The carotid bodies of spontaneously hypertensive rats (SHR): a functional and morphologic study

The parameters of the acid-base-state of the arterial blood were measured in spontaneously hypertensive rats of the Okamoto-strain (SHR) and in normotensive Wistar rats (NWR) of a random-bred strain. The animals were anaesthetized with chloralose-urethane and breathed normal air under sea-level conditions. Structure and size of their carotid bodies were studied by light-microscopic methods. When compared with the NWR, the SHR showed a respiratory alkalosis and enlarged carotid bodies. In the SHR, never in the NWR, the lumen of the branches of the glomic arteries was narrowed by pad-like structures. The data suggest that systemic hypertension leads to morphologically and functionally detectable alterations of both carotid body structure and function. The interdependence of arterial chemoreceptor activity, sodium household, and the adjustment of systemic arterial blood pressure is briefly discussed.     

Respective contribution of age, mean arterial pressure, and body weight on central arterial distensibility in SHR

In spontaneously hypertensive rats (SHR), carotid and aortic distensibilities measured at operational blood pressure (BP) are reduced. Increased body weight and mean arterial pressure (MAP) are both known to reduce distensibility independently. However, whether, after adjustment to body weight and mean BP, distensibility remains reduced in SHR has never been investigated. Carotid and abdominal aorta distensibilities were measured under anesthesia in SHR at 5, 12, 52, and 78 wk of age, and measurements were compared with age-matched normotensive Wistar rats. Each age group was composed of 9 or 10 animals. We determined distensibility using echo-tracking techniques of high resolution. Compared with Wistar rats, carotid and aortic distensibilities measured at operational MAP are reduced in SHR. This reduction is accentuated with age, particularly for the carotid artery. After adjustment to body weight and MAP, carotid and aortic distensibilities become identical in Wistar and SHR (or even slightly increased in SHR) but continue to be reduced with age, mainly for the carotid artery. In conclusion, in SHR, age and high BP do not have a parallel and similar influence on the reduction of arterial distensibility. Aging constantly reduces arterial distensibility, whereas MAP levels contribute to maintenance of arterial function.     

Hypoxic modulation of systolic blood pressure and urinary sodium excretion in spontaneously hypertensive rats after carotid body denervation

To explore the role of arterial chemoreceptors, the effect of hypobaric hypoxia on urinary sodium excretion and systolic blood pressure was investigated in conscious spontaneously hypertensive rats (SHR) with carotid body denervation (CBD) or after sham-operation (SO). Denervation of the carotid bodies was performed by section of the carotid sinus nerves. Exposure to hypobaric hypoxia equivalent to high altitude of 4000 m led to a more pronounced decrease in systolic blood pressure in CBD-rats than in SO-rats. The pattern of urinary sodium excretion observed on the first two days of hypoxia in both groups was not affected by the chemodenervation. It is being suggested that arterial chemoreceptors do not play a critical role in blood pressure and natriuretic responses to hypobaric hypoxia in conscious SHR.     

Physiological chemoreceptor stimulation decreases enkephalin and substance P in the carotid body

Neuroactive peptides, including the enkephalins (Met- and Leu-enkephalin; ME, LE) and substance P (SP) are known to be present in the mammalian carotid body, an arterial chemoreceptor organ sensitive to the O2, CO2 and pH levels in blood. The principal parenchymal (type I) cells of the organ, which receive sensory innervation from the carotid sinus nerve (CSN), have been shown to contain both ME and SP; SP is also present in CSN afferent fibers. In the present study, rabbits were exposed in a chamber to a physiological chemoreceptor stimulus (5% O2 in N2) for one hour, then anesthetized during surgical removal of both carotid bodies for later RIA measurement of ME and SP levels in the tissue; control animals were exposed to air in the chamber, but otherwise treated as the hypoxic animals. Both ME and SP levels were significantly reduced (approximately 40%) in the carotid bodies from hypoxic rabbits, compared to their normoxic controls. The results suggest that these neuroactive peptides are released from carotid body elements during physiological stimulation, and consequently may play a role in the transduction of chemosensory information between the type I cells and their apposed afferent terminals.     

