Joseph R. Haywood

Interactions of vasopressin with the area postrema in arterial baroreflex function in conscious rabbits.

This study compares the effect of arginine-vasopressin with phenylephrine on arterial pressure, heart rate, and renal sympathetic nerve activity in conscious rabbits with and without functional arterial baroreflexes and in rabbits with lesions of the area postrema. In intact rabbits, progressive infusions of arginine-vasopressin result in large decreases in renal sympathetic nerve activity and heart rate for a given increase in blood pressure as compared to progressive infusions of phenylephrine. In sinoaortic-denervated rabbits, the responses of arterial pressure on heart rate and renal sympathetic nerve activity to both arginine-vasopressin and phenylephrine are markedly attenuated, indicating the necessity for afferent baroreceptor activity in this response. This observation indicates that arginine-vasopressin is acting centrally to enhance the baroreflex. A central site of action of circulating vasopressin may be the area postrema, since it is the only circumventricular organ in the hindbrain. Lesioning the region of the area postrema resulted in a normalization of the responses evoked with arginine-vasopressin and phenylephrine. There was no difference in the phenylephrine responses of arterial pressure on renal sympathetic nerve activity or heart rate in area postrema-lesioned animals, compared to control rabbits. Therefore, we conclude that the area postrema or its surrounding tissue is either a site of action of circulating arginine-vasopressin or contains fibers of passage from another site where arginine-vasopressin acts to enhance baroreflex activity.

Gender differences in sympathetic nervous system regulation

1. Females are protected against the development of hypertension. The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho‐adrenal nervous system and to determine if these differences support the hypothesis that, in females, the regulation of the sympathetic nervous system (SNS) is altered such that sympatho‐adrenal activation is attenuated or sympatho‐adrenal inhibition is augmented.

Cardiovascular responses to bicuculline in the paraventricular nucleus of the rat.

The present study was undertaken to determine whether y-aminobutyric acid in the paraventricular nucleus contributes to the regulation of cardiovascular function. Blood pressure and heart rate were recorded and plasma catecholamines were measured in conscious rats receiving microinfusions of either artificial cerebrospinal fluid or a y-aminobutyric acid antagonist, bicuculline methiodide, bilaterally into the paraventricular nucleus. Artificial cerebrospinal fluid had no effect on any of the recorded variables. In contrast, infusion of bicuculline into the region of the paraventricular nucleus produced increases in blood pressure (20 ±2 mm Hg), heart rate (110±ll beats/min), and plasma concentrations of norepinephrine (640±107 pg/ml) and epinephrine (lt266±267 pg/ml). Pretreatment with a ganglionic blocking agent abolished both the blood pressure (-1±2 mm Hg) and heart rate (5±18 beats/min) effects. Bilateral adrenal medullectomy reduced the changes in plasma norepinephrine concentrations (81 ±14 pg/ml) significantly and abolished the changes in plasma epinephrine concentrations (5±4 pg/ml). Conversely, adrenal medullectomy reduced the pressor effects (18±2 mm Hg) only slightly while the heart rate responses were attenuated (42 ±9 beats/min) by approximately 50%. These results suggest that an endogenous y-aminobutyric acid system exerts a tonic inhibitory effect on the sympathetic nervous system at the level of the paraventricular nucleus of the hypothalamus.

Ovariectomy Augments Hypertension in Aging Female Dahl Salt-Sensitive Rats

The ovariectomized (OVX) Dahl salt-sensitive (DS) rat fed a low-salt diet is a model of postmenopausal hypertension. In addition to estrogen loss, aging can also contribute to postmenopausal hypertension. We hypothesized that: (1) female DS rats on a low-salt diet become hypertensive with age; (2) ovariectomy accelerates age-dependent hypertension in the DS rat caused by estrogen depletion; and (3) this hypertension correlates with increased type 1 angiotensin receptor (AT1R) number (Bmax). Blood pressure was monitored by telemetry from 3 to 12 months and AT1R Bmax was determined by Scatchard analysis in glomeruli and adrenal cortex. Three groups of DS rats were studied: intact, OVX, and 17&bgr;-estradiol–replaced OVX (OVX+E). In intact rats, aging to 12 months resulted in hypertension (159±6 mm Hg) and an 82% decrease in estrogen. Blood pressure in OVX was significantly higher than OVX+E through 12 months of age (173±4 versus 150±8 mm Hg). At 4 months, OVX increased AT1R Bmax compared with intact and OVX+E in both glomeruli and adrenal cortex. Aging also increased AT1R Bmax in these tissues in intact rats. In summary, female DS rats fed a low-salt diet have hypertension develop with age, that is accelerated by OVX and attenuated by estrogen replacement. Concurrently, AT1Rs are upregulated by age and OVX, which is prevented by estrogen replacement. This study suggests that an increased activity of the renin angiotensin system contributes to the development of hypertension, and estrogen protects against this process.

Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus

The purpose of the present study was to determine the overall cardiovascular and sympathetic nervous system responses to stimulation of neuronal cell bodies in the paraventricular nucleus (PVN) of the hypothalamus. Bilateral microinjections (50 nl) of monosodium glutamate or sodium acetate were made into the PVN of conscious unrestrained rats. Blood pressure, heart rate and plasma concentrations of norepinephrine and epinephrine were measured. The injection of sodium acetate as an osmotic control was without effect on any of the recorded variables. In contrast, the injections of glutamate were associated with a rapid increase in both blood pressure and heart rate. At doses of 15, 25, and 50 nmol blood pressure increased by 13 +/- 2, 14 +/- 3 and 16 +/- 1 mmHg while heart rate increased by 64 +/- 15, 73 +/- 8 and 50 +/- 8 bpm. These responses were associated with increases in plasma norepinephrine concentrations of 51 +/- 8, 100 +/- 16 and 62 +/- 13 pg/ml while epinephrine concentrations rose by 42 +/- 17, 58 +/- 18 and 38 +/- 17 pg/ml. The responses of glutamate (25 nmol) were not affected by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me)AVP (10 micrograms/kg) (blood pressure: pre 15 +/- 3 vs post 13 +/- 3 mmHg, heart rate: pre 77 +/- 9 bpm vs post 91 +/- 7 bpm, plasma norepinephrine: pre 106 +/- 22 vs post 121 +/- 28 pg/ml and plasma epinephrine: pre 61 +/- 25 vs post 34 +/- 30 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Role of Female Sex Hormones in the Development and Reversal of Dahl Hypertension

Female sex hormones protect against the development of Dahl hypertension mediated by increases in dietary sodium. The role of female sex hormones in the reversal of Dahl hypertension mediated by decreases in dietary sodium is unknown. The goal of this study was to identify sex differences in the reversal of Dahl hypertension and the associated changes in water and electrolyte homeostasis. Male (M, n=8), female (F, n=8), and ovariectomized female (OVX, n=9) Dahl salt-sensitive rats were instrumented with an abdominal radiotelemetry device for 24-hour monitoring of blood pressure (BP) and heart rate. Daily measurements of food intake, water intake, and urine output were recorded as diet was changed from a low-sodium diet (0.15% NaCl) to a diet containing 8% NaCl. The diet was then changed back to 0.15% NaCl. The responses to changes in the salt diet were compared with responses observed in rats (M, n=4; F, n=4; OVX, n=4) that were maintained on 0.15% NaCl during the experiment. Sex differences in BP were observed when M, F, and OVX rats were fed 8% NaCl diet for 2 weeks (152+/-4, 141+/-3, and 154+/-5 mm Hg, respectively). BP was significantly greater (P<0.05) in M and OVX rats than in F rats. Fluid balance (water intake minus urine volume) and sodium balance (sodium intake minus sodium excretion) were similar in all groups on the 8% NaCl diet. BP in time-control M, F, and OVX rats was 121+/-3, 130+/-4, and 162+/-11 mm Hg, respectively. Compared with time-control groups, differences in BP while rats were eating the 8% NaCl diet were observed in M and F rats but not OVX rats. Reinstatement of an NaCl-deficient diet reversed the hypertension in M and F but not OVX rats (124+/-4, 124+/-2, and 145+/-5 mm Hg, respectively). The changes in dietary sodium caused similar changes in renal handling of sodium and water in all groups of rats; therefore, the effect on blood pressure was independent of renal excretory function. The inability to reverse the hypertension by decreasing sodium intake in OVX rats and the development of spontaneous hypertension in OVX females maintained on a low-sodium diet indicates that removal of the female sex hormones predisposes the animal to the development of hypertension that is sodium independent. We conclude that female sex hormones protect Dahl S rats against the development of sodium-dependent and -independent hypertension.

