INTERACTIONS BETWEEN ANGIOTENSIN II AND THE SYMPATHETIC NERVOUS SYSTEM IN THE THE LONG-TERM CONTROL OF ARTERIAL PRESSURE

1. The role of the renin-angiotensin system in long-term control of sympathetic activity and arterial pressure is reviewed. 2. There is evidence that favours a necessary role for the sympathetic nervous system in long-term arterial pressure regulation. First, appropriate changes in sympathetic activity appear to be produced in response to chronic changes in blood volume or blood pressure. Second, prevention of the normal homeostatic decrease in sympathetic activity in response to an increase in sodium intake produces hypertension. 3. Long-term changes in sympathetic activity cannot be mediated by the baroreceptor reflex, because it adapts to sustained changes in pressure. Therefore, an hypothesis is presented that evokes a key role for angiotensin II (AngII) in determining the chronic level of sympathetic activity. The key feature of this model is that the role of AngII is non-adaptive: chronic changes in extracellular fluid volume produce sustained reciprocal changes in AngII, and long-term increases in AngII produce sustained increases in sympathetic activity. 4. Evidence is reviewed that suggests that a lack of the normal suppression in AngII and/or sympathetic activity in response to an increase in sodium intake produces salt-sensitive hypertension.     

THE SYMPATHETIC NERVOUS SYSTEM AND LONG-TERM REGULATION OF ARTERIAL PRESSURE: WHAT ARE THE CRITICAL QUESTIONS?

1. The role of the sympathetic nervous system in long-term control of arterial pressure remains unclear despite decades of intense research. 2. Previous studies have shown that denervation of arterial baroreceptors does not chronically increase arterial pressure. As baroreceptors are thought to provide the primary ‘error signal’ to the autonomic nervous system, this has been interpreted as evidence against neural control of arterial pressure over long periods of time. 3. The possibility that other ‘error signals’ are important in the long-term control of sympathetic activity (and arterial pressure) is introduced. 4. The following ‘Critical Questions’ are presented for subsequent discussion: (i) is the sympathetic nervous system a ‘major player’ in the long-term control of arterial pressure; (ii) why doesn't arterial pressure remain at hypertensive levels after arterial baroreceptor denervation; and (iii) which ‘error signals’ are most important in the long-term control of sympathetic outflow?     

CONTRIBUTION OF THE SYMPATHETIC NERVOUS SYSTEM TO THE CENTRALLY-INDUCED PRESSOR ACTION OF ANGIOTENSIN II IN RATS

Angiotensin II (ANG II) may increase blood pressure by central nervous system mechanisms. The involvement of the sympathetic nervous system in the centrally-induced pressor effect of ANG II in the rat was investigated. 2 Plasma noradrenaline concentrations, measured as an index of sympathetic nervous system activity, increased after intracerebroventricular (i.e.v.) injection of pressor doses of ANG II, both in normotensive and in spontaneously hypertensive rats. 3 To assess the functional significance of this, the sympathetic nervous system was inhibited by phentolamine, reserpine, and guanethidine. In phentolamine-infused rats, low doses of i.c.v. ANG II elicited a blood pressure decrease, but at maximal pressor doses, no difference between phentolamine-treated and control rats was observed. In reserpinized rats, the central pressor effect of ANG II was greater than in controls. Guanethidine pretreatment did not affect the blood pressure response to i.c.v. injected ANG II. 4 It is concluded that the central pressor effects o f ANG II are accompanied by a stimulation of the sympathetic nervous system. In the rat, this stimulation may be functionally important for the initial phase of the central pressor action. This could not be established for the maximal pressor responses.     

AUTONOMIC NERVOUS SYSTEM AS A TARGET FOR CARDIOVASCULAR DRUGS

1. Drugs acting within the autonomic nervous system (ANS) are of particular interest when autonomic abnormalities are implicated in the development and maintenance of various cardiovascular pathologies. For example, it has been documented that in the early stages of hypertensive disease (i.e. hyperkinetic borderline hypertension) a sympathetic hyperactivity associated with a decreased parasympathetic activity results in increased cardiac output and heart rate.
2. Several classes of drugs acting within the central, as well as the peripheral ANS, are very efficient in treating hypertensive disease. One of these classes of drugs, the second generation of centrally acting drugs, has proved beneficial in this respect because, in addition to their therapeutic efficacy, these drugs are well tolerated.
3. The central nervous system may also be the target for drugs with the potential to treat other cardiovascular diseases. Some recent experimental and clinical data supporting such new perspectives concerning idiopathic dysrhythmias, angina pectoris and congestive heart failure will be summarized.     

ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE ONSET OF HYPERTENSION IN THE RAT: THE EFFECT OF 6-OH-DOPAMINE

1. The effect of chemical sympathectomy with 6-OH-dopamine (6-OHDA) on the onset of adrenocorticotrophin (ACTH)-induced hypertension was examined in Sprague-Dawley rats (n = 23). 2. 6-OHDA injection produced a fall in systolic blood pressure (SBP) from 100 +/- 5 mmHg control to 74 +/- 4 mmHg post-6-OHDA Treatment Day 1 (P less than 0.001), but did not alter food or water intake, urine volume or electrolyte excretion. 3. Compared with sham injection, ACTH-treated rats showed an increase in blood pressure (sham: 98 +/- 7 mmHg; ACTH: 123 +/- 9 mmHg on Treatment Day 10; P less than 0.01), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise on ACTH was greater in 6-OHDA-treated rats than in intact control rats. Metabolic changes were similar. 5. Chemical sympathectomy with 6-OHDA did not delay or block the onset of ACTH hypertension in the rat.     

TIME COURSE OF CHANGES IN BARORECEPTOR REFLEX CONTROL OF HEART RATE IN CONSCIOUS SHR AND WKY: CONTRIBUTION OF THE CARDIAC VAGUS AND SYMPATHETIC NERVES

1. The aim of this study was to assess the vagal and sympathetic nerve contribution to the relationship between mean arterial pressure (MAP) and heart rate (HR) at 6, 9, 14 and 20 weeks of age in conscious Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) with methoxamine- and nitroprusside-induced steady-state changes in blood pressure. 2. MAP increased with age in both strains but was 17-23% higher in SHR. 3. By contrast baroreflex parameters (HR range: difference between upper and lower HR plateaus, and gain: average slope between inflection points of the logistic MAP-HR relationship) decreased with age in SHR but increased in WKY. 4. After methylatropine, no differences in the cardiac sympathetic baroreflex range or gain parameters were observed between strains or ages. 5. It was concluded that older SHR have normal sympathetic but reduced vagal capacity to control HR in response to changes in MAP, but that this deficit was not dependent on the absolute level of blood pressure. 6. Because the differences were confined to one effector, SHR may have different central rather than arterial baroreceptor afferent mechanisms.     

A NEW MODEL FOR THE GENERATION OF SYMPATHETIC NERVE ACTIVITY

1. Sympathetic discharges from multifibre nerve recordings vary in their frequency of occurrence which displays both slow and fast rhythms and in their amplitude which reflects the number of activated fibres. It has been shown that the frequency of occurrence of these rhythms varies according to baroreceptor activity (via blood pressure and heart rate) while the number of activated fibres is independently affected by chemoreceptor activity. 2. A new model is proposed for the generation of sympathetic nerve activity by the central nervous system to account for these results. The upper layer of the model comprises two oscillators, a fast and a slow cycle frequency oscillator, with the balance and occurrence maintained by afferent inputs such as the baroreceptors. 3. It is hypothesized that two central oscillators impinge on a lower layer of the model influencing the number of activated fibres within each postganglionic sympathetic burst. This is independent of the frequency control and affected by separate afferent inputs such a chemoreceptors.     

Area postrema and sympathetic nervous system effects of vasopressin and angiotensin II

1. Precise control over the cardiovascular system requires the integration of both neural and humoral signals related to blood volume and blood pressure. Humoral signals interact with neural systems, modulating their control over the efferent mechanisms that ultimately determine the level of pressure and volume. 2. Peptide hormones such as angiotensin (Ang)II and arginine vasopressin (AVP) act through circumventricular organs (CVO) to influence cardiovascular regulation. 3. The area postrema (AP), a CVO in the brainstem, mediates at least some of the central actions of these peptides. Vasopressin appears to act in the AP to cause sympathoinhibition and a shift in baroreflex control of the sympathetic nervous system (SNS) to lower pressures. These effects of AVP and the AP appear to be mediated by alpha2-adrenoceptor and glutamatergic mechanisms in the nucleus tractus solitarius. 4. In contrast to AVP AngII has effects in the AP to blunt baroreflex control of heart rate and cause sympathoexcitation. The effects of chronic AngII to increase activity of the SNS may be due to AP-dependent activation of neurons in the rostral ventrolateral medulla.     

