Quantitative and temporal differential recovery of articular and muscular limitations of knee joint contractures; results in a rat model.

Joint contractures alter the mechanical properties of articular and muscular structures. Reversibility of a contracture depends on the restoration of the elasticity of both structures. We determined the differential contribution of articular and muscular structures to knee flexion contractures during spontaneous recovery. Rats (250, divided into 24 groups) had one knee joint surgically fixed in flexion for six different durations, from 1 to 32 wk, creating joint contractures of various severities. After the fixation was removed, the animals were left to spontaneously recover for 1 to 48 wk. After the recovery periods, animals were killed and the knee extension was measured before and after division of the transarticular posterior muscles using a motorized arthrometer. No articular limitation had developed in contracture of recent onset (≤2 wk of fixation, P > 0.05); muscular limitations were responsible for the majority of the contracture (34 ± 8° and 38 ± 6°, respectively; both P < 0.05). Recovery for 1 and 8 wk reversed the muscular limitation of contractures of recent onset (1 and 2 wk of fixation, respectively). Long-lasting contractures (≥4 wk of fixation) presented articular limitations, irreversible in all 12 durations of recovery compared with controls (all 12 P < 0.05). Knee flexion contractures of recent onset were primarily due to muscular structures, and they were reversible during spontaneous recovery. Long-lasting contractures were primarily due to articular structures and were irreversible. Comprehensive temporal and quantitative data on the differential reversibility of mechanically significant alterations in articular and muscular structures represent novel evidence on which to base clinical practice.

Effect of timing of surgical SSP tendon repair on muscle alterations.

To investigate the impacts of delayed repairs of a supraspinatus tendon tear on the supraspinatus muscle, we used an animal model data from two previously published studies in which one supraspinatus (SSP) tendon was detached. In one cohort, the rabbits were killed in groups of 10 at 4, 8, and 12 weeks. In the other cohort, a repair was done at these time points, 12 rabbits each, and the animals killed were 12 weeks later. SSP fossa volume (Muscle belly plus extramuscular fat [e-fat] volume), percentage of intramuscular fat (i-fat), and muscle tissue volume (muscle belly volume minus i-fat), as well as CT determination of e-fat and i-fat of both cohorts, were compared. Fossa volume increased (p < 0.05). Muscle belly and muscle tissue volumes did not increase after repair (p > 0.05), but early repair prevented further volume losses, a fact not seen after 8 and 12 weeks delay of repair. No reversal of e-fat or of i-fat occurred, in fact i-fat almost doubled after 4 weeks delay of repair (p < 0.05). CT studies confirmed the fat results. We conclude that early repair prevented loss of muscle belly and muscle tissue volumes, but that it has no positive influence on fat accumulation.

Do high doses of AT(1)-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure?

In patients with CHF (chronic heart failure) sympathetic activity increases as cardiac performance decreases and filling pressures increase. We hypothesized that in patients with mild-to-moderate CHF, higher than conventional doses of an AT1-receptor [AngII (angiotensin II) type 1 receptor] antagonist would achieve greater central AT1-receptor blockade, resulting in diminished MSNA (muscle sympathetic nerve activity) and augmented MSNA variability, two indices of central effects on sympathetic outflow. In total, 13 patients with ischaemic cardiomyopathy [NYHA (New York Heart Association) class II-III] were weaned off all pharmacological RAS (renin-angiotensin system) modifiers, and then randomized to receive a low (50 mg/day) or high (200 mg/day) dose of losartan. Central haemodynamics, MSNA and its variability, plasma catecholamines, AngI (angiotensin I) and AngII and aldosterone were assessed both before and 3 months after randomization. Neither dose altered BP (blood pressure), PCWP (pulmonary capillary wedge pressure) or CI (cardiac index) significantly. Compared with 50 mg daily, losartan 200 mg/day decreased MSNA significantly (P<0.05), by approximately 15 bursts/min, and increased MSNA variability within the 0.27-0.33 Hz high-frequency range by 0.11 units(2)/Hz (P=0.06). PNE [plasma noradrenaline (norepinephrine)] fell in parallel with changes in MSNA (r=0.62; P<0.05). These findings support the hypothesis that higher than conventional doses of lipophilic ARBs (AT1-receptor blockers) can modulate the intensity and variability of central sympathetic outflow in patients with CHF. The efficacy and safety of this conceptual change in the therapeutic approach to heart failure merits prospective testing in clinical trials.

Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men.

