Role of the autonomic nervous system, renin-angiotensin system, and arginine vasopressin during the onset and maintenance of ACTH hypertension in sheep

The roles of the autonomic nervous system, renin-angiotensin system, and arginine vasopressin (AVP) during the onset of ACTH-induced hypertension were investigated in conscious sheep. Autonomic ganglion blockade or combined adrenergic and cholinergic receptor blockade demonstrated that an intact sympathetic nervous system was not essential for the development or maintenance of the hypertension. Autonomic blockade augmented the pressor response to ACTH, indicating that baroreceptor-mediated reflexes normally operate to suppress the degree of hypertension produced by ACTH. Evidence was obtained suggesting that the renin-angiotensin system and AVP may partially contribute to the maintenance of ACTH hypertension in the presence of autonomic blockade. However, the precise mechanism by which ACTH raises arterial pressure remains to be elucidated.     

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.     

New mechanisms to control aldosterone synthesis.

Arterial hypertension is a frequent and leading cardiovascular risk factor, and primary aldosteronism is a well-recognized cause of secondary hypertension. Aldosterone is the basic regulator of extracellular fluid volume and electrolyte balance. Alterations in plasma aldosterone levels significantly contribute to the development and the severity of hypertension. Adrenal steroidogenesis is controlled by two major feedback loops: the hypothalamic-pituitary-adrenal axis, which regulates cortisol synthesis, and the renin-angiotensin-aldosterone system, which directs aldosterone production. In addition to angiotensin, potassium, and corticotropin-which belong to the classic stimulators of aldosterone-neuropeptides, catecholamines, and prostaglandins are also known to stimulate aldosterone synthesis. Recently, several new mechanisms have been characterized that control the release of aldosterone by adrenocortical cells, among them endothelial cell-derived factors and adipokines. Further identification and characterization of these factors may help in the development of novel therapies for the treatment of arterial hypertension, various metabolic diseases, and other disorders.     

Mineralocorticoid receptors and hypertension

Mineralocorticoid receptors (MR) have equal affinity for the mineralocorticoid aldosterone, and the physiological glucocorticoids cortisol and corticosterone. In epithelial tissues in vivo, MR are protected against glucocorticoid occupancy by the enzyme 11β-hydroxysteroid dehydrogenase, allowing access by the lower circulating levels of the physiological mineralocorticoid aldosterone. In non-epithelial tissues, including the heart and most areas of the central nervous system, MR are not so protected, and their physiological ligand is cortisol/corticosterone. Intracerebroventricular infusion studies have shown that aldosterone occupancy of such unprotected circumventricular MR is necessary for mineralocorticoid hypertension, and the hypertensinogenic effects of peripherally infused aldosterone can be blocked by intracerebroventricular infusion of the MR antagonist RU28318. Prolonged (8 weeks) administration of mineralocorticoids to salt-loaded rats has been shown to be followed by hypertension, cardiac hypertrophy and cardiac fibrosis. Whether the hypertrophy and fibrosis reflect primary effects of aldosterone via cardiac MR, or effects secondary to occupancy of protected, epithelial MR, remains to be determined, as does the mechanism of action of salt loading in this model of mineralocorticoid hypertension.     

Natriuretic and diuretic action of centrally administered rat atrial natriuretic peptide (99-126): possible involvement of aldosterone and the sympathoadrenal system

Intracerebroventricular (ICV) administration of rat atrial natriuretic peptide (99-126) (rANP) to conscious male hydrated rats resulted in a dose-related increase in urinary volume and sodium excretion over a 6-h period of urine collection. A diminished mineralocorticoid effect on the kidneys may explain the natriuretic phenomenon. This hypothesis was tested by ICV rANP injection (1.25 microgram/5 microL) in conscious hydrated rats pretreated beforehand with d-aldosterone (20 micrograms/kg, ip). Although the absolute amount of sodium excreted was reduced, aldosterone did not affect rANP-induced sodium output at 1 and 3 h. Rats that were sham-operated or bilaterally adrenalectomized after 4 days were pretreated with aldosterone and given an oral water load followed by ICV rANP or saline. The possible participation of the peripheral sympathetic nervous system in the central action of rANP was evaluated in rats pretreated with 6-hydroxydopamine. In sympathectomized and adrenalectomized rats natriuresis and diuresis were still evident after rANP. Our results indicate that the natriuretic effect of ICV rANP is independent of mineralocorticoids. Likewise, diuresis and natriuresis can occur in the absence of the adrenal glands and are independent from the neural tone that the adrenergic system exerts on sodium reabsorption.     

