Functional and structural behavior of the cardiovascular system of normotonic and spontaneously hypertensive rats following chemical sympathectomy and angiotensin administration

The non-cleared influences of the sympathetic nervous system [sN] on structural reactions of SHR and on the direct cardiac effects of AII and the structural vascular behavior were investigated. In 67 spontaneously hypertensive rats (Okamoto-Aoki) and 55 normotonic Wistar rats (NR) the blood pressure behaviour, the structural vascular and organ reactions and the noradrenaline (NA) content of the myocardium were examined with an intact sympathetic nervous system as well as after its almost complete elimination by chemical sympathectomy with 6-hydroxy-dopamine (6-OH-DA). Moreover, the functional and structural responsiveness of the arterial vessels of sympathectomized animals to angiotensin II administrations was investigated. 6-OH-DA in the dosage applied, induces during its time of action in NR a smaller, in SHR a larger decrease of blood pressure and, presumably induced by intense NA-depletion of the myocardium, myocardial alterations. Despite extensive AII-induced alterations of the already early hypertrophically-hyperplastically changed vascular wall, the structural and functional responsiveness of the arterial vascular system was maintained even after sympathectomy, and the sensitivity of the SHR to AII remained. For maintaining hypertension, the cooperation of structural and functional influences is necessary, as is indicated by the reduction of blood pressure in sympathectomized SHR and its regular return to the daily initial values of normotonic animals under additional AII administration. Besides the vascular alterations contributing to the exacerbation of the hypertension, here the sNS is of essential importance. For obtaining a total pressure effect of AII the sNS obviously has not necessarily to be intact, though its activity state can influence the responsiveness of the arterial vascular system to AII. The reduction of the sympathicotonus by sympathectomy seems to have a protective effect on the development of AII-induced structural vascular alterations; in contrast to the myocardium in SHR, in which it induces an exacerbation and an increase in the AII-induced myocardial alteration. These findings obtained from rats are supposed to be important also for the essential hypertension in man. By maintaining the functional responsiveness of the arterial vascular system, antihypertensives which react with the different parts of the sNS cab become effective while structural alterations of the vascular wall can be influenced, too. The possibility of the simultaneous development of myocardial alterations should be taken into special consideration.     

Portal and arterial free and conjugated noradrenaline in two models of portal hypertension in rats

Free and conjugated noradrenaline concentrations were measured in portal-venous and arterial plasma from sham-operated rats or rats with portal hypertension. Two types of portal hypertension in rats were evaluated: in portal vein stenosed rats, the liver was normal, whereas cirrhosis developed in bile duct ligated rats. In cirrhotic rats, arterial free noradrenaline level was higher than in both sham-operated and portal-stenosed rats, this indicating that enhanced sympathetic nervous activity depends on the development of cirrhosis. In all groups of rats, portal venous plasma free noradrenaline was higher than arterial plasma level, indicating a production of noradrenaline by splanchnic organs. Arterial noradrenaline level may be mainly dependent on this splanchnic production in case of portal hypertension. Sulfoconjugated and glucuronoconjugated noradrenaline plasma levels were similar in the three groups of rats. This shows that alteration in conjugation is not likely to be a major factor in the abnormal circulating levels of free noradrenaline observed in cirrhotic rats.     

The neurogenic constrictor response of isolated rat saphenous artery is reduced after 2-week tail suspension

Under real or simulated microgravity conditions the control of arterial vascular tone is greatly disturbed. The low arterial vessel reactivity to sympathetic influences may be the cause of an increase in flow in hind limb skeletal muscles in tail-suspended (TS) rats. Our previous experiments with constant pressure perfusion of rat hind limb demonstrated the reduced vasoconstrictor responses to sympathetic nerve stimulation in TS rats. Responses to exogenous noradrenaline depended on the perfusion conditions. It is known that the vessels of various branching orders noticeably differ in nerve density and in sensitivity to vasoconstrictor agonists. So under neurogenic or exogenous noradrenaline influences the vascular resistance may be increased at different levels of vascular bed, thus making the data analysis seriously complicated. This uncertainty may be overcome by investigation of a single vessel isolated from hind limb vascular bed. The saphenous artery, a resistance artery with dense innervation, is a very convenient object for this purpose. Thus, this study was aimed at comparing the effects of 2-week tail suspension upon the constrictor responses of isolated saphenous artery to neurogenic and exogenous noradrenaline stimuli in rats.     

