Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats.

BACKGROUND AND PURPOSE: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. EXPERIMENTAL APPROACH: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. KEY RESULTS: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. CONCLUSION AND IMPLICATION: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

The impact of one or two missed doses on the duration of action of combined perindopril and indapamide.

To evaluate the persistence of the antihypertensive effect of perindopril 4 mg+indapamide 1.25 mg once daily for up to 72 h using the 'missed-dose' technique. Hypertensive patients were initially treated with perindopril 2 mg+indapamide 0.625 mg once daily. After 4 weeks, the 135 of 216 patients who still had a diastolic BP> or =85 mm Hg went on to receive perindopril 4 mg+indapamide 1.25 mg daily for a further 8 weeks. During either week 9 or 11, placebo was substituted for perindopril 4 mg+indapamide 1.25 mg on either one or two consecutive days to simulate BP changes, which might occur after one or two missed doses. A 24-h ambulatory BP recording was performed at baseline, after 9 or 11 weeks of perindopril+indapamide therapy and during the simulated missed doses, 24- 48 and 48-72 h after the administration of perindopril 4 mg+indapamide 1.25 mg. Significant (P<0.001) reductions in mean (+/-s.d.) 24-h ambulatory BP (mm Hg) during the first 24 h after perindopril 4 mg+indapamide 1.25 mg therapy versus baseline were noted for patients later randomized to the one missed dose (-15.9+/-10.5/-9.4+/-7.6) or two missed dose (-17.4+/-8.7/-10.3+/-5.1) sub-groups. A significant reduction in BP (P<0.001 versus baseline) was still present on the days when placebo was substituted for perindopril 4 mg+indapamide 1.25 mg with decreases in mean 24-h ambulatory BP from 24 to 48 h and 48 to 72 h after dosing being -11.9+/-10.1/-6.9+/-6.2 and -10.6+/-9.9/-5.8+/-5.7, respectively. Use of the 'missed-dose' technique has demonstrated a prolonged antihypertensive effect for perindopril 4 mg+indapamide 1.25 mg for up to 72 h, supporting the use of this combination as therapy for hypertension.

Role of brain aldosterone and mineralocorticoid receptors in aldosterone-salt hypertension in rats.

Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1 µg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. Other sets of rats received chronic intra-cerebroventricular (icv) infusion of aldo synthase (AS) inhibitor FAD286, MR blocker eplerenone or vehicle, electrolytic or sham lesions of the SFO, or intra-PVN infusion of AAV-MR-siRNA or AAV-AT1aR-siRNA. Infusion of aldo had no effect on 11ßHSD2, MR and AT1R mRNA in different nuclei but increased CYP11B2 mRNA in the SFO, and serum and glucocorticoid-kinase 1 (Sgk1) and epithelial sodium channel (ENaC) γ subunit mRNA in the SFO and supraoptic nucleus (SON). MR-siRNA decreased both MR and AT1R mRNA in the PVN by ∼ 60%, but AT1aR-siRNA only decreased AT1R mRNA. SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼ 50% and hypertension by ∼ 70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.

Brain 'ouabain,' sodium, and arterial baroreflex in spontaneously hypertensive rats.

To assess the possible role of brain "ouabain" in modulating arterial baroreflex function in salt-sensitive hypertension, arterial baroreflex control of renal sympathetic nerve activity and heart rate was evaluated in conscious spontaneously hypertensive rats and compared with that in Wistar-Kyoto rats. A regular sodium or high sodium diet was provided from 5 to 9 weeks of age, with intracerebroventricular infusion of antibody Fab fragments, which bind ouabainlike substances with high affinity, or, as control, nonspecific gamma-globulins (200 micrograms.12 microL-1.d-1 for both). Baroreflex function was assessed by plotting changes in renal sympathetic nerve activity or heart rate against changes in mean arterial pressure by phenylephrine and nitroprusside. In control Wistar-Kyoto rats, high sodium intake did not increase resting blood pressure but sensitized baroreflex control of renal sympathetic nerve activity. In control spontaneously hypertensive rats, high sodium intake significantly increased blood pressure but did not enhance renal sympathetic nerve activity responses. However, in spontaneously hypertensive rats given high sodium diets and treated with Fab fragments, blood pressure did not increase and the baroreflex control of renal sympathetic nerve activity was sensitized significantly. We conclude that in spontaneously hypertensive rats, increase of central "ouabain" by high sodium intake prevents an increase in the sensitivity of arterial baroreflex control of renal sympathetic nerve activity, as observed in Wistar-Kyoto rats on high sodium diets.

