Importance of Central Vasomotor Effects in Angiotensin-induced Hypertension

Ablation of the areas postrema in 10 dogs caused a highly significant reduction in the pressor response to intravenous infusions of angiotensin yet was without significant effect on the pressor response to intravenous infusions of noradrenaline. The reduction in the pressor response to angiotensin is almost certainly due to abolition of the specific central autonomic effects of the hormone which are dependent on the integrity of the areas postrema. It is suggested that this central effect also contributes to the cardiovascular response to endogenous angiotensin.     

Participation of the area postrema in cardiovascular control in the dog

Investigations have demonstrated that the pressor effects of low-dose intravertebral angiotensin II (Ang II) in the dog are mediated by the area postrema (AP). Chronic ablation of the AP has been shown to produce both mild hypotension and blunting of the pressor effects of peripherally administered Ang II, which suggests a tonic influence by this structure on the regulation of blood pressure. These findings motivated a correlated series of neurophysiological and anatomical studies to characterize further the AP pressor pathway. The pressor response to electrical stimulation of the AP was shown to be mediated by increased central sympathetic outflow, as shown previously for the response to intravertebral Ang II, and unopposed by the central nervous system baroreflex pathways. Neuroanatomical investigations demonstrated a three-layer structure in the dog's AP, with efferent projections into the medial nucleus tractus solitarii bilaterally. These studies have provided new evidence about the functional and structural mechanisms by which the AP participates in cardiovascular regulation.     

The renin-angiotensin system and the central nervous system.

One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons in the brain merits investigation.     

Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion

Increased dietary sodium enhances both excitatory and inhibitory blood pressure responses to stimulation of the central sympathetic nervous system (SNS) centers. In addition, long-term (hours to days) administration of ANG II increases blood pressure by activation of the SNS. These studies investigated the effects of increased dietary sodium on SNS control of blood pressure during 0- to 24-h infusion of ANG II in conscious, male rats consuming either tap water or isotonic saline (Iso) for 2 to 3 wk. The SNS component (evaluated by ganglionic blockade with trimetaphan) of both control blood pressure and the pressor response to intravenous ANG II was reduced in Iso animals. Furthermore, although the pressor response to intravenous ANG II infusion was similar between groups, the baroreflex-induced bradycardia during the initial 6 h of ANG II infusion was significantly greater, whereas the tachycardia accompanying longer infusion periods was significantly attenuated in Iso animals. These data suggest that in normal rats increased dietary sodium enhances sympathoinhibitory responses during intravenous ANG II.     

Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep

Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II (3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) (1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 +/- 7% (P < 0.001) and mean arterial pressure (MAP) by 7.6 +/- 1.2 mmHg (P < 0.001) but did not significantly change heart rate (n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right (P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 +/- 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors.     

Enhancement of the pressor response to norepinephrine by angiotensin in the conscious rabbit

The pressor interactions between angiotensin II and norepinephrine were investigated in conscious New Zealand white rabbits receiving a low sodium diet. Angiotensin II was administered continuously by intraperitoneal osmotic pumps in a subpressor dose so as to avoid the potentially confounding effects of experimentally-induced hypertension. Norepinephrine challenges were given as a series of graded intravenous boluses. During the 3 days of study the baseline blood pressure in the angiotensin-treated rabbits (n=10) did not differ from that in controls (n=10) whose intraperitoneal pumps contained only diluent. After 24 hours the systolic and diastolic blood pressure responses to norepinephrine in the angiotensin-treated group were, on average, 45% and 30% higher than in the controls; after 72 hours, they were 46% and 34% higher. Although the pressor amplitudes were increased by angiotensin II, they were not prolonged. Thus, facilitation by the subpressor angiotensin II of the blood pressure responses to norepinephrine did not seem dependent upon alterations in endogenous sympathetic mechanisms or the uptake of norepinephrine; nor could it be explained by sodium retention. It is possible that angiotensin II exhibits its effect by enhancing contractile responsiveness to norepinephrine at the postreceptor level.     

