Virginia L. Brooks

TRANSLATION OF SALT RETENTION TO CENTRAL ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN HYPERTENSION

1. Increased dietary salt increases blood pressure in many hypertensive individuals, producing salt‐sensitive hypertension (SSH). The cause is unknown, but a major component appears to be activation of the sympathetic nervous system. The purpose of this short review is to present one hypothesis to explain how increased dietary salt increases sympathetic activity in SSH.

Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats

Non‐technical summary  Though the pancreatic hormone insulin is known to act in the brain to increase sympathetic nerve activity and baroreflex control of sympathetic nerve activity, its specific site of action had yet to be identified. We show that a region in the hypothalamus, the arcuate nucleus, is the site at which insulins effects are initiated. This new information may lead to a greater understanding of the role of insulin in the brain in adverse cardiovascular complications, like hypertension and heart attacks, which are associated with insulin‐resistant states, such as obesity and diabetes.

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.

Osmolality: A physiological long-term regulator of lumbar sympathetic nerve activity and arterial pressure

Acute infusion of hypertonic fluid increases mean arterial pressure (MAP) in part by elevating nonrenal sympathetic activity. However, it is not known whether chronic, physiological increases in osmolality also increase sympathetic activity. To test this hypothesis, MAP, heart rate (HR), and lumbar sympathetic nerve activity (LSNA) were measured in conscious, 48-h water-deprived rats (WD) during a progressive reduction in osmolality produced by a 2-h systemic infusion (0.12 ml/min) of 5% dextrose in water (5DW). Water deprivation significantly increased osmolality (308 +/- 2 vs. 290 +/- 2 mosmol/kgH2O, P < 0.001), HR (453 +/- 7 vs. 421 +/- 10 beats/min, P < 0.05), and LSNA (63.5 +/- 1.8 vs. 51.9 +/- 3.8% baroreflex maximum, P < 0.01). Two hours of 5DW infusion reduced osmolality (-15 +/- 5 mosmol/kgH2O), LSNA (-23 +/- 3% baseline), and MAP (-10 +/- 1 mmHg). To evaluate the role of vasopressin in these changes, rats were pretreated with a V1-vasopressin receptor antagonist. The antagonist lowered MAP (-5 +/- 1 mmHg) and elevated HR (32 +/- 7 beats/min) and LSNA (11 +/- 3% baseline) in WD (P < 0. 05), but not in water-replete, rats. 5DW infusion had a similar cumulative effect on all variables in V1-blocked WD rats, but had no effect in water-replete rats. Infusion of the same volume of normal saline in WD rats did not change osmolality, LSNA or MAP. Together these data indicate that, in dehydrated rats, vasopressin supports MAP and suppresses LSNA and HR and that physiological changes in osmolality directly influence sympathetic activity and blood pressure independently of changes in vasopressin and blood volume.Acute infusion of hypertonic fluid increases mean arterial pressure (MAP) in part by elevating nonrenal sympathetic activity. However, it is not known whether chronic, physiological increases in osmolality also increase sympathetic activity. To test this hypothesis, MAP, heart rate (HR), and lumbar sympathetic nerve activity (LSNA) were measured in conscious, 48-h water-deprived rats (WD) during a progressive reduction in osmolality produced by a 2-h systemic infusion (0.12 ml/min) of 5% dextrose in water (5DW). Water deprivation significantly increased osmolality (308 ± 2 vs. 290 ± 2 mosmol/kgH2O, P < 0.001), HR (453 ± 7 vs. 421 ± 10 beats/min, P < 0.05), and LSNA (63.5 ± 1.8 vs. 51.9 ± 3.8% baroreflex maximum, P < 0.01). Two hours of 5DW infusion reduced osmolality (-15 ± 5 mosmol/kgH2O), LSNA (-23 ± 3% baseline), and MAP (-10 ± 1 mmHg). To evaluate the role of vasopressin in these changes, rats were pretreated with a V1-vasopressin receptor antagonist. The antagonist lowered MAP (-5 ± 1 mmHg) and elevated HR (32 ± 7 beats/min) and LSNA (11 ± 3% baseline) in WD ( P < 0.05), but not in water-replete, rats. 5DW infusion had a similar cumulative effect on all variables in V1-blocked WD rats, but had no effect in water-replete rats. Infusion of the same volume of normal saline in WD rats did not change osmolality, LSNA or MAP. Together these data indicate that, in dehydrated rats, vasopressin supports MAP and suppresses LSNA and HR and that physiological changes in osmolality directly influence sympathetic activity and blood pressure independently of changes in vasopressin and blood volume.