Brain 'ouabain' and desensitization of arterial baroreflex by high sodium in Dahl salt-sensitive rats.

In Dahl salt-sensitive (S) rats, high sodium intake further desensitizes arterial baroreflex function. To assess the possible involvement of brain "oubain," we gave Dahl S rats a regular or high sodium diet from 4 to 7 weeks of age and administered intracerebroventricular antibody Fab fragments, which bind ouabain with high affinity, or gamma-globulins as control (200 micrograms/12 microL per day for both) using osmotic minipumps. We assessed arterial baroreflex function by plotting changes in renal sympathetic nerve activity or heart rate against changes in mean arterial pressure of conscious rats elicited by intravenous phenylephrine and nitroprusside. Dahl S rats on high sodium treated with gamma-globulins showed a significantly higher resting mean arterial pressure versus other rats (130 to 140 versus 95 to 105 mm Hg). In rats treated with gamma-globulins, high sodium desensitized baroreflex control of renal sympathetic nerve activity compared with rats on regular sodium (average gain: -1.88 +/- 0.12 versus -2.73 +/- 0.13, P < .05). In contrast, in rats treated with Fab fragments, high sodium did not increase blood pressure and did not desensitize but slightly sensitized reflex control of renal sympathetic nerve activity. Changes in reflex control of heart rate were similar to those of renal sympathetic nerve activity. These data indicate that blockade of brain "oubain" prevents sodium-induced hypertension as well as the desensitization of the arterial baroreflex in Dahl S rats. Increased brain "oubain" may desensitize the arterial baroreflex and thereby facilitate the hypertension in Dahl S rats on high sodium.

Effects of arterial vasodilators on cardiac hypertrophy and sympathetic activity in rats.

In spontaneously hypertensive rats (SHR), the progression (or absence of regression) of cardiac hypertrophy despite adequate blood pressure (BP) control by arterial vasodilators has been attributed to increased cardiac sympathetic activity. We evaluated changes in indices of general and cardiac sympathetic tone in relation to changes in cardiac anatomy during treatment of normotensive rats and SHR with hydralazine, 120 mg/L, or minoxidil, 120 mg/L of drinking water. In SHR, both vasodilators reduced BP rapidly and consistently. Significant increases in heart rate and plasma norepinephrine were observed only in the initial 2 days of arterial vasodilator treatment. After 5 weeks of treatment, marked increases in left and right ventricular sympathetic activity (as assessed by norepinephrine turnover rates) were present, but no increase was seen in heart rate and plasma norepinephrine. Intravascular volume expansion was observed on Day 14 of minoxidil and Day 35 of hydralazine treatment. Prolonged treatment with minoxidil induced significant increases in left ventricular internal diameter, as well as in left and right ventricular weights, but not in the wall thickness of the left ventricle. Treatment with hydralazine did not affect left ventricular weight and caused a small increase in the weight of the right ventricle. In normotensive rats, both vasodilators initially decreased BP, but tolerance developed within 1 to 2 weeks of treatment. Plasma norepinephrine and heart rate showed increases only at Day 1 of either treatment, whereas cardiac sympathetic hyperactivity persisted at 2 and 5 weeks of treatment. Changes in cardiac anatomy were qualitatively similar to those observed in SHR. We conclude that, during treatment of normotensive rats and SHR with arterial vasodilators, cardiac sympathetic hyperactivity persists and may be involved in the cardiac effects of arterial vasodilators. However, other mechanisms, such as chronic cardiac volume overload, may also play an important role, particularly with minoxidil.

Brain 'ouabain' in the median preoptic nucleus mediates sodium-sensitive hypertension in spontaneously hypertensive rats.