Noradrenaline synthesis during the first week of life and development of inherited stress-induced arterial hypertension in rats

Increasing of the noradrenaline synthesis with daily i.p. administration of synthetic noradrenaline precursor DL-Threo on the 21-25th day of life of the rats with inherited stress-induced arterial hypertension (ISIAH) resulted in a drop of basal and stress-induced blood pressure in adult animals with no changes in response of the hypothalamic-pituitary-adrenocortical system (HPAS). Reduction of the noradrenaline synthesis with daily i.p. administration of dopamine-hydroxylase inhibitor FLA-57 in 21-25th day old Wistar rats induced no arterial hypertension in adults but decreased their adrenocortical response to emotional stress. Noradrenaline deficit in the brain structures on the 4th week of life in rats seems to be associated with arterial hypertension only in presence of genetic defect determining this pathology. Changes in adult HPAS function due to shortage of noradrenaline in the brain in the end of the 1st month of life do not depend on hypertension.     

Blood pressure responsiveness to sympathetic agonists in anaesthetised diabetic rats

Chronic diabetes alters sympathetic modulation of the cardiovascular system. In the present work, we examined if the cardiovascular system also demonstrates an impaired responsiveness to sympathetic control. The effects of streptozotocin-induced diabetes on pressure responses to noradrenaline or isoproterenol infusion of diabetic rats in vivo are studied. Systolic and diastolic pressures were recorded through a cannula implanted in the right carotid artery. Increasing doses of noradrenaline or isoproterenol were infused through a catheter implanted in the left jugular vein. The dose-response curves for the effects of noradrenaline on blood pressure were altered in streptozotozin-induced diabetic rats. Noradrenaline induced a statistically significant higher increase of both systolic and diastolic pressure in control than in diabetic rats. The maximum depressor response of systolic pressure to isoproterenol was lower in diabetic than in control animals. Diabetes fully abolishes the effect of beta-adrenoceptor stimulation on diastolic blood pressure. The present results demonstrate that streptozotocin-induced diabetes reduces systolic and diastolic arterial pressure, and diminishes the arterial pressure reactivity to sympathetic stimulation.     

The relationship between altered blood vessel structure, hypertension, and the sympathetic nervous system

The relationship between sympathetic innervation and arterial medial development has been examined in normotensive, hypertensive, and diabetic rats. Using the jejunal artery as a model, the number of nerve fibres innervating the artery as determined from fluorescent preparations, and the medial thickness and lumen diameter as measured from resin embedded specimens were correlated from animals prepared in various ways. The rats used were normal Sprague-Dawley (SD), SD with induced hypertension, SD with diabetes induced with streptozotocin, SD sympathectomized with 6-hydroxydopamine, spontaneously hypertensive rats (SHR), SHR treated with capsaicin to prevent hypertension development, Wistar Kyoto rats (WKY), and WKY treated with capsaicin. Examination of the jejunal arteries from these rats at 12 weeks of age following normal development, or 8 weeks of hypertension development, or 8 and 12 weeks of diabetes, showed that increased innervation occurred in the SHR under all conditions, and in the diabetic rats after 8 weeks of diabetes. Medial hypertrophy occurred in the SHR and in the SD hypertensive only. It is concluded that the special relationship which exists between the sympathetic innervation and arterial media in the SHR does not occur during hypertension development in the SD rat, nor is it necessary for normal medial development in the SD rat. The sympathetic innervation does appear to have a trophic influence on vascular smooth muscle of diabetic rats, at least in the early stages of the disease.     

Somatosympathetic reflex in rats with various models of arterial hypertension

Spontaneous and reflex activities of sympathetic nerve were compared in animals with arterial hypertension of different aetiology. Reflex discharges elicited by single-shock stimulation of afferent fibres were recorded. In acute experiences on anaesthetized rats with renovascular and spontaneous (SHR) model of arterial hypertension, electric basal and evoked activity (somatosympathetic reflex) in cervical sympathetic trunk were recorded. It is shown, that the spontaneous electric activity in sympathetic nerve of hypertensive rats is larger than spontaneous activity of normotensive control animals. The somatosympathetic reflex in hypertensive rats differs from that of control animals. In rats with renovascular model of hypertension, the reflex magnitude is reduced, and in the SHR the reflex is increased. Time characteristics of the reflex in hypertensive rats differed among them. It is suggested that functional activities of the brain stem in rats with different arterial hypertension model are unequal.     