Pregnancy attenuates activity of the baroreceptor reflex.

1. Pregnancy‐induced changes in acute blood pressure regulation are reviewed.

Deoxycorticosterone Acetate–Salt Rats: Hypertension and Sympathoexcitation Driven by Increased NaCl Levels

Using deoxycorticosterone acetate (DOCA)–salt rats, we tested the hypothesis that increased plasma NaCl concentration supports sympathetic activity and blood pressure (BP) during salt-sensitive hypertension. One day before experimentation, femoral catheters and an electrode for measurement of lumbar sympathetic nerve activity (LSNA) probe were surgically positioned in DOCA-salt and Sham-salt rats. DOCA-salt rats exhibited increased (P<0.05) BP and NaCl concentration (BP, 163±8 mm Hg; NaCl, 260.8±3.3 mEq/L [DOCA-salt]: BP, 106.3±4.2 mm Hg; NaCl, 254.3±1.7 mEq/L [Sham-salt]). After V1 vasopressin blockade (Manning compound, 5 &mgr;g IV), infusion (0.12 mL/min) of 5% dextrose in water decreased NaCl concentrations, BP (−28±7 mm Hg), and LSNA (−39±5%) in DOCA-salt but not Sham-salt rats. To explain how such small (≈2%) increases in plasma NaCl could underlie the hypertension, we hypothesized that DOCA augments the pressor and sympathoexcitatory actions of NaCl. To address this hypothesis, animals with equally elevated NaCl but no DOCA (Sham-1.7% salt) and animals with increased DOCA but normal NaCl levels (DOCA-water) were prepared and administered the infusion of 5% dextrose in water. BP and LSNA were not altered in DOCA-water rats. In the Sham-1.7% salt rats, BP fell (P<0.05), but not LSNA, and the responses were significantly smaller than that observed in the DOCA-salt animals. Collectively, these data suggest that increased NaCl levels contribute to sympathoexcitation and hypertension in DOCA-salt rats because of amplification of the NaCl signal by DOCA.

The interaction of angiotensin II and osmolality in the generation of sympathetic tone during changes in dietary salt intake: An hypothesis

Abstract: At rest, sympathetic nerves exhibit tonic activity which contributes to arterial pressure maintenance. Significant evidence suggests that the absolute level of sympathetic tone is altered in a number of physiologic and pathophysiologic states. However, the mechanisms by which such changes in sympathetic tone occur are incompletely understood. The purpose of this review is to present evidence that humoral factors are essential in these changes and to detail specifically an hypothesis for the mechanisms that underlie the changes in sympathetic tone that are produced during increases or decreases in dietary salt intake. It is proposed that the net effect of changes in dietary salt on sympathetic activity is determined by the balance between simultaneous and parallel sympathoinhibitory and sympathoexcitatory humoral mechanisms. A key element of the sympathoinhibitory mechanism is the chronic sympathoexcitatory effects of angiotensin II (ANG II). When salt intake increases, ANG II levels fall, and the sympathoexcitatory actions of ANG II are lost. Simultaneously, a sympathoexcitatory pathway is triggered, possibly via increases in osmolality which activate osmoreceptors or sodium receptors. In normal individuals, the sympathoinhibitory effects of increased salt predominate, sympathetic activity decreases, and arterial pressure remains normal despite salt and water retention. However, in subjects with salt‐sensitive hypertension, it appears that the sympathoexcitatory effects of salt predominate, possibly due to an inability to adequately suppress the levels or actions of ANG II. The net result, therefore, is an inappropriate increase in sympathetic activity during increased dietary salt which may contribute to the hypertensive process.