Pressor responses to an acute increase in cerebrospinal fluid sodium and exaggeration of the hypertension and sympathetic hyperreactivity in spontaneously hypertensive rats (SHR) by high sodium diet involve release of brain "ouabain" and subsequent activation of the brain renin-angiotensin system. In the present study, we determined whether release of "ouabain" in the median preoptic nucleus participates in these responses. In conscious Wistar rats, the pressor and heart rate responses to central hypertonic saline (0.3 mol/L NaCl, 3.8 microL/min over 10 minutes) and ouabain (0.6 microgram) were compared after median preoptic nucleus injection of either gamma-globulins or Fab fragments binding ouabain and brain "ouabain" with high affinity. Microinjection of Fab fragments into the median preoptic nucleus abolished the pressor and tachycardic responses to central hypertonic saline and significantly reduced the pressor response to central ouabain. In SHR on high sodium, microinjection of Fab fragments into the median preoptic nucleus significantly decreased baseline blood pressure to a level not different from that in SHR on regular sodium (149 +/- 7 versus 145 +/- 5 mm Hg), whereas the enhanced responses to air stress were not affected. Our results support the concept that blood pressure responses to central hypertonic saline and exaggeration of the hypertension in SHR by high sodium diet depend on release of brain "ouabain" in the median preoptic nucleus.

Brain "ouabain" and angiotensin II in salt-sensitive hypertension in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) received from 5 to 9 weeks of age a high or regular sodium diet and concomitant intracerebroventricular infusions via minipumps of the following compounds: antibody Fab fragments (200 micrograms/d), which bind ouabain and related steroids with high affinity; the angiotensin II (Ang II) type 1 receptor blocker losartan (1 mg/kg per day); a combination of Fab fragments and losartan; and as control, gamma-globulins (200 micrograms/d). The same doses of Fab fragments and losartan were also given intravenously. At 9 weeks of age, compared with SHR on regular sodium, SHR on high sodium that were treated with gamma-globulins had higher resting blood pressure and showed significantly enhanced excitatory responses of blood pressure, renal sympathetic nerve activity, and heart rate to air stress and inhibitory responses to the central alpha 2-agonist guanabenz. Central Fab fragments and losartan alone or combined prevented all these effects of high sodium. Intravenous Fab fragments or losartan was ineffective. Compared with control SHR on high sodium, SHR on high sodium that were treated with Fab fragments had significantly increased sympathoexcitatory and pressor responses to central Ang II injection, consistent with a decrease in brain Ang II receptor occupancy. These data indicate that both increased brain "ouabain" and Ang II contribute to salt-sensitive hypertension in SHR. Brain Ang II receptor stimulation appears to be downstream of "ouabain" in the pathways mediating sympathoexcitatory and pressor effects of high sodium.

Both brain angiotensin II and "ouabain" contribute to sympathoexcitation and hypertension in Dahl S rats on high salt intake.

-Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats from 5 to 9 weeks of age received a regular or high salt diet and concomitantly an intracerebroventricular infusion of the angiotensin type 1 blocker losartan (1 mg. kg-1. d-1) or antibody Fab fragments, which bind ouabain and related steroids with high affinity, or gamma-globulins as control (200 microg/d for both). At 9 weeks of age, blood pressure (BP), heart rate (HR), central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air stress and to intracerebroventricular alpha2-agonist guanabenz (50 microg) and ouabain (0.5 microg). Baroreflex function was assessed by acute volume expansion with intravenous 5% dextrose and ramp changes of BP by +/-50 mm Hg induced by intravenous phenylephrine and sodium nitroprusside. In Dahl S but not R rats, high salt significantly increased BP and HR; enhanced BP, HR, and renal sympathetic nerve activity responses to air stress and guanabenz; and attenuated cardiopulmonary and arterial baroreflex control of renal sympathetic nerve activity and HR. Both losartan and Fab fragments prevented these responses to high salt to a similar extent in Dahl S rats but had no effect in Dahl R rats on high salt. Sympathoexcitatory responses to ouabain were attenuated in Dahl S on high versus regular salt and were abolished in Dahl R or S treated with losartan or Fab fragments. Consistent with previous studies in SHR, the present data indicate that in Dahl S on high salt, both brain "ouabain" and angiotensin II contribute to decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex, and therefore hypertension.