Renal responses to stressful environmental stimuli

The effects of stressful environmental stimuli on urinary sodium excretion in conscious dogs, rats, and humans are reviewed. Environmental stress can increase sympathetic neural outflow and decrease sodium excretion. The antinatriuretic response to environmental stress is accompanied by an unchanged renal blood flow and glomerular filtration rate, which indicates mediation via an increased renal tubular sodium reabsorption. The antinatriuresis resulting from environmental stress is associated with increased renal sympathetic nerve activity, and is abolished by surgical renal denervation. In the central nervous system, but not in the kidney, beta adrenoceptors mediate the increased renal sympathetic nerve activity and antinatriuretic responses to environmental stress. The increased renal sympathetic nerve activity and antinatriuretic responses to environmental stress are greater in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In SHR, but not WKY rats, the increased renal sympathetic nerve activity and antinatriuretic responses are enhanced by a high-sodium diet. Similarly, stressful competition in human young adult males results in an antinatriuresis only if a positive family history of hypertension is present. Thus, environmental stress can increase renal tubular sodium reabsorption via a central beta-adrenoceptor mechanism with activation of the renal sympathetic nerves in both conscious dogs and SHR. The antinatriuretic response to environmental stress is greater in rats and humans with a genetic predisposition to develop hypertension.     

A prolonged pressor response to intraventricular angiotensin II following bilateral nephrectomy

Intravenous injections of renin have been reported to produce a prolonged pressor response in nephrectomized rats which is mediated by angiotensin II (AII) and is shortened by anesthesia. Here we report a similar prolonged blood pressure increase for intraventricular AII but not for intravenous injections of AII. The extended pressor effects of central AII injections following nephrectomy are not due to water intake but may be partially accounted for by a prolonged action of antidiuretic hormone. The central effects of AII may explain the prolonged pressor action of intravenous renin injections in unanesthetized, nephrectomized rats, although an interaction with the sympathetic nervous system at two different sites of action is also possible. It is suggested that the anti-hypertensive action of the kidneys is through the release of a humoral agent, possibly prostaglandins.     

Central administration of angiotensin II receptor antagonists and arterial pressure regulation: a note of caution.

The blunting of arterial pressure increases to a variety of pressor agents or the lowering of arterial pressure in some models of hypertension following intracerebroventricular administration of an angiotensin II (AII) antagonist, has been interpreted as prima facie evidence for the involvement of the central AII system in these situations. Central administration of vasopressin or carbachol (a cholinergic agonist) produces pressor effects which have been reported to be due to an increase in the activity of the sympathetic nervous system. We now report that central administration of AII antagonists [either (Sar-1, Ile-8) AII or (Sar-1, Ala-8) AII] in rats prevents the majority (greater than 70%) of the pressor effects of intraventricular vasopressin or carbachol. These results can be interpreted in two ways. The first is that all of these pressor agents use a central angiotensinergic mechanism(s) to increase sympathetic nervous system activity. An alternative hypothesis is that centrally administered AII antagonists non-specifically inhibit sympathetic nervous system function.     

17 beta-Estradiol inhibits angiotensin II activation of area postrema neurons

It is well established that the area postrema, as a circumventricular organ, is susceptible to modulation by circulating hormones and peptides. Furthermore, activation of the area postrema has been shown to modulate central neurons involved in the regulation of cardiovascular function and blood pressure. In particular, the vasoactive peptide angiotensin II (ANG II) has been shown to inhibit baroreflex regulation of heart rate and increase sympathetic outflow and blood pressure via activation of area postrema neurons. Estrogen is thought to protect against hypertension in both humans and animal models and has been shown in a number of systems to alter the effects of ANG II. The purpose of the present study was to determine the effects of estrogen on ANG II activation of area postrema neurons. In this study, the effects of ANG II and KCl on fura 2-measured cytosolic Ca2+ concentration ([Ca2+]i) responses in cultured area postrema neurons in the presence and absence of 12-h exposure to 100 nM 17 beta-estradiol (E2) were evaluated. In neurons incubated in control vehicle media, 50 nM ANG II increased [Ca2+]i by 92 +/- 12%. In neurons preincubated with 100 nM E2, ANG II increased [Ca2+]i by only 68 +/- 11%, for a total inhibition of the ANG II-evoked response of 24%. Coapplication of the estrogen receptor antagonist ICI-182,780 did not inhibit the effects of E2. In the same cells in which the effects of E2 on ANG II-evoked responses were tested, the effects of incubation in E on the depolarization-induced increased [Ca2+2]i due to 60 mM KCl were also tested. Incubation of the cells with 100 nM E increased the KCl-evoked [Ca2+2]i response, and this response was blocked by ICI-182,780. These results suggest that in the area postrema, estrogen may utilize multiple pathways to modulate neural activity and responses to ANG II.     