EFFERENT MECHANISMS RESPONSIBLE FOR THE BRADYCARDIA PRODUCED BY LESIONS COINCIDING WITH THE A1 GROUP OF CENTRAL CATECHOLAMINE NEURONS IN THE CONSCIOUS RABBIT

1. The effector mechanisms responsible for the bradycardia evoked by bilateral lesions of the brainstem coinciding with the A1 catecholamine cells were analyzed in four groups of rabbits. Sham or lesion operations were carried out in animals with intact cardiac effectors, with cardiac sympathetic block induced by propranolol, with cardiac vagal block induced by methylscopolamine and with total cardiac autonomic block induced by the use of both drugs together. 2. Lesions produced a transient increase in blood pressure of 25 (s.e.m. =4) mmHg and a transient bradycardia, or increase in heart period of 141 (s.e.m. =18) ms. The bradycardia had both baroreflex-independent and baroreflex-dependent components as determined from analysis of stimulus response curves relating heart period to mean arterial pressure. 3. The ‘baroindependent’ component of the bradycardia, measured as a lengthening in heart period, ranged from 35–49 ms in the four groups of animals and was unaffected by administration of propranolol alone, methylscopolamine alone, or of both together. These findings suggest that the baroindependent slowing of the heart is not mediated through changes in activity of either the cardiac sympathetic nerves or of the vagal fibres innervating the heart. 4. The ‘baroreceptor’ component of the bradycardia reflects that portion of the decrease in heart rate resulting directly from the increase in blood pressure. This component was found to account for a lengthening in the heart period of 81 (s.e.m. =23) ms in animals with intact effector mechanisms: it was virtually abolished by methylscopolamine (0 ms, s.e.m. =13) but not significantly affected by propranolol (54 ms, s.e.m. =25), indicating that this barodependent component is predominantly mediated through the vagus.     

THE NATURE OF THE PRESSOR RESPONSE TO CAROTID ARTERY OCCLUSION IN THE HEXAMETHONIUM-TREATED RAT

1. The blood pressure monitored from the cannulated right carotid artery and heart rate responses to occlusion of the intact left carotid artery were investigated in rats. 2. Hexamethonium abolished the response to ganglion stimulants but not that to carotid occlusion, although the time course and nature of the response were altered. 3. The pressor response to carotid occlusion in the presence of hexamethonium was not abolished by carotid sinus denervation, vagal section, tubocurarine, atropine, ethyl alcohol or an angiotensin II antagonist, but it was abolished by high doses of phenoxybenzamine. In six out of eight experiments the response was not abolished by cervical cord section. 4. It was concluded that the pressor response to carotid occlusion in the presence of hexamethonium in the rat involves an adrenergic mechanism which is at least in part independent of the autonomic ganglia, and which is mediated by an agent liberated from the brain, possibly under conditions of cerebral ischaemia.     

ROLE OF THE AUTONOMIC NERVOUS SYSTEM IN THE ACUTE RESPONSES TO RENAL ARTERY PRESSURE REDUCTION IN CONSCIOUS DOGS

1. Plasma renin and arterial pressure responses to acute renal artery pressure reduction were compared in intact dogs and ‘autonomically-blocked’ dogs subjected to adrenalectomy, chronic guanethidine treatment and acute vagal block (methscopolamine). 2. Following reduction of renal artery pressure plasma renin activity and concentration rose more in the autonomically blocked dogs than in the intact dogs. When renal artery pressure was held at 30 mmHg for 1 h, plasma renin activity rose by 19-1 ng/ml per h (range 11-6-28-7) in autonomically blocked dogs and 3-65 ng/ml per h (range 1-54-5-89) in intact dogs. When renal artery pressure was held at 60 mmHg plasma renin activity rose 3-28 ng/ml per h (range 2-4-4-7) and 1-90 ng/ml per h (range 1-30-3-56), respectively. 3. Arterial blood pressure also rose more in autonomically blocked dogs in accord with the greater rise in plasma renin activity. The relationships between the increases in arterial pressure and plasma renin were closely similar in the two groups. 4. We conclude that the relase of renin and increase in arterial blood pressure in response to renal artery stenosis is normally inhibited by arterial baroreflexes.     

INTERACTION OF VASOPRESSIN, ANGIOTENSIN AND α-ADRENERGIC SYSTEM IN SODIUM DEPLETION IN THE RAT

1. The role of vasopressin in cardiovascular adaptation to sodium depletion was examined in rats after 6 days on a low sodium diet. Studies were performed after selective or combined blockade with d(CH2)5 Tyr(Me)AVP (AVPA), enalaprilat (CEI) and phentolamine (PHENTOL). AVPA alone had no effect on systemic haemodynamics or regional blood flow distribution. After CEI or PHENTOL pretreatment, AVPA led to significant falls in peripheral resistance and increases in cardiac output and renal blood flow. In sodium depletion, endogenous vasopressin acts as a vasoconstrictor hormone, particularly in the kidney, when either the renin-angiotensin or alpha-adrenergic system is inhibited.     