Sympathoinhibitory effects of central nifedipine in spontaneously hypertensive rats on high versus regular sodium intake.

-The putative central sympathoinhibitory actions of the dihydropyridine calcium antagonist nifedipine and the effect of dietary sodium on these actions were investigated in spontaneously hypertensive rats (SHR). Regular or high dietary salt was administered from 4 to 8 weeks of age. At 8 weeks, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity were recorded in conscious rats at rest as well as in response to intravenous (50 microg/kg) and intracerebroventricular (5 and 50 microg/kg) injections of nifedipine and intracerebroventricular injections of vehicle. Resting mean arterial pressure was higher in SHR on high versus regular salt (159+/-3 versus 135+/-4 mm Hg; P<0. 05). Nifedipine administered intracerebroventricularly decreased BP as well as renal sympathetic nerve activity and HR in a dose-related manner. The responses reached their peak at 3 to 5 minutes and lasted approximately 30 minutes. Peak decreases in BP, renal sympathetic nerve activity, and HR in response to both doses of nifedipine were significantly larger in SHR on high versus regular salt. Nifedipine administered intravenously also decreased BP but, in contrast, caused (reflex) increases in renal sympathetic nerve activity and HR. On both diets, intracerebroventricular vehicle did not affect mean arterial pressure, renal sympathetic nerve activity, or HR. These data indicate that in contrast to its peripheral vasodilator effect, centrally administered nifedipine may decrease sympathetic outflow and therefore BP and HR. The enhanced sympathoinhibitory and depressor responses to nifedipine in SHR on high versus regular salt suggest that the sympathetic hyperactivity induced by high salt intake is dependent on neuronal calcium influx via L-type channels.

Brain renin-angiotensin system and ouabain-induced sympathetic hyperactivity and hypertension in Wistar rats.

In Dahl salt-sensitive rats on a high salt diet or normotensive rats with chronic central infusion of sodium, increased brain "ouabain" results in sympathetic hyperactivity and hypertension, possibly by activating the brain renin-angiotensin system. In the present study, we tested whether the hypertension caused by exogenous ouabain also depends on activation of brain renin-angiotensin system. In Wistar rats, ouabain (50 micrograms/d) was infused subcutaneously for 14 days with the use of osmotic minipumps. Concomitantly, in one group, the angiotensin II type 1 receptor blocker losartan (1 mg/kg per day) was infused intracerebroventricularly. On day 15, mean arterial pressure, heart rate, central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, intracerebroventricular injection of the alpha(2)-agonist guanabenz (25 and 75 micrograms) or angiotensin II (30 ng), acute volume expansion, and ramp changes of blood pressure by +/-50 mm Hg with phenylephrine and nitroprusside. Compared with control rats, in rats treated with ouabain, resting mean arterial pressure was significantly increased (111+/-4 versus 93+/-3 mm Hg; P<0.05), and increases or decreases in mean arterial pressure, heart rate, and renal sympathetic nerve activity in response to air stress or guanabenz were enhanced significantly. These effects of ouabain were prevented when losartan was given concomitantly. Maximal slopes of arterial baroreflex control of renal sympathetic nerve activity and heart rate tended to be decreased in ouabain-treated versus control rats and were significantly increased in ouabain-treated rats with versus without losartan. No differences in cardiopulmonary baroreflex function were detected. It seems that by day 14 to 15, the central effect of ouabain on baroreflex control prevails over its peripheral sensitizing effect on baroreceptors, leading to a tendency of desensitization. These results indicate that chronic administration of ouabain activates the brain renin-angiotensin system, resulting in decreased sympathoinhibition and increased sympathoexcitation, impairment of baroreflex function, and hypertension.

Chronic central versus peripheral ouabain, blood pressure, and sympathetic activity in rats.