Carotid sinus reflex and norepinephrine release following acute volume depletion in dogs.

Norepinephrine (NE) release and pressor response to sympathetic stimulation were studied in dogs under furosemide-induced acute volume depletion. The rise in blood pressure observed following carotid clamping proved similar before and after acute salt and water depletion in the first group of animals and NE rose comparably in these two conditions. Similar results were obtained in a second group of dogs that received an angiotensin II converting enzyme inhibitor (CEI). This study shows that contrary to isotonic saline loading, acute salt and water depletion cause a progressive increase in NE plasma levels. Moreover, these results clearly demonstrate that the decrease in sympatho--adrenergic response and the predominant role played by the renin--aniotensin system during chronic salt depletion are not observed in acute conditions.     

Role of the sympathetic nervous system in the alcohol-guanabenz hemodynamic interaction.

The present study evaluated the contribution of the sympathetic nervous system to the adverse hemodynamic action of ethanol on hypotensive responses in conscious unrestrained spontaneously hypertensive rats. Ethanol caused a dose-related attenuation of the hypotensive effect of guanabenz. An equivalent hypotensive response to sodium nitroprusside was not influenced by ethanol, which indicates a potential specific interaction between ethanol and guanabenz. Alternatively, it is possible that a preexisting high sympathetic nervous system activity, which occurred during nitroprusside infusion, may mask a sympathoexcitatory action of ethanol. Further, ethanol (1 g/kg) failed to reverse the hypotensive effect of the ganglionic blocker hexamethonium. This suggests that a centrally mediated sympathoexcitatory action of ethanol is involved, at least partly, in the reversal of hypotension. In addition, the antagonistic interaction between ethanol and guanabenz seems to take place within the central nervous system and involves opposite effects on central sympathetic tone. Finally, changes in plasma catecholamines provide supportive evidence for the involvement of the sympathetic nervous system in this interaction. In a separate group of conscious spontaneously hypertensive rats, ethanol (1 g/kg) reversed the guanabenz-evoked decreases in blood pressure and plasma catecholamine levels. It is concluded that (i) ethanol adversely interacts with centrally acting antihypertensive drugs through a mechanism that involves a directionally opposite effect on sympathetic activity, and (ii) a sympathetically mediated pressor effect of ethanol is enhanced in the presence of an inhibited central sympathetic tone.     

Nonalgebraic interaction between pressor and depressor reflexes in dogs: evidence for a central site of action

In a previous study (Kendrick, JE and Matson, G 1979, Amer J Physiol 327:H662-H667) we demonstrated that the vascular responses in dogs to electrical stimulation of aortic nerve (AN) pressor and carotid sinus nerve (CSN) depressor afferents did not sum algebraically. We suggest this results from a reflex interaction which occurs in the central nervous system. The present study extends earlier studies by recording sympathetic vasomotor in chloralose-anesthetized dogs. Stimulation of the CSN reduced sympathetic activity by 51 +/- 20 (SD)%. AN stimulation (2 Hz) caused a 17 +/- 12% increase in sympathetic activity. Combined stimulation of the ipsilateral CSN and AN caused 0 +/- 28% change rather than a 34% decrease expected by an additive interaction. The interaction recorded in this study from the sympathetic outflow is therefore consistent with the previously reported vascular responses (cited above) and implicates central nervous site(s) of action. A conditioning stimulus train to CSN inhibited sympathetic discharges to AN test stimuli. This inhibition was prevented by pairing an AN stimulus with the CSN stimulus train. The AN pressor reflexes act in part by increasing sympathetic activity and in part by suppressing the baroreflexes.     

