Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men

Cardiovagal baroreflex sensitivity (BRS) declines with advancing age in healthy men. We tested the hypothesis that oxidative stress contributes mechanistically to this age-associated reduction. Eight young (23 +/- 1 yrs, means +/- SE) and seven older (63 +/- 3) healthy men were studied. Cardiovagal BRS was assessed using the modified Oxford technique (bolus infusion of 50-100 microg sodium nitroprusside, followed 60 s later by a 100- to 150-microg bolus of phenylephrine hydrochloride) in triplicate at baseline and during acute intravenous ascorbic acid infusion. At baseline, cardiovagal BRS (slope of the linear portion of the R-R interval-systolic blood pressure relation during pharmacological changes in arterial blood pressure) was 56% lower (P < 0.01) in older (8.3 +/- 1.6 ms/mmHg) compared with young (19.0 +/- 3.1 ms/mmHg) men. Ascorbic acid infusion increased plasma concentrations similarly in young (62 +/- 9 vs. 1,249 +/- 72 micromol/l for baseline and during ascorbic acid; P < 0.05) and older men (62 +/- 4 vs. 1,022 +/- 55 micromol/l; P < 0.05) without affecting baseline blood pressure, heart rate, carotid artery compliance, or the magnitude of change in systolic blood pressure in response to bolus sodium nitroprusside and phenylephrine hydrochloride infusion. Ascorbic acid (vitamin C) infusion increased cardiovagal BRS in older (Delta58 +/- 16%; P < 0.01), but not younger (Delta - 4 +/- 4%) men. These data provide experimental support for the concept that oxidative stress contributes mechanistically to age-associated reductions in cardiovagal BRS in healthy men.     

Individualizing the aorto-radial pressure transfer function: feasibility of a model-based approach

We fitted a three-segment transmission line model for the radial-carotid/aorta pressure transfer function (TFF) in 31 controls and 30 patients with coronary artery disease using noninvasively measured (tonometry) radial and carotid artery pressures (P(car)). Except for the distal reflection coefficient (0.85 +/- 0.21 in patients vs. 0.71 +/- 0.25 in controls; P < 0.05), model parameters were not different between patients or controls. Parameters were not related to blood pressure, age, or heart rate. We further assessed a point-to-point averaged TFF (TFF(avg)) as well as upper (TFF(max)) and lower (TFF(min)) enveloping TFF. Pulse pressure (PP) and augmentation index (AIx) were derived on original and reconstructed P(car) (P(car,r)). TFF(avg) yielded closest morphological agreement between P(car) and P(car,r) (root mean square = 4.3 +/- 2.3 mmHg), and TTF(avg) best predicted PP (41.5 +/- 11.8 vs. 41.1 +/- 10.0 mmHg measured) and AIx (-0.02 +/- 0.19 vs. 0.01 +/- 0.19). PP and AIx, calculated from P(car) or P(car,r), were higher in patients than in controls, irrespectively of the TFF used. We conclude that 1) averaged TFF yield significant discrepancies between reconstructed and measured pressure waveforms and subsequent derived AIx; and 2) different TFFs seem to preserve the information in the pressure wave that discriminates between controls and patients.     

High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men.

Resting whole leg blood flow and vascular conductance decrease linearly with advancing age in healthy adult men. The potential role of age-related increases in oxidative stress in these changes is unknown. Resting leg blood flow during saline and ascorbic acid infusion was studied in 10 young (25 +/- 1 yr) and 11 older (63 +/- 2 yr) healthy normotensive men. Plasma oxidized LDL, a marker of oxidative stress, was greater in the older men (P < 0.05). Absolute resting femoral artery blood flow at baseline (iv saline control infusion) was 25% lower in the older men (238 +/- 25 vs. 316 +/- 38 ml/min; P < 0.05), and it was inversely related to plasma oxidized LDL (r = -0.56, P < 0.01) in all subjects. Infusion of supraphysiological concentrations of ascorbic acid increased femoral artery blood flow by 37% in the older men (to 327 +/- 52 ml/min; P < 0.05), but not in the young men (352 +/- 41 ml/min; P = 0.28), thus abolishing group differences (P = 0.72). Mean arterial blood pressure was greater in the older men at baseline (86 +/- 4 vs. 78 +/- 2 mmHg; P < 0.05), but it was unaffected by ascorbic acid infusion (P >/= 0.70). As a result, the lower baseline femoral artery blood flow in the older men was mediated solely by a 32% lower femoral artery vascular conductance (P < 0.05). Baseline femoral vascular conductance also was inversely related to plasma oxidized LDL (r = -0.65, P < 0.01). Ascorbic acid increased femoral vascular conductance by 36% in the older men (P < 0.05) but not in the young men (P = 0.31). In conclusion, ascorbic acid infused at concentrations known to scavenge reactive oxygen species restores resting femoral artery blood flow in healthy older adult men by increasing vascular conductance. These results support the hypothesis that oxidative stress plays a major role in the reduced resting whole leg blood flow and increased leg vasoconstriction observed with aging in men.     