Apelin/APJ system: a promising therapy target for hypertension

Apelin is a recently described endogenous peptide and its receptor APJ, is a member of the G protein-coupled receptors family. Apelin and APJ are widely distributed in central and peripheral tissues exert important biological effects on cardiovascular system. Recent studies have suggested that apelin/APJ system involves in decreasing the blood pressure and have a close relationship with hypertension, presumably, pathophysiology of hypertension as well. Such as, apelin/APJ system may be concerned in hyperfunction of the sympathetic nervous system, renin–angiotensin–aldosterone system, endothelial injury, excessive endothelin, sodium retention, vascular remodeling, insulin resistance elicit hypertension, as well as in hypertension-induced organ damaged. Meanwhile, on the ground of the variation of apelin level in hypertension therapeutic process and combining with the recently researches on APJ agonist and antagonist, we could infer that apelin/APJ system would be a promising therapeutic target for hypertension and other cardiovascular disease in the future. However, the role of apelin on these pathogenic conditions was not consistent, consequently, the contradictory role of apelin on these pathogenesis of hypertension would be discussed in this article.     

Sympathetic adrenergic blockade effects upon operantly conditioned blood pressure elevations in baboons

Sympathetic adrenergic nervous activity during operantly conditioned hypertension was evaluated by assessing the effects of specific alpha-(phentolamine or phenoxybenzamine) and beta- (propranolol) adrenergic blockers in baboons reinforced for increasing diastolic pressure in daily, 12-h sessions. In the first 10 min of control (no blockade) sessions, mean heart rate increased 24 bpm (21%) above the value for the 10 min immediately prior to the beginning of the sessions; systolic pressure increased 27 mm Hg (22%) and diastolic pressure increased 24 mm Hg (31%). Betablockade eliminated the tachycardia but did not attenuate the increased blood pressure. Alpha-blockade did not attenuate the increased blood pressure significantly either. Combined alpha- and beta-blockade did significantly attenuate the increase in diastolic pressure, but consistent, significant increases in systolic pressure (17 mm Hg, 17%) and diastolic pressure (16 mm Hg, 26%) still occurred. The results support the participation of the sympathetic adrenergic nervous system in producing operantly conditioned blood pressure changes, but the results are also consistent with the additional participation of nonadrenergic factors in operantly conditioned hypertension.     

The central role of the brain aldosterone–“ouabain” pathway in salt-sensitive hypertension

Na⁺-transport regulating mechanisms classically considered to reflect renal control of sodium homeostasis and BP, i.e. aldosterone–mineralocorticoid receptors (MR)—epithelial sodium channels (ENaC)—Na⁺/K⁺-ATPase have now been demonstrated to also be present in the central nervous system. This pathway is being regulated independently of the peripheral/renal pathway and contributes to regulation of cerebrospinal fluid [Na⁺] by the choroid plexus, of brain tissue [Na⁺] by the ependyma and to neuronal responses to e.g. Na⁺ or angiotensin II. Increases in CSF [Na⁺] by central infusion of Na⁺-rich aCSF or by high salt intake in Dahl S or SHR cause sympatho-excitation and hypertension. These responses appear to depend on activation of a CNS cascade starting with aldosterone–MR–ENaC–“ouabain,” the latter lowering neuronal membrane potential leading to enhanced angiotensin II release in e.g. the PVN. Specific CNS blockade of any of the steps in this cascade from aldosterone synthase blockade to AT₁-receptor blockade prevents the sympathetic hyperactivity and hypertension on high salt intake, irrespective of the presence of a “salt-sensitive kidney.” We propose that in salt-sensitive hypertension an increase in CSF [Na⁺] causes a local increase in aldosterone biosynthesis which activates an aldosterone dependent neuromodulatory pathway which enhances activity of angiotensinergic sympatho-excitatory pathways leading to hypertension.     