Sympathoexcitation by PVN-Injected Bicuculline Requires Activation of Excitatory Amino Acid Receptors

Abstract—Acute blockade of &ggr;-aminobutyric acid (GABA)-A receptors in the hypothalamic paraventricular nucleus (PVN) increases mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). However, the underlying neural mechanisms have not been fully determined. We tested the hypothesis that responses to GABA-A receptor blockade in the PVN require activation of local ionotropic excitatory amino acid (EAA) receptors. MAP, HR, and renal SNA responses to unilateral PVN microinjection of bicuculline methobromide (BIC, 0.1 nmol) were recorded before and after ipsilateral PVN injection of either vehicle (saline), the nonselective ionotropic EAA receptor antagonist kynurenate (KYN), the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5), or the non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX). Responses to PVN-injected BIC were unaltered by vehicle injection. In contrast, injection of KYN (7.2 nmol; n=4) nearly abolished ABP and renal SNA responses to BIC (P <0.01) and significantly attenuated (P <0.05) HR responses as well. Similarly, graded doses of AP5 (0.6, 3, and 6 nmol) and NBQX (0.26, 1.3, and 2.6 nmol) reduced responses to PVN-injected BIC in a dose-related manner, with the 3 nmol (n=7) and 1.3 nmol (n=6) doses producing maximal effects (P <0.05). KYN, AP5, and NBQX did not affect baseline parameters. Effects of a cocktail containing AP5 (3 nmol) and NBQX (1.3 nmol) were greater (P <0.01) than either antagonist alone and were not statistically different from KYN. These data indicate that cardiovascular and renal sympathetic responses to acute GABA-A receptor blockade in the PVN require local actions of EAAs at both NMDA and non-NMDA receptors.

Contribution of the sympathetic nervous system to vascular resistance in conscious young and adult spontaneously hypertensive rats.

SUMMARY Although evidence exists for exaggerated sympathetic nervous system activity in spontaneously hypertensive rats (SHR), there are no studies in conscious animals that directly demonstrate that this increased activity is functionally involved in the elevated vascular resistance of these animals. In our present study, 8-week-old and 13-week-old SHR and Wistar Kyoto controls (WKY) were chronically Instrumented with arterial and venous catheters and miniaturized pulsed Doppler flow probes on the renal and mesenteric arteries and lower abdominal aorta. While the rats were conscious and unrestrained, bexamethonium was administered intravenously to block sympathetic nervous system transmission. Prior to bexamethonlum, the mean arterial pressure of young SHR and WKY averaged 123 ± 5 and 109 ± 4 nun Hg respectively (p < 0.05), while adult SHR and WKY averaged 159 ± 7 and 128 ± 3 mm Hg respectively (p < 0.05). Hexamethonium produced an equivalent fall in arterial pressure of young SHR (-32%) and WKY (-30%) and adult SHR (-39%) and WKY (-41%). Vascular resistance was reduced by hexamethonium in the kidney, gut, and hindquarters, but the percent changes were not significant between SHR and WKY. These data suggest that, in both young and adult SHR, vascular resistance and arterial pressure are sustained at elevated levels by some other mechanism than aeurally-derived vasoconstrictor tone.

Seven Days of Euglycemic Hyperinsulinemia Induces Insulin Resistance for Glucose Metabolism but Not Hypertension, Elevated Catecholamine Levels, or Increased Sodium Retention in Conscious Normal Rats

Epidemiological studies have suggested an association among chronic hyperinsulinemia, insulin resistance, and hypertension. However, the causality of this relationship remains uncertain. In this study, chronically catheterized conscious rats were made hyperinsulinemic for 7 days (∼90 mU/1, i.e., threefold over basal), while strict euglycemia was maintained (∼130 mg/dl, coefficient of variation <10%) by using a modification of the insulin/glucose clamp technique. Control rats received vehicle infusion. Baseline mean arterial pressure and heart rate were 125 ± 5 mmHg and 427 ± 12 beats/min and remained unchanged during the 7-day infusion of insulin (127 ± 7 mmHg; 401 ± 12 beats/min) or vehicle (133 ± 4 mmHg; 411 ± 10 beats/min). Baseline plasma epinephrine (88 ± 15 pg/ml), norepinephrine (205 ± 31 pg/ml), and sodium balance (0.34 ± 0.09 mmol) remained constant during the 7-day insulin or vehicle infusion. After 7 days of insulin or vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-3H]glucose infusion to quantitate whole-body glucose uptake, glycolysis, glucose storage (total glucose uptake minus glycolysis), and hepatic glucose production. Compared with vehicle-treated rats, 7 days of sustained hyperinsulinemia resulted in a reduction (P < 0.01) in insulin-mediated glucose uptake, glucose storage, and glycolysis by 39, 62, and 26%, respectively. Hepatic glucose production was normally suppressed after 7 days of hyperinsulinemia. Neither insulin-stimulated glucose uptake nor glucose storage correlated with blood pressure or heart rate. In conclusion, 7 days of euglycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but does not increase blood pressure, catecholamine levels, or sodium retention. This indicates that hyperinsulinemia-induced insulin resistance is not associated with the development of hypertension in rats who do not have a genetic predisposition for hypertension. Because hyperinsulinemia was initiated in normal rats under euglycemic conditions, additional (inherited or acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.