Non-opiate and peripheral-opiate cardiovascular effects of morphine in conscious dogs

Morphine is generally regarded as having a centrally mediated depressant effect upon the cardiovascular system. We report here that in chronically instrumented conscious dogs, morphine produces a biphasic response; heart rate and mean arterial pressure initially increase followed by a reduction to below baseline levels. Differential inhibition by naloxone (NAL) and methylnaloxone (MRZ), a quaternary opiate antagonist which does not readily enter the CNS, suggests that the initial pressor response is mediated peripherally, while the latter occurring vasodepressor and bradycardic responses are mediated centrally. The initial tachycardia was not inhibited by NAL or MRZ, suggesting that this response is mediated by a non-opiate mechanism.     

Central angiotensin II-induced pressor responses and neural activity in utero and hypothalamic angiotensin receptors in preterm ovine fetus

The central renin-angiotensin system is important in the control of blood pressure in the adult. However, few data exist about the in utero development of central angiotensin-mediated pressor responses. Our recent studies have shown that the application of ANG II into the fetal brain can increase blood pressure at near term. The present study determined fetal blood pressure and heart rate in response to a central application of ANG II in the chronically prepared preterm ovine fetus, determined the action sites marked by c-Fos expression in the fetal central pathways after intracerebroventricular injection of ANG II in utero, and determined angiotensin subtype 1 receptors in the fetal hypothalamus. Central injection of ANG II significantly increased fetal mean arterial pressure (MAP). Adjusted fetal MAP against amniotic pressure was also increased by ANG II. Fetal heart rate was subsequently decreased after the central administration of ANG II and/or the increase of blood pressure. ANG II induced c-Fos expression in the central putative cardiovascular area, the paraventricular nuclei in the brain sympathetic pathway. Application of ANG II also caused intense Fos immunoreactivity in the tractus solitarius nuclei in the hindbrain. In addition, intense angiotensin subtype 1 receptors were expressed in the hypothalamus at preterm. These data demonstrate that central ANG II-related pressor centers start to function as early as at preterm and suggest that the central angiotensin-related sympathetic pathway is likely intact in the control of blood pressure in utero.     

The adrenal and vascular effects of angiotensin II and III in sodium depleted rats

The effects of angiotensin II and angiotensin III on mean arterial pressure, serum aldosterone, and serum corticosterone were studied in normal and sodium depleted, conscious rats. In normal rats, angiotensin III was 76% (p > 0.10) as potent as angiotensin II on aldosterone release but only 31% (p < 0.001) as potent on blood pressure. Following sodium depletion, the pressor responses to both angiotensin II and III were reduced (p < 0.001) (65% and 86% respectively). In addition, the release of aldosterone by both peptides was potentiated by sodium depletion as indicated by an increase in the slope of the dose-response curves. However, in the sodium depleted rats, angiotensin III was only 20% (p < 0.001) as potent as angiotensin II in stimulating aldosterone release. Small changes in serum corticosterone were noted following infusions of both peptides, but unlike the case with aldosterone, sodium depletion did not alter the serum corticosterone responses to the peptides. These $\text{in}$$\text{vivo}$ experiments taken with $\text{in}$$\text{vitro}$ studies support the interpretation that angiotensin III could function to control aldosterone release in altered sodium states either as a circulating hormone if present in concentrations far in excess of those of angiotensin II or as a local hormone formed in the adrenal from angiotensin II.     

The effect of the central iso-renin angiotensin system on pressor responsiveness to angiotensin II

The effect of intraventricular (IVT) infusion of a subpressor dose (6.25 or 12.5 ng/kg/min) of angiotensin II (AII) on the pressor responses to intravenous (IV) infusion of AII were studied in pentobarbital anesthetized rats. This study was undertaken to determine whether the central iso-renin angiotensin system alters pressor responsiveness to IV infused AII. Pressor responses to IV infusion of AII were potentiated by concurrent IVT infusion of a subpressor dose of AII. IVT pressor doses of AII decreased plasma renin activity, however, IVT subpressor doses of AII did not. These results suggest that the central iso-renin angiotensin system plays an important role in pressor responsiveness to IV AII and that the potentiation of IV AII is not related to decreases in endogenous AII as a result of IVT administered AII.     