Central infusion of aldosterone synthase inhibitor prevents sympathetic hyperactivity and hypertension by central Na+ in Wistar rats

In Wistar rats, increasing cerebrospinal fluid (CSF) Na+ concentration ([Na+]) by intracerebroventricular (ICV) infusion of hypertonic saline causes sympathetic hyperactivity and hypertension that can be prevented by blockade of brain mineralocorticoid receptors (MR). To assess the role of aldosterone produced locally in the brain in the activation of MR in the central nervous system (CNS), Wistar rats were infused ICV with artificial CSF (aCSF), Na+ -rich (800 mmol/l) aCSF, aCSF plus the aldosterone synthase inhibitor FAD286 (100 microg x kg(-1) x day(-1)), or Na+ -rich aCSF plus FAD286. After 2 wk of infusion, rats treated with Na+ -rich aCSF exhibited significant increases in aldosterone and corticosterone content in the hypothalamus but not in the hippocampus, as well as increases in resting blood pressure (BP) and sympathoexcitatory responses to air stress, and impairment of arterial baroreflex function. Concomitant ICV infusion of FAD286 prevented the Na+ -induced increase in hypothalamic aldosterone but not corticosterone and prevented most of the increases in resting BP and sympathoexcitatory and pressor responses to air stress and the baroreflex impairment. FAD286 had no effects in rats infused with ICV aCSF. In another set of rats, 24-h BP and heart rate were recorded via telemetry before and during a 14-day ICV infusion of Na+ -rich aCSF with or without FAD286. Na+ -rich aCSF without FAD286 caused sustained increases ( approximately 10 mmHg) in resting mean arterial pressure that were absent in the rats treated with FAD286. These data suggest that in Wistar rats, an increase in CSF [Na+] may increase the biosynthesis of corticosterone and aldosterone in the hypothalamus, and mainly aldosterone activates MR in the CNS leading to sympathetic hyperactivity and hypertension.     

Integrative mechanisms of the formation of the small intestine motor effects

Contractile responses of the small intestine to serotonine and histamine are mediated by cholinergic neurones, while the inhibitory responses of the substances--by nonadrenergic inhibitory neurones of the enterometasympathetic nervous system. An inhibitory response of the small intestine to met-enkephalin results from its depressing action on the effector cholinergic neurones. Catecholamines activate enteric cholinergic neurones via presynaptic beta-adrenoceptors and inhibit them via pre- and postsynaptic alpha-adrenoceptors. The cholinergic neurones of the enterometasympathetic nervous system seem to be under a double adrenergic control, and a mechanisms seems to exist in the small intestine for adrenergic activation of its contractile apparatus.     

Effect of chronic uremia on the cardiovascular alpha 1 receptor

Adrenergic dysfunction in uremia has been well described. Several lines of evidence suggest disorders of blood pressure regulation and myocardial response may occur secondary to adrenergic dysfunction; attenuated pressor response to norepinephrine (NE) in uremia; attenuated chronotropic responses during dialysis induced hypotension. Since the adrenergic receptors are the effector component of the adrenergic nervous system, we have employed the partially nephrectomized uremic rat, to examine the effect of chronic uremia (4-6 weeks) on the binding properties of alpha 1 receptors in rat mesenteric artery and myocardial tissue. The results indicate that moderate levels of uremia alter the binding properties of both the alpha 1 vascular and myocardial receptor.     

Confocal immunohistochemistry of the dermal glands and evolutionary considerations in the caecilian,Typhlonectes natans (Amphibia: Gymnophiona)

An immunohistochemical study of the cutaneous glands of the caecilian Typhlonectes natans was conducted. Analyses of nerve fibres revealed that adrenergic and galanin‐positive axons innervate the MECs and mediate their contraction. These glands may represent one of the main targets of the adrenergic ganglion cells and reflect the prominent preganglionic cell columns of the species studied. But neurochemical features of the sympathetic ganglia and retrograde tract‐tracing studies are necessary to study the morphology and organization of the sympathetic nervous system of studied species.     

Adrenergic and cholinergic innervation of the prostate in laboratory animals

The prostate innervation has been studied in 50 white rats, 12 rabbits, 12 guinea pigs, 6 cats and 6 dogs. Together with the impregnation techniques, Karnovsky-Roots method has been applied, for revealing cholinergic components, and the incubation method in 2% solution of glyoxylic acid, for revealing adrenergic nervous structures. Density of adrenergic and cholinergic nervous plexuses has been estimated by means of the planimetric point method. The prostate of the laboratory animals possesses well manifested adrenergic and cholinergic nervous plexuses. The organ's alveolus and ducts are covered with adrenergic and cholinergic fibers, however, the relative density of the cholinergic plexuses is less than that of the adrenergic ones. The guinea pig prostate is the most richly supplied with the adrenergic nervous plexuses, and the rabbit prostate--with the cholinergic nervous plexuses.     