Bromolasalocid (Ro 20-0006) antihypertensive ionophore

Bromolasalocid (Ro 20-0006) is a calcium ionophore with antihypertensive activity that does not belong to any known class of antihypertensive agents. Bromolasalocid produces a relatively flat systolic blood pressure dose-response effect in the spontaneously hypertensive rat. An intensive cardiovascular evaluation of bromolasalocid at the highest dose used in the dose-response study showed full hemodynamic compensation; there was a significant decrease in both mean arterial blood pressure and peripheral resistance without a significant decrease in cardiac index. The antihypertensive action of bromolasalocid lasts many days after termination of dosing. Bromolasalocid is specifically antihypertensive and does not decrease arterial blood pressure in normotensive animals or in animal models of hypertensive cardiovascular disease with normal pulse pressures. Bromolasalocid is not a vasodilator and appears to mediate its antihypertensive action by restoring compliance of the large conduit arteries. Both the derived arterial compliance index and the blood pressure-pressor response to the carotid occlusion reflex are enhanced in the dog perinephritis model of hypertensive cardiovascular disease treated with bromolasalocid. Bromolasalocid appears to reverse the damage to cardiovascular tissue caused by prolonged hypertension via an action on calcium perturbations in large artery smooth muscle cells.     

Compliance characteristics of the hind-limb arterial system of normal and hypertensive rabbits

Pressure transients resulting from square-wave changes in abdominal aortic blood flow rate were used to derive effective arterial compliance and peripheral resistance of the hind-limb circulation of anaesthetized rabbits. The model for deriving these parameters proved applicable if step changes in flow were kept less than 35% of mean flow. Under resting conditions, the effective hind-limb arterial compliance of normal rabbits averaged 3.46 X 10(-3) mL/mmHg (1 mmHg = 133.322 Pa). Hind-limb arterial compliance decreased with increasing pressure at low arterial pressures, but unlike compliance of isolated arterial segments, compliance did not vary at and above normal resting pressures. Baroreflex destimulation (bilateral carotid artery occlusion) caused an increase in effective hind-limb vascular resistance at 48.4% and a decrease of arterial compliance of 50.7%, so that the constant for flow-induced arterial pressure changes (resistance times compliance) was largely unchanged. Similarly, the arterial time constant for rabbits with chronic hypertension was similar to that for controls because threefold increases in hind-limb vascular resistance were offset by decreases in compliance. Reflex-induced decreases in arterial compliance are probably mediated by sympathetic nerves, whereas decreases associated with hypertension are related to wall hypertrophy in conjunction with increased vasomotor tone. Arterial compliance decreased with increasing pressure in hypertensive animals, but this effect was less pronounced than in normotensive rabbits.     

Regional vascular influences on tail-cuff measurements of drug-induced changes in systolic pressure.

When drug effects are quantified using the tail-cuff method, changes in systemic arterial pressure are extrapolated from those occurring in the caudal artery. The validity of this extrapolation was tested in anesthetized rats by recording drug-induced changes in phasic arterial pressure simultaneously from catheters inserted into the lower abdominal aorta, carotid, and caudal arteries. Pressor responses to norepinephrine or angiotensin were of equal magnitude at all three sites, but phentolamine reduced systolic pressure in the aorta or caudal artery more than that in the carotid artery. Unlike previous discrepancies between carotid and tail-cuff systolic pressures, aortic hypotension caused by injections of phentolamine or pentolinium in awake normotensive or spontaneously hypertensive rats was accurately predicted by the tail-cuff method. Because drug-induced changes in diastolic pressure always varied much less than those in systolic pressure, should indirect measurement of diastolic pressure become technically feasible, it might be preferable for assessing drug effects on blood pressure.     