To assess whether chronic ouabain administration causes hypertension by increasing sympathetic activity, we recorded arterial blood pressure and heart rate at rest and after ganglionic blockade in conscious Wistar rats following 10 to 14 days of central or peripheral administration of ouabain. Intracerebroventricular or intravenous infusion of ouabain (10 micrograms/d for both) as well as subcutaneous ouabain pellets (releasing 25 micrograms ouabain/d per pellet) increased mean arterial pressure by 20 to 30 mm Hg and heart rate by 40 to 60 beats per minute. Ouabain pellets increased blood pressure and heart rate in a dose-related manner. After 2 weeks of all ouabain treatments, ouabainlike activity in plasma was not changed but increased significantly in hypothalamus and adrenals. Ouabainlike activity in the adrenals was increased more by intravenous than subcutaneous or intracerebroventricular ouabain treatment, but the different treatment modes caused similar increases in the hypothalamus. Concomitant central infusion of antibody Fab fragments against ouabain prevented the ouabain pellet-induced increases in blood pressure and heart rate. Ganglionic blockade by intravenous hexamethonium normalized blood pressure and heart rate in ouabain-treated rats. These data suggest that in normotensive rats exogenous ouabain, regardless of the mode of administration, may act centrally to cause sympathoexcitation and thus hypertension.

Digoxin prevents ouabain and high salt intake-induced hypertension in rats with sinoaortic denervation.

Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabain-like activity ("ouabain") in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 microg/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 microg x kg(-1) x d(-1)). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 microg x kg(-1) x d(-1)) or intracerebroventricular (ICV) antibody Fab fragments (200 microg/d), which bind "ouabain" with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na+, K(+)-ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and "ouabain" in the brain, thereby delaying ouabain- and preventing high salt-induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain "ouabain" or ouabain.

Sympathoexcitatory effect of hypothalamic/hypophysary inhibitory factor in rats.

We recorded changes in arterial blood pressure, heart rate, and renal sympathetic nerve activity in response to intracerebroventricular injection of bovine hypothalamic/hypophysary inhibitory factor and ouabain in conscious Wistar rats. Ouabain at 0.3 to 0.6 microgram caused dose-related increases in blood pressure, heart rate, and nerve activity (peak increases: 19 +/- 2 mm Hg, 42 +/- 4 beats per minute, and 48 +/- 4%, respectively; P < .05 versus basal). These responses were all blocked by central antibody Fab fragments, which bind ouabain and related steroids with high affinity. The inhibitory factor significantly increased blood pressure but decreased heart rate and nerve activity. Dose-dependent increases in blood pressure as well as heart rate and nerve activity were observed when the inhibitory factor was injected after intravenous injection of the vasopressin antagonist D-(CH2)5Tyr-(Me)AVP. Central Fab fragments, however, did not affect these responses. Both ouabain and the inhibitory factor inhibited Na+,K+-ATPase activity in vitro. Fab fragments blocked this inhibition by ouabain but not by the inhibitory factor. These data indicate that the ouabainlike sympathoexcitatory effect of this factor is masked probably by a potent central effect on vasopressin release. In contrast to rat brain "ouabain," this factor does not exhibit a high affinity for the Fab fragments, supporting the previous finding that this compound is structurally a nonouabain Na+,K+-ATPase inhibitor.

Patterns of neuronal activation during development of sodium sensitive hypertension in SHR.

The effects of regular (RNa) or high (HNa) sodium diet for 3, 7, and 14 days on Fra-like immunoreactivity (Fra-LI) in the brains of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were examined using an antibody that recognizes all known members of the Fos family (Fos, Fos-B, Fra-1, and Fra-2). Two weeks of HNa significantly exacerbated hypertension in SHR but had no effects in WKY. On RNa, compared with WKY, SHR showed higher Fra-LI in the median preoptic nucleus, supraoptic nucleus, both parts of the paraventricular nucleus, nucleus of the solitary tract, and central gray. Fra-LI in the subfornical organ did not differ between the two strains. On RNa, Fra-LI in the anterior hypothalamic area could be detected only in WKY. In osmoregulatory areas, HNa diet increased Fra-LI in both SHR and WKY to comparable extents, but in the median preoptic nucleus, Fra-LI was increased to a greater extent in SHR. HNa produced smaller increases in the subfornical organ of SHR compared with WKY. In both the parvocellular and magnocellular paraventricular nuclei, increases in Fra-LI by HNa were more pronounced in SHR than in WKY. In the anterior hypothalamic area, Fra-LI could no longer be detected in WKY on HNa, whereas it appeared in SHR. HNa increased Fra-LI in the NTS and central gray to similar levels in WKY and SHR. These results indicate that WKY and SHR differ in the pattern of neuronal activation accompanying maturation on RNa. HNa activates neurons in a number of brain areas, and the pattern of these changes also differs between WKY and SHR.