Effect of an inhibitor of noradrenaline uptake,desipramine, on cell proliferation in the intestinal crypt epithelium

The intestinal mucosa receives an adrenergic innervation for which there is no commonly accepted function. However, in recent years, cell kinetic studies have raised the possibility that this innervation may be an important regulator of crypt cell proliferation. The effects of noradrenaline released from adrenergic nerves is terminated principally by re-uptake of the amine into the nerve and this process can be inhibited by the antidepressant drug, desipramine. In this report desipramine is shown to accelerate crypt cell proliferation in intact, but not in chemically sympathectomized rats, thus adding support to the notion that regulation of crypt cell division is an important function of the sympathetic nervous system.     

Effect of an inhibitor of noradrenaline uptake, desipramine, on cell proliferation in the intestinal crypt epithelium

The intestinal mucosa receives an adrenergic innervation for which there is no commonly accepted function. However, in recent years, cell kinetic studies have raised the possibility that this innervation may be an important regulator of crypt cell proliferation. The effects of noradrenaline released from adrenergic nerves is terminated principally by re-uptake of the amine into the nerve and this process can be inhibited by the antidepressant drug, desipramine. In this report desipramine is shown to accelerate crypt cell proliferation in intact, but not in chemically sympathectomized rats, thus adding support to the notion that regulation of crypt cell division is an important function of the sympathetic nervous system.     

Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.     

A comparison of the effects of sotalol and of the isomers of practolol on adrenergic nervous activity

Spontaneous activity was recorded from postganglionic cardioaccelerator fibers in cats anesthetized with α-chloralose. The effects of sotalol and the d(+)? and 1(?)? isomers of practolol were examined in these experiments. The 1(?)? isomer of practolol caused a dose- related depression of adrenergic nervous activity while d(+)? practolol had no effect. Sotalol had no influence on nervous discharge. The results suggest that 1(?)? practolol depresses adrenergic nervous activity and that this effect may be important in the antiarrhythmic action of this agent.     

Pathophysiological roles of vascular 11beta-hydroxysteroid dehydrogenase and aldosterone

Mineralocorticoid receptor (MR) binding is tightly regulated by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSDII) which selectively metabolizes glucocorticoids to inactive metabolites, thus allowing for MR activation by aldosterone. To examine whether this enzyme is involved in the pathophysiology of salt-sensitive hypertension, 11β-HSDII activity and messenger RNA (mRNA) levels were determined in blood vessels of Dahl Iwai salt-sensitive (DS) and salt-resistant (DR) rats. Decreased 11β-HSDII activity and mRNA levels in mesenteric arteries were observed in 8-week-old DS rats on a high-salt diet, indicating that 11β-HSDII may play a significant role in salt sensitivity and hypertension. It has been suggested that mineralocorticoids act on blood vessels, leading to increased vasoreactivity and peripheral resistance. We present direct evidence that blood vessels are aldosteronogenic. The production of aldosterone in blood vessels was compared between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. Vascular aldosterone and CYP11B2 mRNA levels were significantly increased in 2-week-old SHRSP versus WKY rats. However, the vascular aldosterone levels in 4- and 9-week-old SHRSP and WKY rats were similar. High sodium intake further increased both blood pressure and vascular aldosterone synthesis in the SHRSPs. Both the local renin–angiotensin–aldosterone system (RAAS) and the vascular 11β-HSDII level are critically important in the pathophysiology of cardiovascular disorders.     

Pharmacological analysis of morphofunctional changes in the adrenergic structures of the pancreas as affected by lesions of the endocrine and exocrine pancreas

The adrenergic section of the vegetative pancreatic innervation has been examined, using morphological, histochemical and biochemical methods, during neurogenic injury, acute experimental pancreatitis and alloxan diabetes. It has been established that the development of those etiologically different processes was accompanied by catecholamine level reduction in the adrenergic structures of the pancreas which can be prevented by ganglioblockers. It is concluded that sympathetic nervous system participates in etiopathogenesis of a number of pancreatic diseases and that it is possible to prevent and treat them with sympathotropic agents.