Relative latency of responses of chemoreceptor afferents from aortic and carotid bodies

Discharges from aortic and carotid body chemoreceptor afferents were simultaneously recorded in 18 anesthetized cats to test the hypothesis that aortic chemoreceptors, because of their proximity to the heart, respond to changes in arterial blood gases before carotid chemoreceptors. We found that carotid chemoreceptor responses to the onset of hypoxia and hypercapnia, and to the intravenously administered excitatory drugs (cyanide, nicotine, and doxapram), preceded those of aortic chemoreceptors. Postulating that this unexpected result was due to differences in microcirculation and mass transport, we also investigated their relative speed of responses to changes in arterial blood pressure. The aortic chemoreceptors responded to decreases in arterial blood pressure before the carotid chemoreceptors, supporting the idea that the aortic body has microcirculatory impediments not generally present in the carotid body. These findings strengthened the concept that carotid bodies are more suited for monitoring blood gas changes due to respiration, whereas aortic bodies are for monitoring circulation.     

The effect of prostaglandins E2 and F2 alpha on carotid blood flow in rats with renovascular hypertension

The effect of i.v. bolus administration of PGE2 and PGF2 alpha on carotid blood flow (Q) and mean arterial blood pressure (MAP) was recorded in 21 anaesthetized normotensive control (N) and 12 rats with 1K1C renovascular hypertension (RH). From the measured parameters the regional vascular impedance (PVI) and the change in blood volume were calculated. In normotensive animals both PGs elicited a dose-dependent initial fast increase of Q (threshold dose 0.4 ng/kg) and a decrease of MAP and PVI (threshold dose 0.4 micrograms/kg). Subsequently, Q decreased below the initial level. MAP and PVI remained depressed after E2 but increased after F2 alpha. The time course of the Q and MAP responses was analyzed in more detail at a standard dose 4 micrograms/kg. The average time to peak of the first phase was 12 s and of the second approximately 80 s. The initial levels of Q and MAP were reestablished within 3 to 4 minutes. The total volume of carotid blood flow obtained by planimetric integration was unaltered after F2 alpha but depressed after E2. In hypertensive animals both phases of the response to E2 were significantly retarded and the Q response was nearly abolished. On the other hand, the time course of the reaction to F2 alpha was unchanged but the magnitude of the second pressoric phase was reduced. Thus, the capacity of the carotid vascular bed to dilate remains the same in RH while the ability to constrict is limited. It is concluded that the response of MAP and Q to both PGs are relatively independent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different cardiorespiratory responses to hemorrhage and hyperoxia in normotensive (WKY) and spontaneously hypertensive (SHR) rats

OBJECTIVE: To compare the cardiorespiratory responses underlying the beneficial effects of hyperoxia during blood loss between normotensive (WKY) and hypertensive (SHR) rats. METHODS: Experiments were carried out in anesthetized animals with both carotid bifurcations either innervated or denervated. The effects of breathing 60% O2 in N2 were studied either in combination with non-hypotensive hemorrhage or during hemorrhagic hypotension. RESULTS: In normoxia arterial pressure fell more in SHR than in WKY for a given blood loss. During hyperoxia, nerve-intact rats showed initial suppression of ventilation, but bifurcation-denervated rats a powerful enhancement. In all groups, hyperoxia increased the overall tone of venous capacitance vessels. CONCLUSIONS: The greater blood loss in SHR than in WKY when bleeding down to a given arterial pressure results from a stronger constriction of venous capacitance vessels. Hyperoxia improves the ability of the cardiorespiratory system to resist the effects of hemorrhage by increasing the overall venous tone, thus supporting cardiac filling, and in some cases also by increasing alveolar ventilation, probably secondary to improved cerebral oxygenation. The beneficial effects of hyperoxia were: (i) not prevented by carotid denervation, and thus were presumably direct tissue effects of oxygen, (ii) strikingly weaker in SHR than in normotensive (WKY) rats.     