Chronic dietary tyrosine supplements do not affect mild essential hypertension.

The blood pressure and plasma norepinephrine response to oral tyrosine, the precursor of norepinephrine, supplementation (2.5 g t.i.d.) of regular meals was examined in 13 untreated patients with mild essential hypertension. Using a randomized double-blind crossover design, each 2-week treatment was followed by a 2-week supplement-free interval. Supine and standing blood pressure and plasma norepinephrine levels were measured at the beginning and end of each 2-week treatment. Plasma tyrosine levels increased (p less than 0.001) from 71.2 +/- 8.0 nM/ml at baseline to 152.8 +/- 17.4 nM/ml 2 hours after the tyrosine supplement. Blood pressure under control conditions was 144 +/- 3 Hg systolic, 91 +/- 2 mm Hg diastolic (109 +/- 2 mm Hg mean) after 30 minutes in the supine position and 148 +/- 4 mm Hg systolic, 102 +/- 3 mm Hg diastolic (117 +/- 3 mm Hg mean) after 5 minutes of standing. Plasma norepinephrine levels were 191 +/- 18 pg/ml in the supine subjects and 390 +/- 33 pg/ml in the standing subjects. No difference in systolic, diastolic, or mean blood pressure, heart rate, or plasma norepinephrine levels were seen between the beginning and end of each period or between groups. Individual changes in blood pressure showed no correlation with individual changes in norepinephrine levels. These results indicate that the addition of a tyrosine supplement to the usual diet of mild hypertensive subjects has no beneficial effect on blood pressure.

Aging and cardiovascular responsiveness to beta-agonist in humans: role of changes in beta-receptor responses versus baroreflex activity.

OBJECTIVES: To assess age-related changes in the cardiac chronotropic and inotropic responses and arterial responses to beta-receptor stimulation and the potential role of the arterial baroreflex on these responses. METHODS AND RESULTS: Isoproterenol alone was infused in 14 young subjects (age, 30 +/- 2 years) and 15 older healthy volunteers (age, 60 +/- 2 years) and together with ganglionic blockade (trimethaphan) in eight young and eight older subjects. Isoproterenol was infused at 3 to 4 incremental rates. Cardiac function was assessed by echocardiography and peripheral arterial responses were measured by venous occlusion plethysmography. Before ganglionic blockade, isoproterenol at infusion rates from 0.005 to 0.03 micrograms/kg/min caused similar changes in heart rate, ejection fraction, and mean normalized systolic ejection rate in the young and older subjects. With concomitant use of trimethaphan, isoproterenol at infusion rates from 0.0025 to 0.01 micrograms/kg/min caused in young subjects a larger increase in heart rate (29 +/- 2 beats/min [young] versus 20 +/- 3 [older] at peak infusion; p = 0.03), ejection fraction (11% +/- 2% [young] versus 6% +/- 1% [older]; p < 0.01), and mean normalized systolic ejection rate (1.13 +/- 0.2 ml/sec [young] versus 0.48 +/- 0.09 [older]; p < 0.01). Whereas percentage changes in total peripheral resistance were larger in the young subjects, there were no significant age-related differences in the responses of forearm blood flow and resistance before or after ganglionic blockade. CONCLUSIONS: These results indicate an age-related decrease in beta-receptor responsiveness of both sinoatrial node and ventricular myocardium that is masked by a concomitant decrease in the baroreflex control of the heart.

Catecholamines and heart function in heart transplant patients: effects of beta1- versus nonselective beta-blockade.