Does nitric oxide buffer arterial blood pressure variability in humans?

Animal studies suggest that nitric oxide (NO) plays an important role in buffering short-term arterial pressure variability, but data from humans addressing this hypothesis are scarce. We evaluated the effects of NO synthase (NOS) inhibition on arterial blood pressure (BP) variability in eight healthy subjects in the supine position and during 60 degrees head-up tilt (HUT). Systemic NOS was blocked by intravenous infusion of N(G)-monomethyl-L-arginine (L-NMMA). Electrocardiogram and beat-by-beat BP in the finger (Finapres) were recorded continuously for 6 min, and brachial cuff BP was recorded before and after L-NMMA in each body position. BP and R-R variability and their transfer functions were quantified by power spectral analysis in the low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15-0.35 Hz) ranges. L-NMMA infusion increased supine BP (systolic, 109 +/- 4 vs. 122 +/- 3 mmHg, P = 0.03; diastolic, 68 +/- 2 vs. 78 +/- 3 mmHg, P = 0.002), but it did not affect supine R-R interval or BP variability. Before L-NMMA, HUT decreased HF R-R variability (P = 0.03), decreased transfer function gain (LF, 12 +/- 2 vs. 5 +/- 1 ms/mmHg, P = 0.007; HF, 18 +/- 3 vs. 3 +/- 1 ms/mmHg, P = 0.002), and increased LF BP variability (P < 0.0001). After L-NMMA, HUT resulted in similar changes in BP and R-R variability compared with tilt without L-NMMA. Increased supine BP after L-NMMA with no effect on BP variability during HUT suggests that tonic release of NO is important for systemic vascular tone and thus steady-state arterial pressure, but NO does not buffer dynamic BP oscillations in humans.     

Relationships between high-sensitive C-reactive protein and markers of arterial stiffness in hypertensive patients. Differences by sex

ABSTRACT: BACKGROUND: The present study was designed to evaluate the relationship between high-sensitivity Creactive protein (hs-CRP) and arterial stiffness according to sex in patients with arterial hypertension. METHODS: A case-series study was carried out in 258 hypertensive patients without antecedents of cardiovascular disease or diabetes mellitus. Nephelometry was used to determine hs-CRP. Office or clinical and home blood pressures were measured with a validated OMRON model M10 sphygmomanometer. Ambulatory blood pressure monitoring was performed with the SpaceLabs 90207 system. Pulse wave velocity (PWV) and central and peripheral augmentation index (AIx) were measured with the SphygmoCor system, and a Sonosite Micromax ultrasound unit was used for automatic measurements of carotid intima-media thickness (IMT). Ambulatory arterial stiffness index and home arterial stiffness index were calculated as "1-slope" from the within-person regression analysis of diastolic-on-systolic ambulatory blood pressure. RESULTS: Central and peripheral AIx were greater in women than in men: 35.31 +/- 9.95 vs 26.59 +/- 11.45 and 102.06 +/- 20.47 vs 85.97 +/- 19.13, respectively. IMT was greater in men (0.73 +/- 0.13 vs 0.69 +/- 0.10). hs-CRP was positively correlated to IMT (r = 0.261), maximum (r = 0.290) and to peripheral AIx (r = 0.166) in men, and to PWV in both men (r = 0.280) and women (r = 0.250). In women, hs-CRP was negatively correlated to central AIx (r = 0.222). For each unit increase in hs-CRP, carotid IMT would increase 0.05 mm in men, and PWV would increase 0.07 m/sec in men and 0.08 m/sec in women, while central AIx would decrease 2.5 units in women. In the multiple linear regression analysis, hs-CRP explained 10.2 % and 6.7 % of PWV variability in women and men, respectively, 8.4 % of carotid IMT variability in men, and 4.9 % of central AIx variability in women. CONCLUSIONS: After adjusting for age, other cardiovascular risk factors and the use of antihypertensive and lipid-lowering drugs, hs-CRP was seen to be positively correlated to carotid IMT in men, and negatively correlated to central AIx in women. The association of hs-CRP to arterial stiffness parameters differs between men and women.     