Influence of experimental diabetes on regulatory mechanisms of vascular response of rabbit carotid artery to acetylcholine

The purpose of this study was to analyse the influence of experimental diabetes on vascular response of rabbit carotid artery to acetylcholine (Ach). We compared the Ach-induced relaxant response of isolated arterial segments obtained from both control and diabetic animals. To assess the influence of the endothelium, this cell layer was mechanically removed in some of the arterial segments ("rubbed arteries") from each experimental group. Ach induced a concentration-related endothelium-mediated relaxation of carotid artery from control rabbits that was significantly higher with respect to that obtained in diabetic animals. Pre-treatment with N(G)-nitro-L-arginine (L-NA) induced a concentration-dependent inhibition of relaxant response to Ach, which was significantly higher in carotid arteries isolated from diabetic rabbits. Incubation of rubbed arteries with L-NA almost abolished the relaxant response to Ach in arterial segments from both control and diabetic animals. Indomethacin potentiated Ach-induced response of carotid arteries from control rabbits, without modifying that obtained in those from diabetic animals. Aminoguanidine did not significantly inhibit the relaxant action of Ach in arterial segments from either control or diabetic rabbits. These results suggest that diabetes impairs endothelial modulatory mechanisms of vascular response of rabbit carotid artery to Ach. This endothelial dysfunction is neither related with a lower release of nitric oxide (NO) or prostacyclin. Diabetes impairs the production of some arachidonic acid vasoconstrictor derivative. There has been observed an increased modulatory activity of NO, but this is not related with the expression of an inducible isoform of NO synthase.     

Vascularization and morphology of carotid bodies in patients with essential hypertension

Vascularization and morphology of carotid bodies in 100 necropsies of patients with essential hypertension in comparison with the 83 normotensives were studied. The statistically significant differences between the two groups were found. The carotid bodies of hypertensive subjects were vascularized by a lower number of arteries than those of the normotensives. This difference seems to be genetically determined. The mean combinated mass of carotid bodies of hypertensive subjects was higher than this of normotensive ones. The hyperplasia of the type I cells in carotid bodies of hypertensives was found. The subjects with a lower number of glomic arteries are more susceptible to disturbation of blood flow to the carotid body, overstimulation of carotid chemoreceptors and consequent hypertension. The results of study done may support the concept of the possible role of carotid body in the pathogenesis of essential hypertension.     

Impaired UTP-induced relaxation in the carotid arteries of spontaneously hypertensive rats

Uridine 5′-triphosphate (UTP) has an important role as an extracellular signaling molecule that regulates inflammation, angiogenesis, and vascular tone. While chronic hypertension has been shown to promote alterations in arterial vascular tone regulation, carotid artery responses to UTP under hypertensive conditions have remained unclear. The present study investigated carotid artery responses to UTP in spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY). Accordingly, our results found that although UTP promotes concentration-dependent relaxation in isolated carotid artery segments from both SHR and WKY after pretreatment with phenylephrine, SHR exhibited significantly lower arterial relaxation responses compared with WKY. Moreover, UTP-induced relaxation was substantially reduced by endothelial denudation and by the nitric oxide (NO) synthase inhibitor N^G-nitro-L-arginine in both SHR and WKY. The difference in UTP-induced relaxation between both groups was abolished by the selective P2Y₂ receptor antagonist AR-C118925XX and the cyclooxygenase (COX) inhibitor indomethacin but not by the thromboxane-prostanoid receptor antagonist SQ29548. Furthermore, we detected the release of PGE₂, PGF_2α, and PGI₂ in the carotid arteries of SHR and WKY, both at baseline and in response to UTP. UTP administration also increased TXA₂ levels in WKY but not SHR. Overall, our results suggest that UTP-induced relaxation in carotid arteries is impaired in SHR perhaps due to impaired P2Y₂ receptor signaling, reductions in endothelial NO, and increases in the levels of COX-derived vasoconstrictor prostanoids.