Neurohumoral mechanisms of sodium-dependent hypertension

The contribution of neurohumoral factors to arterial pressure has been studied in several models of sodium-dependent hypertension including the deoxycorticosterone-saline, Dahl salt-sensitive rats, and reduced renal mass-saline. Observations from these animals have largely pointed to the sympathetic nervous system and arginine vasopressin (AVP) as the critical factors responsible for mediating the increased arterial pressure. Our work has indicated that the one-kidney, figure-8 renal wrap model of experimental hypertension is also sodium dependent. In these rats, prior sodium depletion prevented the development of hypertension whereas high sodium intake exacerbated the increase in arterial pressure. An activation of the sympathetic nervous system and increased AVP activity appeared to be responsible for the hypertension in rats maintained on normal and high sodium intake. Stimulation of the AVP and sympathetic nervous systems in sodium-dependent hypertension may be associated with a suppression of cardiovascular gamma-aminobutyric acid (GABA)-ergic function in the central nervous system. The inhibitory neurotransmitter, GABA, and an inhibitor of GABA uptake, nipecotic acid, lowered arterial pressure in a sodium-stimulated model of hypertension.     

Elevated plasma dopamine beta hydroxylase activity in rats with neurogenic hypertension.

Increased plasma dopamine beta hydroxylase, DBH, activity has been cited as evidence of increased sympathetic function in essential hypertension. Here-to-fore, experimental hypertension in animals has been associated with normal plasma DBH activity. This study shows that rats with neurogenic hypertension, induced by sinoaortic denervation, SAD, have elevated DBH activity; the mean increase in plasma DBH measured 3 days to 11 weeks after operation was 74% higher in the SAD group than in the sham-operated, control group. DBH activity showed a positive correlation with arterial pressure. Mesentery DBH activity was inversely related to plasma enzyme activity in SAD rats, indicating sympathetic nerve terminals in mesentery are a source of plasma DBH. We conclude that plasma DBH activity is an index of increased sympathetic function since it is consistently elevated in rats with neurogenic hypertension resulting from sustained central activation of the sympathetic nervous system.     

Comparison of vascular function and structure of iliac artery in spontaneously hypertensive and hereditary hypertriglyceridemic rats

The aim of this study was to compare the vascular reactivity and morphology of iliac artery (IA) in adult spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic (hHTG) rats. The isolated rings of iliac artery (IA) from Wistar rats (controls), SHR and hHTG rats were used for measurement of relaxant responses to acetylcholine (ACh) and contractile responses to noradrenaline (NA). Morphological changes of IA were measured using light microscopy. Systolic blood pressure (BP) measured by plethysmographic method was increased in SHR approximately by 88 % and in hHTG rats by 44 % compared to controls. BP increase was accompanied by cardiac hypertrophy. In both SHR and hHTG groups (experimental groups) reduced relaxation to ACh and enhanced maximal contraction and sensitivity to adrenergic stimuli were observed. The sensitivity to NA in SHR was higher also in comparison with hHTG. Geometry of IA in both experimental groups revealed increased wall thickness and wall cross-sectional area, in SHR even in comparison with hHTG. Inner diameter was decreased in both experimental groups. Thus, independently of etiology, hypertension in both models was connected with impaired endothelial function accompanied by structural alterations of IA. A degree of BP elevation was associated with arterial wall hypertrophy and increased contractile sensitivity.     