Nitric oxide increases fluid extravasation from the splenic circulation of the rat

We hypothesized that nitric oxide (NO) contributes to intrasplenic fluid extravasation by inducing greater relaxation in splenic resistance arteries than veins such that intrasplenic microvascular pressure (P(C)) rises. Fluid efflux was estimated by measuring the difference between splenic blood inflow and outflow. Intrasplenic infusion of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) (0.3 microg. 10 microl(-1). min(-1)) caused a significant increase in intrasplenic fluid efflux (baseline: 0.8 +/- 0.4 ml/min, n = 10 vs. peak rise during SNAP infusion: 1.3 +/- 0.4 ml/min, n = 10; P < 0.05). Intrasplenic P(C) was measured in the isolated, blood-perfused rat spleen. Intrasplenic infusion of SNAP (0.1 microg. 10 microl(-1). min(-1)) caused a significant increase in P(C) (saline: 10.9 +/- 0.2 mmHg, n = 3 vs. SNAP: 12.2 +/- 0.2 mmHg, n = 3; P < 0.05). Vasoreactivity of preconstricted splenic resistance vessels to sodium nitroprusside (SNP) (1 x 10(-12)-1 x 10(-4) M) and SNAP (1 x 10(-10)-3 x 10(-4) M) was investigated with the use of a wire myograph system. Significantly greater relaxation of arterioles than of venules occurred with both SNP (%maximal vasorelaxation: artery 96 +/- 2.3, n = 9 vs. vein 26 +/- 1.9, n = 10) and SNAP (%maximal vasorelaxation: artery 50 +/- 3.5, n = 11 vs. vein 32 +/- 1.7, n = 8). These results are consistent with our proposal that differential vasoreactivity of splenic resistance arteries and veins to NO elevates intrasplenic P(C) and increases fluid extravasation into the systemic lymphatic system.     

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Antecedent hypoglycemia leads to impaired counterregulation and hypoglycemic unawareness. To ascertain whether antecedent portal vein hypoglycemia impairs portal vein glucose sensing, thereby inducing counterregulatory failure, we compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the counterregulatory response to subsequent hypoglycemia. Male Wistar rats were chronically cannulated in the carotid artery (sampling), jugular vein (glucose and insulin infusion), and mesenteric vein (glucose infusion). On day 1, the following three distinct antecedent protocols were employed: 1) HYPO-HYPO: systemic hypoglycemia (2.52 +/- 0.11 mM); 2) HYPO-EUG: systemic hypoglycemia (2.70 +/- 0.03 mM) with normalization of portal vein glycemia (portal vein glucose = 5.86 +/- 0.10 mM); and 3) EUG-EUG: systemic euglycemia (6.33 +/- 0.31 mM). On day 2, all groups underwent a hyperinsulinemic-hypoglycemic clamp in which the fall in glycemia was controlled so as to reach the nadir (2.34 +/- 0.04 mM) by minute 75. Counterregulatory hormone responses were measured at basal (-30 and 0) and during hypoglycemia (60-105 min). Compared with EUG-EUG, antecedent hypoglycemia (HYPO-HYPO) significantly blunted the peak epinephrine (10.44 +/- 1.35 vs. 15.75 +/- 1.33 nM: P = 0.01) and glucagon (341 +/- 16 vs. 597 +/- 82 pg/ml: P = 0.03) responses to next-day hypoglycemia. Normalization of portal glycemia during systemic hypoglycemia on day 1 (HYPO-EUG) prevented blunting of the peak epinephrine (15.59 +/- 1.43 vs. 15.75 +/- 1.33 nM: P = 0.94) and glucagon (523 +/- 169 vs. 597 +/- 82 pg/ml: P = 0.66) responses to day 2 hypoglycemia. Consistent with hormonal responses, the glucose infusion rate during day 2 hypoglycemia was substantially elevated in HYPO-HYPO (74 +/- 12 vs. 49 +/- 4 micromol x kg(-1) x min(-1); P = 0.03) but not HYPO-EUG (39 +/- 7 vs. 49 +/- 4 micromol x kg(-1) x min(-1): P = 0.36). Antecedent hypoglycemia local to the portal vein is required for the full induction of hypoglycemia-associated counterregulatory failure with slow-onset hypoglycemia.     

