occurs early in hypertension which, besides the left heart and systemic arteries, affects the precapillary resistance vessels in a hemodynamically most important way. Here a wall (mainly media) thickening takes place which tends to encroach upon the inner radius, thus raising the w/r_i ratio. The rapidity, generalization and extent of this precapillary ‘“structural autoregulation” to average changes in pressure load makes it crucial both for the initiation and maintenance of a chronic high-pressure state, whichever the initiating elements are. The same principle of hypertrophic adaptation in the left heart and large arteries leads to a functionally important displacement of the “Starling curve” towards the right (Hallbäck, Isaksson and Noresson 1975) and to baroreceptor resetting (e.g. Jones 1977).     

Neural control of sympathetic nerve response to cardiogenic hypotension in anesthetized cat

The present study was designed to determine effect of the preganglionic splanchnic nerve activity (SNA) on the brief hypotension accompanied with the occlusion of left circumflex coronary artery (CxCAO) in chloralose anesthetized cats. Following CxCAO in animals with neuraxis intact, no significant alterations of SNA occurred despite the significant fall in mean blood pressure (MBP). A significant fall in MBP also occurred in vagotomized animals with arterial baroreceptors intact, but SNA was significantly augmented from 12.9 +/- 2.7 impulses/sec before CxCAO to 24.4 +/- 4.3 impulses/sec 60 sec after the occlusion. In vagotomized animals, in which their carotid sinuses were isolated and perfused with the constant pressure at a level equal to systemic blood pressure (112 +/- 6 mmHg) and with higher pressure (167 +/- 7 mmHg), SNA was not altered significantly during the hypotension due to CxCAO. When the carotid sinuses were perfused with lower pressure (53 +/- 8 mmHg), a significant increase in SNA occurred simultaneously with the decrease in MBP after CxCAO. The peak decreases in blood pressure during the coronary occlusion were significantly greater in the vagotomized group (-46 +/- 5 mmHg) and in the Low-CSP group (-50 +/- 5 mmHg) than in other groups. Onset of this excitatory efferent sympathetic response to the hypotension due to the coronary occlusion in the vagotomized and Low-CSP groups was delayed significantly despite a significant fall in arterial blood pressure. These results show that vagal afferents from the heart may play a role of inhibiting the sympathetic augmentation mediated by arterial baroreceptors during cardiogenic hypotension. An excessive activation of cardiac receptors with sympathetic afferents may be induced by the profound fall in blood pressure, resulting in further impairment of cardiac function due to progressive myocardial ischemia under the condition of high sympathetic tone activated by baroreceptor reflex.     

Adrenergic and pressure-induced modulation of carotid sinus baroreceptors in rabbit

The sympathetic control of the carotid sinus baroreceptor activity was studied in rabbits. Stimulation of the cervical sympathetic trunk (10 Hz, 1 ms, 4–12 V) elicited an increase in discharge frequency of the non-medullated baroreceptor afferents but not of the medullated fibers. An isolated carotid sinus area preparation was used to examine the influence of noradrenaline perfusion on baroreceptor activity. Non-medullated baroreceptor afferents, but not the medullated afferents, responded to noradrenaline perfusion (10^-6 g/ml) with a significant increase in firing rate. Short-term resetting of the baroreceptors was also studied with the same preparation. After perfusing the sinus at a hypertensive level for 30 min the pressure-response curves of both the non-medullated and the medullated baroreceptor afferents shifted to the right with increased thresholds and decreased maximal discharge frequencies. The extent of the short-term resetting was greater in non-medullated afferents than in medullated ones. It is concluded that the carotid sinus baroreceptors with non-medullated afferents are under the sympathetic control. The physiological significance of this is discussed.     

Influence of sodium withdrawal by a diuretic agent or peritoneal dialysis on arterial pressure in one-kidney goldblatt hypertension in the rat

Summary In rats made hypertensive by partial constriction of one renal artery and contralateral nephrectomy, large doses of furosemide had no hypotensive effect. However, when furosemide natriuresis was followed by removal of the clamped kidney, arterial blood pressure was greatly reduced. The fall of blood pressure induced in this manner was significantly correlated with the amount of sodium and water lost. The absence of a hypotensive effect of furosemide in rats with one-kidney Goldblatt hypertension appeared to be due to enhanced renin secretion. Furosemide not followed by nephrectomy caused a fall of blood pressure in rats with one-kidney Goldblatt hypertension after renin-depletion by desoxycorticosterone and salt treatment. Sodium wastage induced by peritoneal dialysis after removing the clamped kidney also lowered the blood pressure of hypertensive rats.Supported by Fonds National Suisse de la Recherche Scientifique Grants No. 5313.3 and 3369.70Preliminary communication: Liard, 1973 [5].     

Depressed endothelium-dependent relaxation in hypertension: relation to increased blood pressure and reversibility

Endothelium-dependent relaxation effects have been reported to be impaired in thoracic aorta from genetic and experimentally induced hypertensive rats. This study extends these observations to carotid artery and abdominal aorta from renovascular hypertensive rats. It was also found that rats with coarctation of aorta show depressed endothelium-dependent relaxation responses in thoracic aorta above the stenosis (high pressure region) while no depressed responses are observed in abdominal aorta below the stenosis (normal pressure region). Reversibility of the depression of endothelium-dependent relaxation was investigated on aorta from renovascular hypertensive rats in which blood pressure was normalized by removal of the stenotic kidney three months after induction of hypertension. Endothelium-dependent responses were restored partially after 1–2 weeks and completely after two months of normalization of blood pressure. These results indicate that the increased blood pressure is indeed the causative factor responsible for the impaired endothelium-dependent relaxations in arteries from experimental hypertensive rats, a phenomenon which is reversible, at least in our experimental conditions.