Enhanced alveolar fluid clearance following 72 h of continuous isoproterenol infusion in rats.

AIM: We wished to determine the effect of continuous ß-receptor stimulation on alveolar fluid clearance and to elucidate the mechanisms behind this effect. METHODS: Alveolar fluid clearance was measured in anaesthetized rats pretreated for 72 h with the ß-agonist isoproterenol (200 µg kg(-1) h(-1) sc) or vehicle. Alveolar fluid clearance in artificially ventilated rats was determined over 1 h by infusion of isotonic Ringer solution containing (125) I-albumin into the lungs. Additionally, alveolar fluid clearance was determined when amiloride or l-cis-diltiazem was added to the solution to block ENaC and cyclic nucleotide-gated (CNG) channels respectively. RESULTS: Isoproterenol treatment induced a 42% increase in alveolar fluid clearance (18.9 ± 1.4%) vs. vehicle (13.3 ± 3.3%). Addition of amiloride resulted in a net decrease of 8% in both groups, while l-cis-diltiazem caused a net decrease of 12% in isoproterenol-treated animals, but only 5% in vehicle-treated animals. Western blotting showed that isoproterenol treatment increased the abundance of the α-ENaC and ß-ENaC subunits (223 ± 51% and 274 ± 55% of vehicle, respectively) but we saw no changes in protein level of the γ-EnaC subunit. CONCLUSION: Continuous ß-adrenoceptor stimulation with isoproterenol enhances alveolar fluid clearance through alternative pathways involving l-cis-diltiazem-sensitive channels.

Endogenous NO does not regulate baseline pulmonary pressure, but reduces acute pulmonary hypertension in dogs.

UNLABELLED: It has remained unclear whether endogenous production of nitric oxide (NO) plays an important role in the regulation of physiologically normal pulmonary pressures. Severe alveolar hypoxia is accompanied by decreased pulmonary NO production, which could contribute to the development of hypoxic pulmonary hypertension. On the other hand, pharmacological NO inhibition further augments this hypertensive response. AIMS: The aims of the present study were to test: (a) whether NO contributes importantly in the maintenance of baseline pulmonary pressure; and (b) to which degree NO is involved in the pulmonary haemodynamic adjustments to alveolar hypoxia. METHODS: In anaesthetized dogs (n=37), the systemic and pulmonary haemodynamic effects of the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 20 mg kg(-1)) and substrate, L-arginine (200-500 mg kg(-1)), were determined at baseline and during alveolar hypoxia. Constant blood flows were accomplished by biventricular bypass, and systemic normoxaemia was maintained by extracorporeal oxygenation. RESULTS: The primary findings were: (a) L-NAME failed to increase baseline mean pulmonary arterial pressure (10.1 +/- 0.7 vs. 10.5 +/- 0.5 mmHg, P=ns), despite effective NO synthase inhibition as evidenced by robust increases in systemic arterial pressures; (b) L-NAME augmented the pulmonary hypertensive response to alveolar hypoxia (10.2 +/- 0.7 to 19.5 +/- 1.7 with L-NAME vs. 9.9 +/- 1.1 to 15.5 +/- 1.0 mmHg without L-NAME, P<0.05); and (c) L-arginine failed to decrease baseline or elevated pulmonary pressures. Instead, prolonged L-arginine caused increases in pulmonary pressure. CONCLUSION: These findings suggest that NO plays no significant role in the tonic physiological control of pulmonary pressure, but endogenous NO becomes an important vasodilatory modulator during elevated pulmonary pressure.

Impaired fibrinolysis determines the outcome of percutaneus transluminal coronary angioplasty (PTCA).

BACKGROUND: Coronary artery stenosis lesions dilated by percutaneus transluminal coronary angioplasty (PTCA) show a disappointingly frequent recurrence of stenosis. We have investigated the possible role of fibrinolysis and various platelet-release factors - specifically in the locality of the affected vessel - by following 19 patients for 6 months after PTCA. METHODS: PTCA was performed on 19 patients with a significant primary coronary stenosis, proven by quantitative CAAS analysis. Blood for measurement of local fibrinolysis and platelet activity was drawn from the aortic root and the coronary sinus, at three times: just before PTCA, 10 min after it, and 6 months later. RESULTS: The incidence of restenosis at the 6 months follow-up was 37%. PTCA almost doubled the platelet-derived growth factor level (PDGF) in coronary sinus blood in all patients. The seven restenosis patients had a substantially higher tissue plasminogen activator inhibitor antigen (PAI-1ag) level in the aortic root before PTCA than the 12 who remained stenosis-free (mean 62.4 +/- 31.6 ng mL -1 compared with 33.1 + 25.3; P < 0.04) and a lower tissue plasminogen activator activity (t-PAac) level (mean 0.32 +/- 0.19 IU mL-1 compared with 0.68 +/- 0.34; P < 0.03). This was corroborated by the levels of tissue plasminogen activator inhibitor activity (PAI-1ac). At reassessment after 6 months, the restenosis patients had developed, in coronary sinus blood, a large rise of PAI-1ac (7.7 +/- 4.8 IU mL-1 rising to 15.7 +/- 13.9, P < 0.04) and a large rise of of PAI-1ag (48.8 +/- 31.3 ng mL-1 vs. 72.4 +/- 47.2; P < 0.03). But no such increase occurred in the patients who remained stenosis-free. Conclusion Our results indicate that the minor balloon injury, which is inseparable from PCTA, stimulates the local release of PDGF. We suggest that, in those patients whose fibrinolytic activity is inherently low, this rise of PDGF could be a major causative factor in restenosis. We also discuss the possibility that the preoperative level of PAI-1ac could provide a limited but useful prediction of the outcome of PTCA.