Low-dose estrogen therapy does not change postexercise hypotension, sympathetic nerve activity reduction, and vasodilation in healthy postmenopausal women

The aim of this study was to determine whether estrogen therapy enhances postexercise muscle sympathetic nerve activity (MSNA) decrease and vasodilation, resulting in a greater postexercise hypotension. Eighteen postmenopausal women received oral estrogen therapy (ET; n=9, 1 mg/day) or placebo (n=9) for 6 mo. They then participated in one 45-min exercise session (cycle ergometer at 50% of oxygen uptake peak) and one 45-min control session (seated rest) in random order. Blood pressure (BP, oscillometry), heart rate (HR), MSNA (microneurography), forearm blood flow (FBF, plethysmography), and forearm vascular resistance (FVR) were measured 60 min later. FVR was calculated. Data were analyzed using a two-way ANOVA. Although postexercise physiological responses were unaltered, HR was significantly lower in the ET group than in the placebo group (59+/-2 vs. 71+/-2 beats/min, P<0.01). In both groups, exercise produced significant decreases in systolic BP (145+/-3 vs. 154+/-3 mmHg, P=0.01), diastolic BP (71+/-3 vs. 75+/-2 mmHg, P=0.04), mean BP (89+/-2 vs. 93+/-2 mmHg, P=0.02), MSNA (29+/-2 vs. 35+/-1 bursts/min, P<0.01), and FVR (33+/-4 vs. 55+/-10 units, P=0.01), whereas it increased FBF (2.7+/-0.4 vs. 1.6+/-0.2 ml x min(-1) x 100 ml(-1), P=0.02) and did not change HR (64+/-2 vs. 65+/-2 beats/min, P=0.3). Although ET did not change postexercise BP, HR, MSNA, FBF, or FVR responses, it reduced absolute HR values at baseline and after exercise.     

Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women

The mechanisms mediating arterial stiffening with aging and menopause are not completely understood. We determined whether administration of tetrahydrobiopterin (BH(4)), a critical cofactor for endothelial nitric oxide synthase to produce nitric oxide, would increase vascular endothelial-dependent vasodilatory tone and decrease arterial stiffness in estrogen-deficient postmenopausal women. Additionally, we examined whether the beneficial effects of estrogen on vascular function were possibly related to BH(4). Arterial stiffness (carotid artery compliance) and endothelial-dependent vasodilation [brachial artery flow-mediated dilation (FMD)] were measured in postmenopausal (n = 24; 57 ± 1 yr, mean ± SE) and eumenorrheic premenopausal (n = 9; 33 ± 2 yr) women before and 3 h after the oral administration of BH(4). Subsequently, in postmenopausal women, vascular testing (before and after BH(4)) was repeated following randomization to either 2 days of transdermal estradiol or placebo. Baseline carotid artery compliance and brachial artery FMD were lower in postmenopausal than in premenopausal women (P < 0.0001). BH(4) administration increased carotid artery compliance (0.61 ± 0.05 to 0.73 ± 0.04 mm(2)·mmHg(-1)·10(-1) vs. baseline, P < 0.0001) and brachial artery FMD (P < 0.001) in postmenopausal women but had no effect in premenopausal women (P = 0.62). Carotid artery compliance (0.59 ± 0.05 to 0.78 ± 0.06 mm(2)·mmHg(-1)·10(-1), P < 0.001) and FMD increased in postmenopausal women in response to estradiol (P = 0.02) but were not further improved with the coadministration of BH(4), possibly because estrogen increased BH(4) bioavailability. Carotid artery compliance and FMD increased with BH(4) in the placebo group (P = 0.02). Although speculative, these results suggest that reduced vascular BH(4) may be an important contributor to arterial stiffening in estrogen-deficient postmenopausal women, related in part to reduced endothelial-dependent vasodilatory tone.     

Y1- and alpha1-receptor control of basal hindlimb vascular tone

The role of endogenous Y(1)-receptor activation on skeletal muscle vasculature under baseline conditions is currently debated and no in vivo studies have been performed to address this issue. Therefore, this study was designed to address the effect of Y(1)-receptor and/or alpha(1)-adrenoceptor antagonism on basal hindlimb vascular conductance in male Sprague-Dawley rats in vivo. Left hindlimb vascular conductance, carotid artery mean arterial pressure, and heart rate were measured during low volume infusion of N(2)-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-d-arginine amide (BIBP3226; 100 microg/kg), prazosin (20 microg/kg), and combined blockade to the left hindlimb. Vascular conductance increased 1.5 +/- 0.5 microl.min(-1).mmHg(-1) with BIBP3226 infusion, 1.7 +/- 0.5 microl.min(-1).mmHg(-1) with prazosin infusion, and 4.8 +/- 1.0 microl.min(-1).mmHg(-1) with combined blockade (P < 0.05). Interestingly, systolic vascular conductance increased in all three conditions, but diastolic vascular conductance only increased in the two conditions where BIBP3226 was present. These data indicate that Y(1)-receptor activation plays an important role in the regulation of vascular conductance in the resting rat hindlimb. Furthermore, this effect was of the same magnitude as the alpha(1)-adrenoceptor contribution. The differential flow profiles following alpha(1) blockade with and without Y(1)-receptor blockade supports local differences in receptor distribution.     