Chronic Infusion of Angiotensin II Resets Baroreflex Control of Heart Rate by an Arterial Pressure–Independent Mechanism

The purpose of this study was to test the hypothesis that chronic infusion of angiotensin II (Ang II) in rabbits resets the cardiac baroreflex to a higher arterial pressure level by a pressure-independent mechanism. This hypothesis was tested by determining whether the resetting would be reversed soon after the Ang II infusion was stopped even if the hypertension was maintained by infusion of another vasoconstrictor. Relationships between arterial pressure and heart rate were determined by infusion of increasing doses of nitroprusside to decrease pressure and increase heart rate, followed by increasing doses of phenylephrine to increase pressure and decrease heart rate. After 9 to 10 days of Ang II infusion (20 ng.kg-1.min-1) arterial pressure was increased from 62 +/- 2 to 94 +/- 3 mm Hg (P < .001), and heart rate was unchanged from control values of 126 +/- 7 beats per minute. The baroreflex relationship between arterial pressure and heart rate was shifted to a higher pressure level after 3 to 4 and 9 to 10 days of Ang II infusion. On these same days the Ang II infusion was replaced with phenylephrine (5.0 +/- 0.4 micrograms.kg-1.min-1), and 30 minutes later arterial pressure decreased slightly (P < .05); however, despite the relative hypotension, heart rate was decreased (P < .005) from 126 +/- 5 to 98 +/- 7 beats per minute (days 3 to 4) and from 132 +/- 4 to 103 +/- 7 beats per minute (days 9 to 10). Moreover, the cardiac baroreflex relationships were shifted back to a lower pressure level (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin in the Brain Increases Gain of Baroreflex Control of Heart Rate and Lumbar Sympathetic Nerve Activity

Chronic central administration of insulin increases the gain of baroreflex control of heart rate, but whether baroreflex control of the sympathetic nervous system is similarly affected is unknown. The sites and mechanisms by which brain insulin influences the baroreflex are also unclear. Therefore, the present study tested the hypothesis that acute infusion of insulin into the brain ventricles of urethane-anesthetized rats increases gain of baroreflex control of heart rate and lumbar sympathetic nerve activity and that this action is gender specific. Furthermore, to identify the location within the brain that mediates these effects, insulin was infused into either the lateral ventricle or the fourth ventricle. Lateral ventricular insulin infusion increased the gain of baroreflex control of heart rate (2.1±0.3 to 4.0±0.6 bpm/mm Hg; P<0.05) and sympathetic activity (2.3±0.3% to 4.8±1.1% control/mm Hg; P<0.05) within 60 to 90 minutes; however, the increase in heart rate gain was similar in males and females. Increases in the maximum of baroreflex control of heart rate (395±10 to 452±13 bpm; P<0.05) and of sympathetic activity (156±13% to 253±22% control; P<0.05) were also observed. In contrast, fourth ventricular insulin infusion failed to alter baroreflex function. In conclusion, increases in brain insulin act acutely in the forebrain to enhance gain of baroreflex control of heart rate and lumbar sympathetic nerve activity.

Pregnancy and the endocrine regulation of the baroreceptor reflex.

The purpose of this review is to delineate the general features of endocrine regulation of the baroreceptor reflex, as well as specific contributions during pregnancy. In contrast to the programmed changes in baroreflex function that occur in situations initiated by central command (e.g., exercise or stress), the complex endocrine milieu often associated with physiological and pathophysiological states can influence the central baroreflex neuronal circuitry via multiple sites and mechanisms, thereby producing varied changes in baroreflex function. During pregnancy, baroreflex gain is markedly attenuated, and at least two hormonal mechanisms contribute, each at different brain sites: increased levels of the neurosteroid 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), acting in the rostral ventrolateral medulla (RVLM), and reduced actions of insulin in the forebrain. 3alpha-OH-DHP appears to potentiate baroreflex-independent GABAergic inhibition of premotor neurons in the RVLM, which decreases the range of sympathetic nerve activity that can be elicited by changes in arterial pressure. In contrast, reductions in the levels or actions of insulin in the brain blunt baroreflex efferent responses to increments or decrements in arterial pressure. Although plasma levels of angiotensin II are increased in pregnancy, this is not responsible for the reduction in baroreflex gain, although it may contribute to the increased level of sympathetic nerve activity in this condition. How these different hormonal effects are integrated within the brain, as well as possible interactions with additional potential neuromodulators that influence baroreflex function during pregnancy and other physiological and pathophysiological states, remains to be clearly delineated.