[Invasive treatment of angina pectoris. A need for re-thinking?]. / Invasiv behandling af angina pectoris. Behov for nytaenkning?

Evaluation and treatment of stable angina pectoris is based on invasive diagnostic and therapeutic procedures focused on identification and treatment of coronary artery stenoses, instead of myocardial ischaemia which is considered the cause of symptoms. Thus, coronary angiography should possibly be preceded routinely by myocardial perfusion imaging, which can provide the diagnosis of ischaemia and determine if the patient will benefit from invasive therapy. As a consequence, treatment of patients without ischaemia and patients with ischaemia so serious that invasive therapy is futile might be avoided. It is unknown exactly how many angiographies and treatments with angioplasty or bypass surgery that could be spared in this way. It is estimated that a patient pathway based on the diagnosis of myocardial ischaemia including the type of ischaemia may render approximately half of the present angiographies and a number of invasive revascularisations redundant. This pathway implies substantial economic savings.

[Thirty years of coronary revascularization in stable angina pectoris. Results of randomized controlled trials]. / Tredive år med koronar revaskularisering ved stabil angina pectoris. Resultater af randomiserede undersøgelser.

From a survey of randomized studies we wanted to elucidate the therapeutic gain and the risk of complications with coronary artery bypass grafting (CABG) and percutaneous transluminal angioplasty (PTCA) in stable angina pectoris. The following main conclusions emerged: Invasive revascularization was associated with increased survival (reduced frequency of cardiac death or myocardial infarction) exclusively in patients with three-vessel disease and/or left main lesion accompanied by a decreased left ventricular function. This group accounted for less than 10% of treated patients. With regard to survival, patients with one- and two-vessel disease were better off with conservative treatment. Relief of angina was achieved for a number of years in the majority of patients. Angina recurred earlier following PTCA than CABG. PTCA is considered less traumatic, but a ten times higher need of additional revascularization seems to eliminate this advantage. The frequency of serious complications (including the higher risk at re-revascularization) was > or = 10% after PTCA and > or = 7% after CABG.

Capillary transfer constant of Gd-DTPA in the myocardium at rest and during vasodilation assessed by MRI.

The purpose of this study was to determine whether the capillary transfer constant (Ki) of gadolinium-DTPA was sensitive to perfusion changes and whether ischemic regions in the myocardium could be identified using the modified Kety formula. Ki was measured at rest and during dipyridamole-induced vasodilation in 10 healthy volunteers and in 10 patients with ischemic heart disease. Ki increased by a factor of 2.5+/-1.2 (mean +/- SD) from 55+/-16 ml 100 g(-1)min(-1) at rest to 136+/-46 ml 100 g(-1)min(-1) (P < 0.01) during vasodilation in the healthy subjects. In the patients, there were no changes in Ki during vasodilation in ischemic regions (50+/-18 versus 49+/-30 ml 100 g(-1)min(-1) (P > 0.4)). Ki increased in nonischemic regions by a factor of 2.0+/-0.8 from 44+/-17 to 81+/-32 ml 100 g(-1)min(-1) during vasodilation (P < 0.02). It is concluded that the capillary transfer constant is sensitive to perfusion changes and that regional ischemia can be detected with MRI. This noninvasive and quantitative method may prove useful in the evaluation of patients with ischemic heart disease.

Effect of alveolar hypoxia on segmental pulmonary vascular resistance and lung fluid balance in dogs.