Electron spin resonance spectroscopy, exercise, and oxidative stress: an ascorbic acid intervention study.

Oxygen free radicals are highly reactive species that are produced in increased quantities during strenuous exercise and can damage critical biological targets such as membrane phospholipids. The present study examined the effect of acute ascorbic acid supplementation on exercise-induced free radical production in healthy subjects. Results demonstrate increases in the intensity of the alpha-phenyl-tert-butylnitrone adduct (0.05 +/- 0.02 preexercise vs. 0.19 +/- 0.03 postexercise, P = 0.002, arbitrary units) together with increased lipid hydroperoxides (1.14 +/- 0.06 micromol/l preexercise vs. 1.62 +/- 0.19 micromol/l postexercise, P = 0.005) and malondialdehyde (0.70 +/- 0.04 micromol/l preexercise vs. 0.80 +/- 0.04 micromol/l postexercise, P = 0.0152) in the control phase. After supplementation with ascorbic acid, there was no significant increase in the electron spin resonance signal intensity (0.02 +/- 0. 01 preexercise vs. 0.04 +/- 0.02 postexercise, arbitrary units), lipid hydroperoxides (1.12 +/- 0.21 micromol/l preexercise vs. 1.12 +/- 0.08 micromol/l postexercise), or malondialdehyde (0.63 +/- 0.07 micromol/l preexercise vs. 0.68 +/- 0.05 micromol/l postexercise). The results indicate that acute ascorbic acid supplementation prevented exercise-induced oxidative stress in these subjects.     

Aldosterone impairs baroreflex sensitivity in healthy adults

Animal studies suggest that acute and chronic aldosterone administration impairs baroreceptor/baroreflex responses. We tested the hypothesis that aldosterone impairs baroreflex control of cardiac period [cardiovagal baroreflex sensitivity (BRS)] and muscle sympathetic nerve activity (MSNA, sympathetic BRS) in humans. Twenty-six young (25 +/- 1 yr old, mean +/- SE) adults were examined in this study. BRS was determined by using the modified Oxford technique (bolus infusion of nitroprusside, followed 60 s later by bolus infusion of phenylephrine) in triplicate before (Pre) and 30-min after (Post) beginning aldosterone (experimental, 12 pmol.kg(-1).min(-1); n = 10 subjects) or saline infusion (control; n = 10). BRS was quantified from the R-R interval-systolic blood pressure (BP) (cardiovagal BRS) and MSNA-diastolic BP (sympathetic BRS) relations. Aldosterone infusion increased serum aldosterone levels approximately fourfold (P < 0.05) and decreased (P < 0.05) cardiovagal (19.0 +/- 2.3 vs. 15.6 +/- 1.7 ms/mmHg Pre and Post, respectively) and sympathetic BRS [-4.4 +/- 0.4 vs. -3.0 +/- 0.4 arbitrary units (AU).beat(-1).mmHg(-1)]. In contrast, neither cardiovagal (19.3 +/- 3.3 vs. 20.2 +/- 3.3 ms/mmHg) nor sympathetic BRS (-3.8 +/- 0.5 vs. -3.6 +/- 0.5 AU.beat(-1).mmHg(-1)) were altered (Pre vs. Post) in the control group. BP, heart rate, and MSNA at rest were similar in experimental and control subjects before and after the intervention. Additionally, neural and cardiovascular responses to a cold pressor test and isometric handgrip to fatigue were unaffected by aldosterone infusion (n = 6 subjects). These data provide direct experimental support for the concept that aldosterone impairs baroreflex function (cardiovagal and sympathetic BRS) in humans. Therefore, aldosterone may be an important determinant/modulator of baroreflex function in humans.     