RESPONSE OF PLASMA RENIN-ANGIOTENSIN SYSTEM TO A SINGLE CAPTOPRIL ADMINISTRATION IN PATIENTS RECEIVING LONG-TERM TREATMENT WITH CAPTOPRIL

1. The responses of angiotensin II (AII), AIII, aldosterone and plasma renin activity (PRA) to a single dose of captopril were investigated in hypertensive patients receiving long-term (more than 1 year) captopril therapy (CT patients) and compared with those of non-treated hypertensive patients (NT patients). 2. Baseline levels of AII and aldosterone were significantly lower in CT patients than in NT patients. AIII tended to be lower and PRA was slightly higher in CT than in NT patients, but these differences were not significant. 3. A single administration of captopril (50 mg orally) significantly decreased plasma levels of AII, AIII and aldosterone as well as blood pressure in both CT and NT patients. 4. These results demonstrate that chronically repeated administration of captopril to hypertensive patients effectively reduces the daily blood pressure and concomitantly the plasma AII level to acceptable levels in patients with no experience of ACE inhibition.     

VASOCONSTRICTOR RESPONSES TO COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN CYCLOSPORIN-INDUCED HYPERTENSION IN THE RAT

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-¹¹-10^?6 mol/L), angiotensin I (10-^l1-10^?6 mol/L) and angiotensin II (10-¹²-10^?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

LONG-TERM SYMPATHO-EXCITATORY EFFECT OF ANGIOTENSIN II: A MECHANISM OF SPONTANEOUS AND RENOVASCULAR HYPERTENSION

1. The peptide hormone angiotensin II (AngII) is acknowledged to be an important factor in the pathophysiology of hypertension. This is particularly the case in hypertension caused by luminal narrowing of one renal artery, (i.e. renovascular hypertension). The primary mechanism by which AngII raises blood pressure, however, is disputed. Strong arguments can be made supporting either vascular contraction, effects on renal excretion of sodium and water, or trophic actions on cardiovascular structures as the key element. In this paper I review evidence that AngII influences blood pressure by modulating autonomic nervous system activity. Modulation can occur at both the peripheral and central aspects of the autonomic system, but I focus on brain pathways involved in determining sympathetic nervous system activity. 2. Experimental and clinical investigations are cited to support the hypothesis that sympathetically mediated pressor effects are increased by both circulating and brain-derived AngII in hypertension. Recent work points specifically to sympathetic pre-motor neurons in the rostral ventrolateral medulla (RVLM) as a critical site of action of brain AngII in normoten-sive and hypertensive animals. 3. This same set of neurons appears to be an important relay in the sympatho-excitatory response to circulating AngII initiated at circumventricular organs, particularly the area pos-trema. AngII has important effects on the baroreflex. These do not mediate the sympatho-excitation elicited by circulating AngII, but rather mask its expression. 4. Substantial data support the hypothesis that increased blood concentrations of AngII in renovascular hypertension elevate blood pressure by causing neurogenic vasoconstriction mediated through the area postrema and RVLM.     

CAPTOPRIL ANTAGONIZES THE HYPOTENSIVE ACTION OF ATRIAL NATRIURETIC PEPTIDE IN THE ANAESTHETIZED RAT

Atrial natriuretic peptide (8-33; ANP) caused a prolonged hypotensive response following intravenous injection in anaesthetized rats. This response was abolished by captopril treatment and restored by concomitant angiotensin II infusion. These results suggest that ANP exerts its hypotensive action in the anaesthetized rat by the antagonism of the vasoconstrictor action of endogenous angiotensin II.     

RENAL SYMPATHETIC BAROREFLEX EFFECTS OF ANGIOTENSIN II INFUSIONS INTO THE ROSTRAL VENTROLATERAL MEDULLA OF THE RABBIT

1. The effects of local infusion of angiotensin II (AII) into the rostral ventrolateral medulla (RVLM) pressor area on the renal sympathetic baroreflex were compared with the excitatory amino acid glutamate in urethane anaesthetized rabbits with chronically implanted renal nerve electrodes. Baroreflex blood pressure-renal nerve activity curves were obtained by intravenous infusion of phenylephrine and nitroprusside before and after treatments. 2. Infusion of 4 pmol/min of All into the RVLM increased blood pressure by 12 ± 2 mmHg and transiently increased resting sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right. The upper plateau of the sympathetic reflex increased by 29 ± 8% (n= 6, P < 0.025). 3. Infusions of glutamate into the RVLM, at a dose which was equipressor to that of AII, also increased resting renal sympathetic nerve activity. In contrast to AII, this increase was maintained throughout the infusion. Glutamate shifted the reflex curve to the right and increased the upper plateau of the sympathetic reflex by 44 ± 5% without affecting the lower plateau. 4. These results support the suggestion that AII can act at the level of the RVLM pressor area to facilitate baroreflex control of renal sympathetic activity in a similar fashion to that produced by fourth ventricular administration. 5. Thus the RVLM is a likely candidate site for modulation of the renal sympathetic baroreflex. The similarity of the actions of AII to those of glutamate suggest that it may directly excite sympathetic vasomotor cells in this region.