Fat accumulates in the bone marrow of lumbar vertebrae with bed rest. Exercise with or without whole body vibration may counter this effect. Our objectives were to measure 1) the vertebral fat fraction (VFF) of men subjected to bed rest who performed resistive exercises with (RVE, n = 7) or without whole body vibration(RE, n = 8) or no exercise (CTR, n = 9) using three MRI techniques; and 2) changes in peripheral blood counts. Twenty-four healthy men (age: 20-45 yr) underwent -6° head-down tilt (HDT) bed rest for 60 days. MRI was performed using three techniques (fat saturation, proton spectroscopy, and in and out of phase) to measure the fat fraction of L(3), L(4), and/or L(5) at baseline, mid-HDT, and end-HDT. Erythrocytes and leukocytes were counted at HDT days 19, 33, 47, 54, and 60. The mean absolute VFF was increased in the CTR group at mid-HDT and end-HDT (+3.9 ± 1.3 and +3.6 ± 1.2%, respectively, both P < 0.05). The RE group had a smaller VFF change than the CTR group at mid-HDT (-0.9 ± 1.2 vs. +3.9 ± 1.3%, P < 0.05). The RVE group had a smaller VFF change than the CTR group at end-HDT (-2.6 ± 1.9 vs. +3.5 ± 1.2%, P < 0.05). Erythrocyte counts were increased in all groups at HDT day 19 and HDT day 33 and in the RE group at HDT day 54 (all P < 0.05). Bed rest for 60 days at -6° HDT increased lumbar VFF in men beyond natural involution. RVE and RE regimens effectively prevented VFF accumulation. Higher erythrocyte counts were not altered by RVE or RE. Whole body vibration, along with RE administered to people with prolonged immobility, may prevent fat accumulation in their bone marrow.

Pharmacokinetic and antihypertensive profile of amlodipine and felodipine-ER in younger versus older patients with hypertension.

To evaluate the impact of age on the pharmacokinetics and blood pressure (BP) responses of a dihydropyridine (DHP) with large versus small first-pass metabolism in hypertensive subjects, younger (n = 28) and older (n = 35) patients with hypertension were randomized to placebo, felodipine-ER 5 mg/d, or amlodipine 5 mg/d. In the young subjects, the first dose of either DHP did not decrease BP and chronic dosing decreased BP by approximately 10 mm Hg, which had disappeared by 24 hours. In the older group, felodipine-ER decreased systolic BP by approximately 10 mm Hg after the first dose and by approximately 20 mm Hg after chronic dosing, which had disappeared after 24 hours. The first dose of amlodipine caused a gradual fall in BP and chronic dosing by approximately 20 mm Hg and still by approximately 10 mm Hg at 120 hours. Older subjects showed approximately 30% higher area under the concentration­time curves and plasma concentrations of felodipine and amlodipine, but (apparent) elimination half-lives did not differ between younger and older subjects. The chronic antihypertensive responses correlated well with both plasma levels and pretreatment BP. Age has only a modest impact on the pharmacokinetics of amlodipine and felodipine-ER but markedly affects the BP response to the first dose of either DHP and the duration of action after chronic dosing of amlodipine.

Effects of ACE inhibitors on cardiac angiotensin II and aldosterone in humans: "Relevance of lipophilicity and affinity for ACE".

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors differ in their lipophilic/hydrophilic index that determines their tissue bioavailability and affinity to ACE, which may result in major differences in the degree of blockade of cardiac ACE. We evaluated the hypothesis that in patients with chronic heart failure (CHF) and activated cardiac renin-angiotensin-aldosterone system (RAAS), lipophilic ACE inhibitors with high affinity for ACE (perindopril and quinapril) will cause marked blockade of cardiac angiotensin (Ang) II and aldosterone generation, but not a hydrophilic ACE inhibitor with low affinity for ACE (lisinopril). METHODS: Patients were randomized to receive perindopril (8 mg/day), quinapril (40 mg/day), or lisinopril (20 mg/day) for 3-4 weeks before cardiac catheterization. The coronary sinus-aortic root gradients for Ang I and II, and aldosterone were determined. RESULTS: A total of 19 patients completed the study. Compared to a healthy control group, all three ACE inhibitors decreased circulating Ang II and aldosterone to a similar extent. There were only minor differences between the three ACE inhibitors for the Ang II gradient between the coronary sinus and aortic root. The gradient for aldosterone tended to be positive in the quinapril group and absent/negative in the lisinopril and perindopril groups. Despite the lowest pulmonary capillary wedge pressure (PCWP), gradients between the coronary sinus and aortic root for Ang II and aldosterone were actually the highest in the quinapril group. CONCLUSIONS: These findings do not support the concept that a hydrophilic ACE inhibitor is less effective in blocking the cardiac RAAS as compared to lipophilic ACE inhibitors.

Does blockade of the renin angiotensin system affect sympathetic and blood pressure responses to amlodipine in young hypertensive patients?