Angiotensin II contributes to arterial compliance in congestive heart failure

Arterial compliance is determined by structural factors, such as collagen and elastin, and functional factors, such as vasoactive neurohormones. To determine whether angiotensin II contributes to decreased arterial compliance in patients with heart failure, this study tested the hypothesis that administration of an angiotensin-converting enzyme inhibitor improves arterial compliance. Arterial compliance and stiffness were determined by measuring carotid artery diameter, using high-resolution duplex ultrasonography, and blood pressure in 23 patients with heart failure secondary to idiopathic dilated cardiomyopathy. Measurements were made before and after intravenous administration of enalaprilat (1 mg) or vehicle. Arterial compliance was inversely related to both baseline plasma angiotensin II (r = -0.52; P = 0.015) and angiotensin-converting enzyme concentrations (r = -0.45; P = 0.041). During isobaric conditions, enalaprilat increased carotid artery compliance from 3.0 +/- 0.4 to 5.0 +/- 0.4 x 10(-10) N(-1). m(4) (P = 0.001) and decreased the carotid artery stiffness index from 17.5 +/- 1.8 to 10.1 +/- 0.6 units (P = 0.001), whereas the vehicle had no effect. Thus angiotensin II is associated with reduced carotid arterial compliance in patients with congestive heart failure, and angiotensin-converting enzyme inhibition improves arterial elastic properties. This favorable effect on the pulsatile component of afterload may contribute to the improvement in left ventricular performance that occurs in patients with heart failure treated with angiotensin-converting enzyme inhibitors.     

Physically active lifestyle enhances vagal-cardiac function but not central autonomic neural interaction in elderly humans

The cause of the age-related impairment of arterial baroreflex function remains ill-defined; moreover, it is unknown whether this impairment results from aging per se or from an inactive lifestyle associated with aging. In this study, we sought to: 1) determine whether elderly individuals who maintained an active lifestyle had an enhanced carotid baroreflex function as compared with their sedentary counterparts; and 2) determine whether this difference was due in part to altered function of the arterial baroreceptor and/or altered central modulation. Eight healthy, sedentary (SED, 68+/-2 yr) and eight physically active (ACT, 68+/-1 yr) elderly men with peak O(2) consumption 25.5+/-1.2 vs 35.7+/-2.4 ml/min/kg (P<0.01), respectively, were assessed with carotid baroreceptor (CBR) function using 5s pulses of neck pressure or suction (ranging from +40 to -80 Torr) delivered to the carotid sinus region at rest and during lower body negative pressure (LBNP) of -15 and -40 Torr. Changes in heart rate (HR) and mean arterial pressure (MAP) were assessed for CBR-HR and CBR-MAP gains, respectively. Overall CBR-HR gains in a range of approximately 120 mmHg of carotid sinus pressure were greater (P<0.01) in ACT than SED at rest and during LBNP. The derived peak CBR-HR slopes between ACT and SED at rest were -0.32+/-0.07 vs -0.11+/-0.02 bpm/mmHg (P=0.007), respectively. However, there was no statistical difference (P=0.37) in CBR-MAP gains between the groups. Neither CBR-MAP (P=0.08) nor CBR-HR (P=0.41) gain was augmented by LBNP in the elderly. CONCLUSION: Active lifestyle enhances the CBR-HR reflex sensitivity as a result of the improved vagal-cardiac function in elderly people. Aging is associated with an absence of central autonomic interaction in the control of blood pressure regardless of physical fitness.     

High dietary salt intake increases carotid blood pressure and wave reflection in normotensive healthy young men

Dietary salt intake is associated with high brachial blood pressure (BP) and increased risk of cardiovascular disease. We investigated whether changes in dietary salt intake are associated with changes in central BP and wave reflection in healthy volunteers. Ten healthy normotensive male volunteers (22-40 yr) participated in a 6-wk double-blind randomized crossover study to compare a low-dietary salt intake (60-80 mmol sodium/day) with a high-salt intake (low salt intake supplemented with 128 mmol sodium/day) on central BP and wave reflection. Brachial and carotid BP, carotid blood flow velocity, forward (P(f)) and backward (P(b)) pressure, wave intensity, body weight, and urinary electrolyte excretion were measured at the end of each crossover period. High salt intake significantly increased carotid systolic BP [98 (SD 11) vs. 91 mmHg (SD 13), P < 0.01] and increased wave reflection [ratio of backward to forward pressure (P(b)/P(f)) 0.13 (SD 0.02) vs. 0.11 (SD 0.03), P = 0.04] despite only small effects on brachial BP [114 (SD 9) vs. 112 mmHg (SD 6), P = 0.1]. Urinary sodium excretion and body weight were also increased following high salt intake. High salt intake disproportionately increases central BP compared with brachial BP as a result of enhanced wave reflection. These effects may contribute to the adverse effect of high dietary salt intake on the risk of cardiovascular disease.     

Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: impact of age and fitness

Diastolic intraventricular pressure gradients (IVPGs) are a measure of the ability of the ventricle to facilitate its filling using diastolic suction. We assessed 15 healthy young but sedentary subjects, aged <50 yr (young subjects; age, 35 +/- 9 yr); 13 healthy but sedentary seniors, aged >65 yr with known reductions in ventricular compliance (elderly sedentary subjects; age, 70 +/- 4 yr); and 12 master athletes, aged >65 yr, previously shown to have preserved ventricular compliance (elderly fit subjects; age, 68 +/- 3 yr). Pulmonary capillary wedge pressure (PCWP) and echocardiography measurements were performed at baseline, during load manipulation by lower body negative pressure at -15 and -30 mmHg, and after saline infusion of 10 and 20 ml/kg (elderly) or 15 and 30 ml/kg (young). IVPGs were obtained from color M-mode Doppler echocardiograms. Baseline IVPGs were lower (1.2 +/- 0.4 vs. 2.4 +/- 0.7 mmHg, P < 0.0001), and the time constant of pressure decay (tau(0)) was longer (60 +/- 10 vs. 46 +/- 6 ms, P < 0.0001) in elderly sedentary than in young subjects, with no difference in PCWP. Although PCWP changes during load manipulations were similar (P = 0.70), IVPG changes were less prominent in elderly sedentary than in young subjects (P = 0.02). Changes in stroke volume and IVPGs during loading manipulations correlated (r = 0.96, P = 0.0002). PCWP and tau(0) were strong multivariate correlates of IVPGs (P < 0.001, for both). IVPG response to loading interventions in elderly sedentary and elderly fit subjects was similar (P = 0.33), despite known large differences in ventricular compliance. The ability to regulate IVPGs during changes in preload is impaired with aging. Preserving ventricular compliance during aging by lifelong exercise training does not prevent this impairment.     

Impact of aging on muscle blood flow in chronic heart failure.

Chronic heart failure (CHF) is manifested principally in the elderly population. Therefore, to understand the causes of exercise intolerance in CHF patients, it is imperative to resolve the effects of aging on muscle blood flow (BF) in CHF. To address this issue, we determined the muscle BF response to submaximal treadmill exercise (20 m/min, 5% grade) in young (Y(CHF): 6-8 mo, 412 +/- 11 g, n = 11) and old (O(CHF): 27-29 mo, 494 +/- 10 g, n = 8) Fischer 344 x Brown Norway rats with similar degrees of myocardial infarction-induced left ventricular (LV) dysfunction [resting LV end-diastolic pressure: Y(CHF) = 24 +/- 2, O(CHF) = 22 +/- 2 mmHg; derivative of LV pressure over time: Y(CHF) = 5,168 +/- 285; O(CHF) = 5,050 +/- 165 mmHg/s; lung weight normalized to body weight: Y(CHF) = 9.14 +/- 0.72; O(CHF) = 8.21 +/- 0.29 mg/g (all P > 0.05)]. The exercising heart rate response was blunted in O(CHF) compared with Y(CHF) rats (Y(CHF) = 454 +/- 8, O(CHF) = 395 +/- 9 beats/min; P < 0.05). BF (radiolabeled microspheres) to the total hindlimb musculature and to each of the 28 individual muscles examined was similar between Y(CHF) and O(CHF) rats under resting conditions. During exercise, BF to five of the hindlimb muscles that normally possess a majority of slow-twitch oxidative and fast-twitch oxidative glycolytic muscle fibers increased significantly less (-25 to -42%) for O(CHF) compared with Y(CHF) rats. In contrast, BF to 14 of the hindlimb muscles that normally possess a majority of fast-twitch glycolytic muscle fibers was increased (+22 to +337%) for O(CHF) vs. Y(CHF) rats, which contributed to a greater mass-specific total hindlimb BF response in O(CHF) rats (Y(CHF) = 78 +/- 5, O(CHF) = 100 +/- 11 ml.min(-1).100 g(-1); P < 0.05) and coincided with greater reductions in BF to the kidneys and splanchnic organs during exercise in O(CHF) vs. Y(CHF). In conclusion, there appears to be a profound age-related redistribution of BF from the highly oxidative to the highly glycolytic muscles of the hindlimb during exercise in O(CHF) compared with Y(CHF) rats. This phenomenon is qualitatively similar to that reported previously for healthy young and old rats.     