OBJECTIVES: To evaluate cardiac responses to norepinephrine and epinephrine in heart transplant patients compared with patients with mild essential hypertension and to evaluate the contribution of beta2-receptors versus beta1-receptors to the cardiac responses by assessing the effects of the 2 agonists after treatment with placebo compared with the beta1-selective blocker atenolol and the nonselective blocker nadolol. METHODS: A double-blind, randomized crossover design was used to study patients after administration of placebo, atenolol, or nadolol for 2 weeks. Infusion of norepinephrine was performed at incremental rates of 12.5, 25, 50, and 100 ng/kg/min and of epinephrine at rates of 20, 40, 80, and 120 ng/kg/min. Blood pressure, heart rate, left ventricular function (by echocardiogram), and venous plasma concentrations were assessed at rest and at the end of each infusion rate. RESULTS: Infusion of epinephrine and norepinephrine was associated with 3-fold and 2-fold higher increases, respectively, in plasma concentrations in the transplant patients versus patients with hypertension. Enhanced blood pressure responses to either agonist were found in the transplant patients, but not when venous plasma concentrations were considered. Norepinephrine decreased heart rate and cardiac index in patients with hypertension receiving placebo and more markedly when receiving atenolol and nadolol. In contrast, heart transplant patients showed increases in heart rate, ejection fraction, and cardiac index, which largely were blocked (but not reversed into decreases) by atenolol and nadolol. In patients with hypertension receiving placebo, epinephrine increased heart rate, ejection fraction, and cardiac index. These responses were enhanced in transplant patients, also relative to plasma concentrations. Atenolol had only minor effects on these cardiac responses. On nadolol epinephrine decreased heart rate, stroke volume, and cardiac index in the patients with hypertension, whereas the transplant patients receiving nadolol showed no longer increases in cardiac function by epinephrine. CONCLUSIONS: Both absence of parasympathetic buffering and diminished systemic clearance contributed to the enhanced cardiac responses to infusion of norepinephrine and epinephrine in heart transplant patients compared with patients with essential hypertension. Cardiac beta2-receptors mediate most of the chronotropic and inotropic responses to epinephrine in both patients with hypertension and heart transplant patients.

Nonselective beta-receptor stimulation and blockade and left ventricular function.

The effects of increasing doses of intravenous isoproterenol on left ventricular (LV) size and function were assessed before and after oral propranolol (80 mg). Eleven normal subjects were studied by M-mode echocardiography. The isoproterenol dose was increased until heart rate had risen by 25 to 30 b.p.m. LV end-diastolic (LVED) dimension (46.6 +/- 1.3 mm) was increased by isoproterenol (to 48.8 +/- 1.5 mm) and decreased by propranolol (to 45 +/- 1 mm). LV end-systolic dimension was decreased by isoproterenol and increased by propranolol. Isoproterenol increased LVED dimension despite the opposing effect of the tachycardia, whereas propranolol decreased LVED dimension despite its negative inotropic and chronotropic effects. These results suggest that nonselective beta-receptor stimulation or blockade can affect cardiac output through direct cardiac actions and by influencing venous return.

Age, hypertension, and cardiac responses to beta-agonist in humans.

OBJECTIVES: To evaluate the effects of hypertension on heart rate and left ventricular responses to beta-agonist in young and older subjects, as well as the modulating effect of the arterial baroreflex on these responses. METHODS: Isoproterenol (INN, isoprenaline) alone was infused in 14 young normotensive subjects (mean age, 30 +/- 2 years), 18 older normotensive subjects (mean age, 60 +/- 2 years), 11 young hypertensive subjects (mean age, 36 +/- 1 years), and 17 older hypertensive subjects (mean age, 59 +/- 1 years); isoproterenol combined with ganglionic blockade (trimethaphan [INN, trimetaphan]) was administered to eight young normotensive subjects and eight young hypertensive subjects. Isoproterenol was infused at three to four incremental rates, each rate for 8 minutes. Left ventricular responses were assessed by echocardiography. RESULTS: Isoproterenol caused similar increases in heart rate in all four groups. With ganglionic blockade, heart rate responses were enhanced but were similar in the young normotensive and hypertensive subjects. In young subjects, hypertension did not affect left ventricular responses to isoproterenol alone, whereas older hypertensive subjects showed some blunting of left ventricular responses compared with older normotensive subjects. With ganglionic blockade, young hypertensive subjects also showed mild blunting of left ventricular responses. CONCLUSION: These results show that, in humans, hypertension does not lead to a decrease in chronotropic responses to infusion of the beta-agonist isoproterenol and causes only a modest decrease in left ventricular responses.