BACKGROUND: Angiotensin II-mediated increases in sympathetic activity may contribute to smaller blood-pressure decreases in response to dihydropyridines in young versus older hypertensive patients. We evaluated whether quinapril unmasks angiotensin II-dependent sympathetic activity on amlodipine. METHODS: In this double-blind, randomized, clinical trial, young mild hypertensives were randomized to quinapril for 1 week (study 1), followed by quinapril + amlodipine for 6 weeks (study 2), followed by amlodipine + placebo for 6 weeks (study 3), or else were randomized to placebo for 1 week (study 1), followed by placebo + amlodipine for 6 weeks (study 2), followed by amlodipine + quinapril for 6 weeks (study 3). Muscle sympathetic nerve activity (MSNA) and plasma hormones were analyzed at the end of each treatment period. Twenty-one subjects completed this study. RESULTS: Quinapril alone decreased BP by 8 +/- 3/6 +/- 3 (mean +/- SD) mm Hg, and amlodipine alone decreased BP by 6 +/- 3/4 +/- 2 (mean +/- SD). Quinapril combined with amlodipine caused a drop of 13 +/- 3/13 +/- 3 (mean +/- SD) mm Hg in one group, and 14 +/- 3/14 +/- 2 (mean +/- SD) mm Hg in the second group. Six weeks after discontinuation of quinapril, amlodipine alone caused no change (0 +/- 3/-2 +/- 3) (mean +/- SD). The MSNA decreased by 3 bursts/100 heartbeats at visits 2 v 1 and 3 v 2 (P = .02 for time effect), regardless of treatment. Angiotensin II showed small increases with each visit in the first group, and small decreases in the second group (P = .02 for treatment effect). CONCLUSIONS: It appears that amlodipine does not activate the renin-angiotensin system to counteract its BP-lowering effect in young hypertensives. Similarly, no angiotensin II-dependent component in MSNA appears to be present at baseline or to be induced by amlodipine.

Prevention of renal dysfunction and hypertension by amlodipine after heart transplant.

To assess whether treatment with a dihydropyridine calcium antagonist can prevent the development of hypertension and renal dysfunction after heart transplantation, 38 patients receiving cyclosporine for immunosuppression were randomized shortly after cardiac transplantation to placebo or amlodipine 2.5 mg/day using a double-blind design. The dose was gradually increased to 10 mg/day as tolerated. At 1, 3, 6, 9, and 12 months, 24-hour ambulatory blood pressure (BP) monitoring was performed for the assessment of BP load, echocardiography for the assessment of left ventricular function and mass, 24-hour urine collection for creatinine clearance, and blood sampling for cyclosporine levels. In the placebo group, BP showed modest increases during follow-up, whereas creatinine clearance decreased by about 10 ml/min. In contrast, in the amlodipine group, systolic BP decreased by 15 to 20 mm Hg and diastolic BP by 7 to 10 mm Hg, whereas creatinine clearance tended to increase. Between-group differences were significant as well. During follow-up, left ventricular mass and function showed small decreases, similar for the 2 groups. Cyclosporine doses and blood levels did not differ during follow-up. In conclusion, the initiation of treatment with the dihydropyridine amlodipine shortly after cardiac transplantation represents an effective strategy to maintain normal BP and renal function for > or =1 year.

Effects of hypertension on cardiovascular responses to epinephrine in humans.

Cardiac beta-receptor responsiveness is diminished by both aging and hypertension. However, concomitant decreases in the activity of counterregulatory mechanisms, such as the arterial baroreflex and neuronal catecholamine uptake, influence the ultimate cardiac responses to adrenergic agents in vivo. In the present study, we evaluated by echocardiography cardiac responses to intravenous infusion of epinephrine in 14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women. To assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall response, infusions were repeated combined with a ganglionic blocker in the young groups. Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects. One may conclude that compared with young normotensive subjects, in hypertensive subjects mechanisms increasing versus decreasing cardiac responses to epinephrine may remain in balance, and, compared with older normotensive subjects, older hypertensive subjects exhibit enhanced cardiac responses to sympathetic stimulation.

Sympatho-excitatory responses to once-daily dihydropyridines in young versus older hypertensive patients: amlodipine versus felodipine extended release.