Disposition of catecholamines in cardiovascular tissues of aorta coarcted hypertensive rats

Aorta-coarcted hypertensive rats and sham-operated normotensive rats were compared in order to assess the contribution of sympathetic nervous system activity to the elevated blood pressure in these rats at an early (6 days) and chronic (42 days) stage of hypertension. Norepinephrine (NE), epinephrine (E) and dopamine (DA) levels were quantitated in plasma, heart and vascular tissues (aorta, inferior vena cava, mesenteric artery and vein) using a radioenzymatic procedure. Body weight was significantly reduced and mean arterial blood pressure (MABP) significantly increased in the coarcted rats at both stages of hypertension. Plasma catecholamines did not differ at either stage of hypertension. The NE content of the heart and mesenteric artery was significantly decreased in the coarcted rats at both stages of hypertension but unchanged in the other vessels studied. E and DA levels in the heart and all vasculature analyzed remained unaltered at both stages of hypertension. The present results suggest that neither E nor DA makes a major contribution to the development and maintenance of hypertension in the aorta-coarcted rat. The observation of the reduced cardiac NE concentration in the coarcted rats together with literature reports of similar observations in other animal models of hypertension suggests that myocardial NE depletion is a common feature of the hypertension and not dependent on the methodology used to produce that hypertension.     

Development of prejunctional alpha 2 adrenergic receptor mediated feedback control of the pressor response to sympathetic nerve stimulation in hypertensive and normotensive rats

Development of prejunctional alpha 2 adrenergic receptor inhibition of pressor responses to sympathetic nerve stimulation in the spontaneously hypertensive Wistar-Kyoto rat was compared with genetically similar (Wistar-Kyoto) and different (Sprague-Dawley) normotensive rats. The sympathetic outflow was stimulated at frequencies of 1 to 20 Hz in pithed rats at 10,14,20 and 60 days of age. The antagonist, rauwolscine was given to block alpha 2 mediated feedback inhibition of noradrenaline release and the incidence of enhanced pressor responses determined. In Sprague-Dawley but not in spontaneously hypertensive or Wistar-Kyoto rats the changes in the incidence of enhanced responses parallel development of indices of sympathetic activity in other studies of the rat. Thus at 10 days of age (when activity is low), the incidence of rauwolscine-enhanced responses was 45%; at 14 days, (coinciding with onset of baroreflex control), incidence fell to 14%; in the 3rd postnatal week (when there is sympathetic hyperactivity), incidence increased to greater than 90%; finally, incidence, like activity declined in adults. In Wistar-Kyoto rats, the incidence of enhanced responses was like the other strains at 10 days but then decreased during development. In spontaneously hypertensive rats, enhanced responses were also less evident during week 3 and greatly diminished in adults. We conclude that in the spontaneously hypertensive and normotensive variants of Wistar-Kyoto strain rats the limit of alpha 2 adrenergic receptor feedback control of noradrenaline release is reached prematurely and is attenuated relative to the level of neuronal activity. In keeping with this hypothesis, the basal rate of noradrenaline utilization (measured in kidney) was higher at 20 days in Wistar-Kyoto than in Sprague-Dawley, but Sprague-Dawley showed greater enhancement of noradrenaline level and utilization after rauwolscine. Thus, the limitation to feedback control may be in development of prejunctional alpha 2 adrenergic receptors and/or their coupling to transmitter synthesis and release. Attenuated prejunctional alpha 2 adrenergic receptor inhibition is not linked obligatorily to development of hypertension in the spontaneously hypertensive Wistar-Kyoto rat.     

Intracellular electrolytes and selected biochemical parameters in patients with borderline arterial hypertension and positive family history of hypertension

The studies involved 22 patients with borderline hypertension and familial history of the arterial blood hypertension (mean age 24.6 years) and 9 patients without familial history of hypertension (mean age 22.2 years). Control group included 10 healthy volunteers (mean age 27.5 years). Erythrocyte Na+ and K+ levels, daily secretion of noradrenaline (NA), adrenaline (A) and dopamine (DA), prostacyclin metabolite 6-keto-PGF1 alpha, beta-thromboglobulin levels (beta-TG), triglyceride cholesterol, and HDL-cholesterol were determined in all examined subjects. Friedewald's equation was used to calculate LDL-cholesterol. Moreover, LCAT activity was measured. An increase in erythrocyte Na+, increased sympathetic activity, excessive platelet activity and decreased 6-keto-PGF1 alpha levels were found in the group of hypertensive patients with familial history of the arterial blood hypertension. HDL-cholesterol was significantly lower in these patients than in the control group. Atherogenic index (cholesterol/HDL-cholesterol ratio) was the highest in the hypertensive patients with familial history of the arterial blood hypertension. The difference was insignificant, however. Patients with the borderline hypertension and familial predisposition to this disease differ from the hypertensive patients without familial history of the arterial hypertension in humoral profile suggesting a contribution of the genetic factors to the development of the arterial blood hypertension.     