Stimulation of NTS A1 adenosine receptors evokes counteracting effects on hindlimb vasculature

Our previous studies concluded that stimulation of the nucleus of the solitary tract (NTS) A2a receptors evokes preferential hindlimb vasodilation mainly via inducing increases in preganglionic sympathetic nerve activity (pre-ASNA) directed to the adrenal medulla. This increase in pre-ASNA causes the release of epinephrine and subsequent activation of beta-adrenergic receptors that are preferentially located in the skeletal muscle vasculature. Selective activation of NTS A1 adenosine receptors evokes variable, mostly pressor effects and increases pre-ASNA, as well as lumbar sympathetic activity, which is directed to the hindlimb. These counteracting factors may have opposite effects on the hindlimb vasculature resulting in mixed vascular responses. Therefore, in chloralose-urethane-anesthetized rats, we evaluated the contribution of vasodilator versus vasoconstrictor effects of stimulation of NTS A1 receptors on the hindlimb vasculature. We compared the changes in iliac vascular conductance evoked by microinejctions into the NTS of the selective A1 receptor agonist N6-cyclopentyladenosine (330 pmol in 50 nl volume) in intact animals with the responses evoked after beta-adrenergic blockade, bilateral adrenalectomy, bilateral lumbar sympathectomy, and combined adrenalectomy + lumbar sympathectomy. In intact animals, stimulation of NTS A1 receptors evoked variable effects: increases and decreases in mean arterial pressure and iliac conductance with prevailing pressor and vasoconstrictor effects. Peripheral beta-adrenergic receptor blockade and bilateral adrenalectomy eliminated the depressor component of the responses, markedly potentiated iliac vasoconstriction, and tended to increase the pressor responses. Lumbar sympathectomy tended to decrease the pressor and vasoconstrictor responses. After bilateral adrenalectomy plus lumbar sympathectomy, a marked vasoconstriction in iliac vascular bed still persisted, suggesting that the vasoconstrictor component of the response to stimulation of NTS A1 receptors is mediated mostly via circulating factors (e.g., vasopressin, angiotensin II, or circulating catecholamines released from other sympathetic terminals). These data strongly suggest that stimulation of NTS A1 receptors exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and beta-adrenergic vasodilation versus vasoconstriction mediated by neural and humoral factors.     

Angiotensin II acutely attenuates range of arterial baroreflex control of renal sympathetic nerve activity

Acutely increasing peripheral angiotensin II (ANG II) reduces the maximum renal sympathetic nerve activity (RSNA) observed at low mean arterial blood pressures (MAPs). We postulated that this observation could be explained by the action of ANG II to acutely increase arterial blood pressure or increase circulating arginine vasopressin (AVP). Sustained increases in MAP and increases in circulating AVP have previously been shown to attenuate maximum RSNA at low MAP. In conscious rabbits pretreated with an AVP V1 receptor antagonist, we compared the effect of a 5-min intravenous infusion of ANG II (10 and 20 ng x kg(-1) x min(-1)) on the relationship between MAP and RSNA when the acute pressor action of ANG II was left unopposed with that when the acute pressor action of ANG II was opposed by a simultaneous infusion of sodium nitroprusside (SNP). Intravenous infusion of ANG II resulted in a dose-related attenuation of the maximum RSNA observed at low MAP. When the acute pressor action of ANG II was prevented by SNP, maximum RSNA at low MAP was attenuated, similar to that observed when ANG II acutely increased MAP. In contrast, intravertebral infusion of ANG II attenuated maximum RSNA at low MAP significantly more than when administered intravenously. The results of this study suggest that ANG II may act within the central nervous system to acutely attenuate the maximum RSNA observed at low MAP.     

Super-long latent somato-sympathetic response in non-anesthesized decerebrate frogs

Somato-sympathetic reflex responses were studied by recording the activity of the renal sympathetic efferents following excitation of sciatic nerve A-afferents in immobilized decerebrated frogs before and during viadril-induced anesthesia. Apart from A-response reported in anesthetized frogs and consisting of excitatory and inhibitory components, in non-anesthetized frogs reflex discharge with a latency over 2 sec was revealed. Unlike the former one, this response disappeared after intravenous injection of viadril. In the same frogs intravenous injection of viadril converted pressor reflexes in response to stimulation of sciatic nerve A-afferents into depressor ones. A-response with superlong latency is assumed to reflect the excitation of those central structures that are responsible for the development of pressor reflexes to somatic A-fiber stimulation. In this respect the described somato-sympathetic A-response seems to be analogous to the very late A-response in the mammals.