BACKGROUND: Once-daily dihydropyridines exert both indirect sympatho-excitatory and direct central sympatho-inhibitory effects. Age may affect this balance by influencing blood pressure (BP) or renin responses. METHODS: We evaluated BP, sympathetic and cardiac responses after the first dose and after 8 weeks of treatment with placebo, amlodipine 5 mg/day or felodipine extended release (ER) 5 mg/day in 29 young (22-50 years) versus 37 older (60-77 years) hypertensive patients, using a double-blind, parallel group design. RESULTS: In the young group, neither dihydropyridine dose decreased BP after the first dose and both caused decreases by 5-10 mmHg after chronic treatment. In the older group, felodipine ER decreased BP rapidly and amlodipine more gradually, and after chronic treatment, systolic BP decreased by 20-25 mmHg. Felodipine ER increased the heart rate by 5-10 bpm after the first dose in both age groups and caused persistent increases in the cardiac index (by 0.2 l/min per square metre) and the ejection fraction only in the older group. Amlodipine did not affect cardiac function in the young, and with chronic dosing decreased the heart rate by 3-5 bpm and the cardiac index by 0.2 l/min per square metre in the older group. In the young hypertensive patients, both dihydropyridines increased plasma norepinephrine (NE) after chronic dosing, with little effect after the first dose. In contrast, in the older group felodipine ER increased plasma NE after the first dose but not with chronic dosing, whereas amlodipine had no effect after the first dose, and after chronic dosing tended to decrease plasma NE. CONCLUSION: We conclude that age is a major determinant not only of the BP but also of the cardiac and sympathetic responses to once-daily dihydropyridines.

Aging and cardiac responses to epinephrine in humans: role of neuronal uptake.

In healthy humans, ganglionic blockade unmasks a clear age-related decrease in cardiac responses to isoproterenol but not to epinephrine. We postulated that an age-related decrease in neuronal uptake (which affects epinephrine but not isoproterenol) may offset a parallel decrease in beta-receptor-mediated responses. To test this concept, nine young (mean 29 +/- 2 yr) and eight older (mean 61 +/- 2 yr) healthy subjects were infused on three different study mornings with epinephrine at increasing rates either alone or combined with desipramine to eliminate differences in neuronal uptake or with desipramine and trimetaphan to induce ganglionic blockade and thereby also eliminate differences in arterial baroreflex activity. Epinephrine caused the expected rate-related increases in systolic blood pressure, heart rate, stroke volume, ejection fraction, and cardiac index. Except for the systolic blood pressure, the extent of the changes was similar in young and older subjects. After desipramine, cardiac responsiveness to epinephrine was markedly enhanced, although more (P < 0.01) in young vs. older subjects for heart rate and cardiac index (+14 vs. 7 beats/min and +1.6 vs. 1.1 l.min(-1).m(-2), respectively, at 20 ng.kg(-1).min(-1)). Combined with desipramine and trimetaphan, cardiac responses to epinephrine were further enhanced, again more (P < 0.01) in young subjects, resulting in large differences in heart rate and ejection fraction increases (+29 vs. 17 beats/min and +14 vs. 7%, respectively, at 20 ng.kg(-1).min(-1)). Here, we show that "healthy aging" in humans is associated with decreased cardiac responsiveness to the beta-agonist epinephrine; however, this decrease can be balanced by concomitant decreases in buffering of these responses by neuronal uptake and the arterial baroreflex.

Effects of low-dose nifedipine GITS on sympathetic activity in young and older patients with hypertension.

BACKGROUND: Dihydropyridines have both sympathoexcitatory and sympathoinhibitory effects. To date, the latter have been characterized only in animals. During chronic treatment with long-acting dihydropyridines, sympathoexcitatory effects mediated via the arterial baroreflex are unlikely. However, increases in plasma angiotensin II in response to dihydropyridines could contribute to increases in sympathetic activity during chronic treatment. Such increases may be less in older than in young patients. METHODS: We evaluated the effects of 4 weeks of treatment with low-dose nifedipine gastrointestinal therapeutic system (GITS; 20 mg/day) compared with placebo on muscle sympathetic nerve activity and plasma noradrenaline, in relation to changes in plasma renin activity and plasma angiotensin II and blood pressure in young and older patients with mild hypertension. RESULTS: Nifedipine GITS decreased systolic and diastolic blood pressures significantly, by 10 +/- 3 mmHg and 7 +/- 2 mmHg respectively, in older patients (age 67 +/- 2 years), but not in younger patients (age 45 +/- 2 years) (decreases of 1 +/- 3 mmHg and 1 +/- 2 mmHg, respectively). Nifedipine GITS caused only minor changes in plasma renin activity and plasma angiotensin II in young and older patients. Compared with changes in response to placebo (-5.7 +/- 2.4 bursts/min), sympathetic activity was increased significantly by nifedipine GITS in the young patients (2.0 +/- 1.7 bursts/min; P < 0.05), but not in older patients (5.4 +/- 1.3 bursts/min by placebo compared with 4.1 +/- 3.5 bursts/min by nifedipine GITS). CONCLUSION: We conclude that age-related differences in the response of muscle sympathetic nerve activity (and plasma noradrenaline) to low-dose nifedipine GITS in patients with mild hypertension are unlikely to be mediated by plasma angiotensin II. An increase in sympathetic activity may contribute to the absent blood pressure response in young patients with hypertension.