     

Inhibition by cinnarizine of the responses of smooth muscle from spontaneously hypertensive and normotensive rats

A comparison was made of the inhibition by cinnarizine, a calcium antagonist, of the contractile responses of aortic, carotid, and iliac arterial strips and vasa deferentia from 15- to 17-week-old spontaneously hypertensive rats (SHR) and their normotensive counterparts, Wistar Kyoto (WKY) rats. KCl-induced responses of the aorta from both strains of rats and carotid arteries from WKY only were more sensitive to inhibition than were responses to norepinephrine. No significant differences were observed in the inhibition of tissue responses from the two strains of rats with the exception of the K+-induced responses of carotid arterial strips from SHR which were significantly less sensitive to inhibition when compared with carotid strips from WKY.     

Tolerance to acute ischemia in adult male and female spontaneously hypertensive rats

Clinical and experimental studies have repeatedly indicated that overloaded hearts have a higher vulnerability to ischemia/reperfusion injury. The aim of the present study was to answer the question whether the degree of tolerance to oxygen deprivation in hearts of spontaneously hypertensive rats (SHR) may be sex-dependent. For this purpose, adult SHR and their normotensive control Wistar Kyoto (WKY) rats were used. The isolated hearts were perfused according to Langendorff at constant pressure (proportionally adjusted to the blood pressure in vivo). Recovery of contractile parameters (left ventricular systolic, diastolic and developed pressure as well as the peak rate of developed pressure) was measured during reperfusion after 20 min of global no-flow ischemia in 5 min intervals. Mean arterial blood pressure was measured by direct puncture of carotid artery under light ether anesthesia in a separate group of animals. The degree of hypertension was comparable in both sexes of SHR. The recovery of contractile functions in SHR males and females was significantly lower than in WKY rats during the whole investigated period. There was no sex difference in the recovery of WKY animals; on the other hand, the recovery was significantly better in SHR females than in SHR males. It may be concluded that the hearts of female SHR are more resistant to ischemia/reperfusion injury as compared with male SHR. This fact could have important clinical implications for the treatment of cardiovascular disease in women.     

An electron microscopic study of the baroreceptors in the internal carotid artery of the spontaneously hypertensive rat

Summary The carotid baroreceptor field of normotensive (NTR) and spontaneously hypertensive rats (SHR) examined in this study extends for about 0.5 mm along the length and about 1/3 to 1/2 of the circumference of the wall of the internal carotid artery opposite to the carotid body. The vascular wall of the baroreceptor field exhibits neither a marked dilation to form a carotid sinus nor histological differences in the intima and media compared to other parts of the carotid artery. Histologically the adventitia of the baroreceptor field is characterized by (1) an increased thickness and by less well developed elastic lamellae in comparison with other parts of the arterial wall, (2) a profuse blood and nerve supply, and (3) a richness of cellular elements. The presumptive baroreceptor terminals are localized in the inner 1/3 of the adventitia and display local enlargements that appear to show preferential association with the cell body or processes of the Schwann cell but not with other components of the adventitia. The enlargements are characterized by an accumulation of very densely packed mitochondria, and glycogen particles. No morphological alterations were noted in the baroreceptor terminals of SHR except for proliferated basal laminae that invest the terminals. Our work does not support the concept that resetting of the baroreceptors is due to degeneration of the terminals.Supported by a grant from the Edward G. Schlieder Educational Foundation. Appreciation is extended to Mrs. Lia Pedroza for technical assistance and to Dr. Edward Frohlich of the Alton Ochsner Medical Foundation for supplying the animals used in this research     

The role of hypertension and hypercholesterolemia on aortic sudanophilia and carotid distensibility in rabbits

These experiments were designed to determine if male New Zealand white rabbits made mildly hypertensive (20-30 mm Hg increase) with bilateral renal artery clips developed more or less sudanophilic lesions than controls, and if the animals responded differently if hypercholesterolemia was produced soon (one week) or late (eight weeks) after the animals were operated on. Both groups received the diet of 2% cholesterol and 6% corn oil for six weeks. We also studied the distensibility of the carotid artery to determine if altered elastic behaviour played a role in lesion development. The experiments showed that the acute hypertensive group developed most lesions (by area), but that the lesions in all groups had the same shape and location. The carotid arteries from the chronic hypertensives were least distensible, and most of the changes appeared to be in the elastance of collagen. The blood pressure actually dropped slightly in the chronic shams after the diet was started. These experiments suggest that, at least, in the rabbit, the duration of the hypertension may determine how the arterial wall responds to hypercholesterolemia. They show that mild hypertension, like hypercholesterolemia, alters the rate at which lesions develop, rather than altering their distribution. The changes do not appear to be related to altered distensibility.     