Stimulation of brain Na+ channels by FMRFamide in Dahl SS and SR rats

Stimulation of brain Na+ channels by Phe-Met-Arg-Phe-NH2 (FMRFamide) increases sympathetic nerve activity and blood pressure (BP) in Wistar rats. Blockade of brain ouabain-like compounds (OLC) by specific antibody Fab fragments prevents these responses to intracerebroventricular FMRFamide. In the present study, we evaluated the effects of high-salt intake on brain FMRFamide levels and the responses of BP and brain OLC to intracerebroventricular infusion of FMRFamide in Dahl salt-sensitive (SS) and salt-resistant (SR) rats. FMRFamide and OLC content was measured with the use of RIA and ELISA, respectively. A high-salt diet (1,370 micromol Na+/g) for 2 wk significantly increased BP in Dahl SS but not in SR rats. On a regular salt diet, Dahl SS and SR rats showed similar FMRFamide levels in the whole hypothalamus, pons and medulla, and spinal cord. A high-salt diet for 2 wk did not affect FMRFamide levels in these tissues in both Dahl SS and SR rats. In Dahl SS but not in SR rats, chronic intracerebroventricular infusion of FMRFamide (200 nmol. kg(-1).day(-1)) for 2 wk significantly increased BP (mean arterial pressure: 116 +/- 5 vs. 100 +/- 2 mmHg; P < 0.01). Chronic intracerebroventricular infusion of FMRFamide significantly increased hypothalamic and pituitary OLC in Dahl SS but not SR rats. These results indicate that Dahl SS rats exhibit enhanced central responses to FMRFamide. In Dahl SS but not in SR rats on a high-salt diet, enhanced Na+ entry through FMRFamide-activated brain Na+ channels may increase brain OLC release, thereby leading to hypertension.     

Methods for assessing hepatic distending pressure and changes in hepatic capacitance in pigs

The equilibrium pressure obtained during simultaneous occlusion of hepatic vascular inflow and outflow was taken as the reference estimate of hepatic vascular distending pressure (P(hd)). P(hd) at baseline was 1.1 +/- 0.2 (mean +/- SE) mmHg higher than hepatic vein pressure (P(hv)) and 0.7 +/- 0.3 mmHg lower than portal vein pressure (P(pv)). Norepinephrine (NE) infusion increased P(hd) by 1. 5 +/- 0.5 mmHg and P(pv) by 3.7 +/- 0.6 mmHg but did not significantly increase P(hv). Hepatic lobar vein pressure (P(hlv)) measured by a micromanometer tipped 2-Fr catheter closely resembled P(hd) both at baseline and during NE-infusion. Dynamic pressure-volume (PV) curves were constructed from continuous measurements of P(hv) and hepatic blood volume increases (estimated by sonomicrometry) during brief occlusions of hepatic vascular outflow and compared with static PV curves constructed from P(hd) determinations at five different hepatic volumes. Estimates of hepatic vascular compliance and changes in unstressed blood volume from the two methods were in close agreement with hepatic compliance averaging 32 +/- 2 ml. mmHg(-1). kg liver(-1). NE infusion reduced unstressed blood volume by 110 +/- 38 ml/kg liver but did not alter compliance. In conclusion, P(hlv) reflects hepatic distending pressure, and the construction of dynamic PV curves is a fast and valid method for assessing hepatic compliance and changes in unstressed blood volume.     

Effect of doxazosin on insulin resistance in hypertensive patients with obesity.

We determined the effect of alpha-adrenergic blocking agent doxazosin on insulin resistance in 19 hypertensive patients (blood pressure [BP] >160/90 mmHg) with obesity (mean body mass index [BMI]: 26.7 +/- 1.9 kg/m (2)). Patients received doxazosin 4 mg/day for 12 months. Systolic and diastolic BP decreased from 169 +/- 10.8 mmHg to 147 +/- 11.9 mmHg (p < 0.0001) and from 102 +/- 8.1 mmHg to 87 +/- 5.0 mmHg (p < 0.0001), respectively. Insulin resistance and fasting immunoreactive insulin (IRI) were lower at study end vs. baseline (HOMA-R = 1.29 +/- 0.38 vs. 3.58 +/- 2.23 [p = 0.022]; IRI = 6.00 +/- 1.88 microU/ml vs 13.74 +/- 8.51 microU/ml [p = 0.046]). Total cholesterol was significantly reduced following treatment. Circulating TNF-alpha and leptin levels decreased significantly within 3 months of treatment; leptin was independently associated with insulin resistance when adjusted for BMI. We conclude that doxazosin improves insulin resistance and improves dyslipidemia in obese hypertensive patients, and has a beneficial effect on adipose endocrine activity.