Characteristics of the central adrenergic mechanisms regulating arterial pressure in rats with hereditary arterial hypertension

Adrenergic mechanisms of blood pressure regulation were studied in a newly developed strain of rats with inherited stress-provoked arterial hypertension, spontaneously hypertensive rats (SHR) and normotensive Wistar rats. A number of adrenergic agonists (noradrenaline, adrenaline, phenylephrine, clonidine, naphazoline, isoproterenol, dobutamine, Alupent) were infused into the lateral brain ventricle under nembutal anesthesia and the reaction of the peripheral blood pressure was measured. It was shown that blood pressure reactions were similar in rats with inherited stress-provoked arterial hypertension and in SHR but significantly differed from those of normotensive Wistar rats. The data obtained suggest that the development of inherited hypertension was accompanied by changes in alpha 1 to alpha 2 adrenoreceptor ratio in pressor and depressor brain regions. A decrease in the depressor effect after stimulation of beta 1 and beta 2 receptors has been also observed.     

The influence of adrenal vein occlusion on whole-kidney hemodynamics in the spontaneously hypertensive rats.

It has been shown that occlusion of the adrenal vein causes an increase in renal vascular resistance in the ipsilateral kidney in Wistar Kyoto rats (WKY). The most probable mechanism of this phenomenon is the direct inflow of adrenal catecholamines to the kidney by the adrenal renal portal circulation (ARPC). As the number of vessels of the ARPC is bigger and the tonic sympathetic activity is higher in spontaneously hypertensive rats (SHR), the aim of the current study was to compare the effect of adrenal vein occlusion on renal vascular resistance between SHR and WKY. Mean arterial blood pressure and renal blood flow (RBF) were measured and renal vascular resistance (RVR) was calculated before and after closure of the adrenal vein. Occlusion of the adrenal vein significantly reduced RBF and increased RVR in both strains of rats. The rise of the RVR was significantly higher in SHR than in WKY. Therefore we assume that the hemodynamic responsiveness of the kidney due to increase in blood flow through ARPC is greater in SHR and may contribute to the development of arterial hypertension in this strain of rat.     

Pharmacologic tools for assessment of adrenergic nerve activity in human hypertension

Measurement of plasma norepinephrine concentration (plasma NE) has not resolved the role of the adrenergic system in the pathogenesis or maintenance of hypertension. A better picture is gained if plasma NE measurement is combined with the assessment of sympathetic drive and reactivity by the use of specific sympathetic antagonists and agonists. In mild hypertension, the decrease in heart rate and cardiac output after beta-adrenoceptor blockade correlates with the level of plasma NE. In established hypertension, the fall in blood pressure or peripheral vascular resistance after alpha-adrenoceptor blockade is related to plasma NE levels. Similarly, changes in forearm vascular resistance induced by local alpha-adrenoceptor blockage correlates with plasma NE in hypertension. Cardiovascular responsiveness to adrenergic agonists is altered in hypertension. The response to cardiac beta-receptor stimulation decreases during the course of the disease. To the contrary, vascular responses to exogenous NE increase with the progression of the hypertensive disease. Results with total autonomic blockade indicate that in some patients with early or borderline hypertension, increased sympathetic tone is involved in the maintenance of blood pressure. In established hypertension, there is no definite indication of increased sympathetic tone, but the sympathetic nervous system may nevertheless play a prominent role in the maintenance of the blood pressure. A vascular hyperreactivity to adrenergic stimulation is characteristically associated with established hypertension. The nature of this hyperreactivity has not been fully elucidated, but it is very likely that it reflects structural vascular changes in hypertension.     

Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide

Oxidative stress because of an excessive production of superoxide anion (O2*-) is associated with hypertension. The present study evaluated the hypothesis that in the rostral ventrolateral medulla (RVLM), where the premotor neurons for the maintenance of vascular vasomotor activity are located, increased O2*- contributes to hypertension in spontaneously hypertensive rats (SHR) by modulating the cardiovascular depressive actions of nitric oxide (NO). Compared with normotensive Wistar-Kyoto (WKY) rats, SHR manifested significantly increased basal O2*- production, along with reduced manganese superoxide dismutase (MnSOD) expression and activity, in the RVLM. The magnitude of hypotension, bradycardia, or suppression of sympathetic neurogenic vasomotor tone elicited by microinjection bilaterally into the RVLM of a membrane-permeable SOD mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (MnTBAP), was also significantly larger in SHR. Transfection bilaterally into the RVLM of adenoviral vectors encoding endothelial nitric oxide synthase resulted in suppression of arterial pressure, heart rate, and sympathetic neurogenic vasomotor tone in both WKY rats and SHR. Microinjection of MnTBAP into the RVLM of SHR further normalized those cardiovascular parameters to the levels of WKY rats. We conclude that an elevated level of O2*- in the RVLM is associated with hypertension in SHR. More importantly, this elevated O2*- may contribute to hypertension by reducing the NO-promoted cardiovascular depression.     

Genetic aspects of arterial hypertension: the role of Y chromosome and mitochondrial DNA

A study on hybrids from reciprocal crossing of the SHR-SP and the WKY has shown that Y-chromosome and mitochondrial DNA the affect development of the spontaneous hypertension. The Y-chromosome takes part in disorders of baroreceptive sensitivity in phenylnephrine assay associated with hypertension. Although our findings suggest that structural remodelling of peripheral vascular resistance and an increase in noradrenaline-dependent vasocostriction is genetically determined in hypertensive rats, we could not corroborate the role of the Y-chromosome and mitochondrial DNA in the process. A difference was shown between male and female SHR-SP in the level of arterial pressure and in development of the vascular structure changes.     

Adrenergic and dopaminergic regulation of circulating beta-endorphin-like immunoreactivity in hypertension.

The central alpha-2-adrenergic receptor agonist, clonidine (300 micrograms daily) significantly increased the plasma beta-endorphin-like immunoreactivity (beta ELI) in 12 patients with mild to moderate essential hypertension in a randomized, crossover study. A significant linear correlation between the increase in plasma beta ELI and the decrease in blood pressure (both systolic and diastolic) was found after clonidine administration. The role of the reduced central sympathetic tone, induced by alpha-2-adrenoceptor stimulation, in the elevation of circulating beta ELI can be suggested. The plasma beta ELI increased also significantly after the dopaminergic D-2 receptor agonist, bromocryptine treatment, (5 mg, daily) in 13 patients with borderline and mild essential hypertension in a randomized, crossover study. A significant drop in circulating noradrenaline and in arterial blood pressure and a significant linear correlation between the changes of plasma noradrenaline level and blood pressure was found after bromocryptine administration. There was no correlation between the rise in plasma beta ELI and the decrease in blood pressure after bromocryptine. The importance of the central sympathetic activity and not only a direct pituitary dopaminergic agonist effect on the beta-endorphin secretion can be stressed in the effect of bromocryptine on the immunoreactive beta-endorphin level.     

Insulin-exacerbated hypertension in captopril-treated spontaneously hypertensive rats: role of sympathoexcitation

Insulin excess exacerbates hypertension in spontaneously hypertensive rats (SHR). This study examined the relative contribution of the renin-angiotensin system and the sympathetic nervous system in this phenomenon. In SHR, daily subcutaneous injections of insulin were initiated either before short-term angiotensin-converting enzyme inhibition with captopril or after lifetime captopril treatment. Insulin treatment resulted in significant increases in mean arterial pressure and heart rate and captopril treatment lowered arterial pressure, but captopril did not lower arterial pressure more in the insulin-treated compared with control rats. To test the contribution of the sympathetic nervous system to this form of hypertension, each rat was intravenously infused with either a ganglionic blocker (i.e., hexamethonium) or a centrally acting alpha2-adrenergic receptor agonist (i.e., clonidine). Administration of either agent largely eliminated the differences in mean arterial pressure and heart rate between the insulin-treated and saline-treated SHR, irrespective of captopril treatment. These data indicate that in SHR, the ability of insulin to increase blood pressure is closely related to sympathoexcitation, which is unresponsive to blockade of angiotensin-converting enzyme.