Changes in the peptidergic innervation in the carotid body of rats chronically exposed to hypercapnic hypoxia: an effect of arterial CO2 tension

The abundance of neuropeptide Y (NPY)-, vasoactive intestinal polypeptide (VIP)-, substance P (SP)-, and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers in the carotid body was examined in chronically hypercapnic hypoxic rats (10% O2 and 6-7% CO2 for 3 months), and the distribution and abundance of these four peptidergic fibers were compared with those of previously reported hypocapnic- and isocapnic hypoxic carotid bodies to evaluate the effect of arterial CO2 tension. The vasculature in the carotid body of chronically hypercapnic hypoxic rats was found to be enlarged in comparison with that of normoxic control rats, but the rate of vascular enlargement was smaller than that in the previously reported hypocapnic- and isocapnic hypoxic carotid bodies. In the chronically hypercapnic hypoxic carotid body, the density per unit area of parenchymal NPY fibers was significantly increased, and that of VIP fibers was unchanged, although the density of NPY and VIP fibers in the previously reportetd chronically hypocapnic and isocapnic hypoxic carotid bodies was opposite to that in hypercapnic hypoxia as observed in this study. The density of SP and CGRP fibers was decreased. These results along with previous reports suggest that different levels of arterial CO2 tension change the peptidergic innervation in the carotid body during chronically hypoxic exposure, and altered peptidergic innervation of the chronically hypercapnic hypoxic carotid body is one feature of hypoxic adaptation.     

Morphological characteristics and peptidergic innervation in the carotid body of spontaneously hypertensive rats

We examined morphological characteristics of the carotid body of spontaneously hypertensive rats (SHR), those of age-matched normotensive Wistar rats (NWR), and age-matched genetically comparable Wistar Kyoto rats (WKY). We examined the distribution and abundance of four different regulatory neuropeptides: substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY) in the carotid bodies of these three strains of rats. The carotid bodies of SHR were larger than those of NWR and WKY. The values of the long axis of the carotid bodies of SHR were significantly larger (1.3 times) than those of NWR and WKY. In the carotid bodies of SHR, the percentage of relatively large vessels was similar to that of the carotid bodies of WKY, although the carotid bodies themselves were significantly larger than in WKY. The density of VIP varicose fibers in the carotid bodies of SHR was lower than in the carotid bodies of WKY, although the density of SP, CGRP and NPY fibers was similar to that of the carotid bodies of NWR and WKY. These findings suggested that VIP was unrelated to enlargement of the carotid body of SHR, but it might modify the sensitivity of chemoreceptors in the carotid body.     

Involvement of angiotensin-mediated renal vasoconstriction in renal hypertension

Systematic arterial blood pressure and renal vascular resistance were found to be significantly greater in morphine, chloraloseurethane anesthetized renal hypertensive dogs than in similarly treated normotensive dogs. A lower dose infusion of the angiotensin antagonist 1-sar-8-ala-angiotensin II in the concentration of 20 mμg/ml into the renal artery decreased renal vascular resistance in the hypertensive, but not in the normotensive animals. The subsequent administration of a higher dose (approximately 50 mμg/ml) of 1-sar-8-ala-angiotensin II produced a decrease in renal vascular resistance in the normotensives, but a still greater effect in the hypertensives. Systemic blood pressure was significantly decreased with the higher dose in the hypertensive, but not in the normotensive group. The results indicate the participation of angiotensin-mediated renal vasoconstriction in the increased renal resistance in the hypertensive animals.