In a biventricular bypass preparation with constant-flow perfusion, pulmonary arterial pressure (Ppa), average pulmonary capillary pressure (Ppc), venous pressure (Pv), extravascular lung water volume (EVWd) and capillary permeability-surface area product for urea (PS) were determined in control animals and in animals subjected to alveolar hypoxia. During hypoxia, Ppa increased in a biphasic manner, the site of hypoxic pulmonary vasoconstriction being located in the arterial upstream segment. At baseline, Ppc values were identical in control and experimental animals (3.4 +/- 0.4 vs. 3.6 +/- 0.2 mmHg). During 150 min of airway hypoxia, the rise in Ppc (5.1 +/- 0.3 mmHg) did not exceed the rise in Ppc (4.9 +/- 0.5 mmHg) recorded in control animals at same time interval during normoxic ventilation. EVWd increased during hypoxia to values significantly higher than those obtained in control animals (0.559 +/- 0.036 vs. 0.466 +/- 0.027 mL water g-1 lung). PS remained unchanged at baseline level throughout experiments in both groups of animals. Present data suggest that lung oedema formation during alveolar hypoxia may be caused by increased transcapillary fluid loss preferentially through transcellular hydraulic pathways in capillary endothelial cells.

[Angiopeptin versus placebo for reductin of restenosis after PTCA treatment. A randomized, double-blind study]. / Angiopeptin versus placebo til reduktion af restenose efter PTCA-behandling. En randomiseret, dobbeltblind undersøgelse.

Angiopeptin, a somatostatin analogue, inhibits intimal hyperplasia after (percutaneous transluminal coronary angioplasty) (PTCA) in several animal models. This pilot study sought to determine the effect of subcutaneous infusion of angiopeptin on clinical events and restenosis in patients undergoing successful PTCA. One hundred and twelve patients were randomized to receive continuous subcutaneous angiopeptin (750 micrograms/day) or placebo infusion from the day before PTCA and for the following four days in a double-blind study. Eighty patients had a successful PTCA, and 75 of these patients with 94 lesions underwent angiography 6 +/- 2 months after PTCA. All 112 patients underwent clinical follow-up at 12 months. The 12-month event rate (death, myocardial infarction, coronary artery bypass grafting and re-PTCA) was reduced from 34% to 25% (p = 0.30) by angiopeptin by intention to treat analysis. Restenosis (> or = 50% diameter stenosis) was significantly reduced in lesions treated with angiopeptin (12% vs 40%; p = 0.003). Late lumen loss was also significantly reduced after angiopeptin treatment (0.12 +/- 0.46 mm vs 0.52 +/- 0.64 mm; p = 0.003). In conclusion, continuous subcutaneous angiopeptin infusion for five days tended to decrease clinical events and restenosis after PTCA.

Effects of 12 weeks of ramipril treatment on the quality of life in patients with moderate congestive heart failure: results of a placebo-controlled trial. Ramipril Study Group.

The assessment of quality of life (QoL) has become recognized as an important tool for evaluating heart failure therapy. The angiotensin-converting enzyme inhibitor ramipril (mean dose 8 mg) was evaluated in 223 patients with moderate chronic congestive heart failure at 24 centers in 4 Nordic countries following a randomized, double-blind, placebo-controlled, parallel group design. The follow-up period was 12 weeks. QoL was evaluated using a questionnaire with 47 items, including the disease-specific Severe Heart Failure Questionnaire, the Sleep Dysfunction Scale, and the Psychological General Well-Being Index. In both treatment groups the total score increased from baseline to 12 weeks for both the Severe Heart Failure Questionnaire and for the Psychological Well-Being Index, reflecting relief of symptoms and improved well-being. However, no significant differences between the placebo and ramipril groups could be detected. Only a trend toward improvement in sleep on ramipril compared with placebo therapy was observed. In conclusion, in this placebo-controlled trial no significant effects of 12-week ramipril treatment of QoL could be demonstrated in patients with moderate congestive heart failure.

Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty.

Angiopeptin, a somatostatin analogue, inhibits intimal hyperplasia after percutaneous transluminal coronary artery balloon angioplasty (PTCA) in several animal models. This pilot study sought to determine the effect of subcutaneous infusion of angiopeptin on clinical events and restenosis in patients undergoing successful PTCA. One hundred twelve patients were randomized to receive continuous subcutaneous angiopeptin (750 micrograms/day) or placebo infusion from the day before PTCA and for the following 4 days in a double-blind study. An additional subcutaneous injection of 375 micrograms of angiopeptin or saline was given immediately before PTCA. Eighty patients had a successful PTCA, and 75 of these patients with 94 lesions underwent angiography 6 +/- 2 months after PTCA. All 112 patients underwent a 12-month clinical follow-up examination. Age, sex, smoking, diabetes, hypertension, hyperlipidemia, and morphologic features of stenosis were similar in both groups. The hierarchical 12-month event rate (death, myocardial infarction, coronary artery bypass grafting, and repeated PTCA) was reduced from 34% to 25% (p = 0.30) by angiopeptin by intention-to-treat analysis. Restenosis (> or = 50% diameter stenosis) was significantly reduced in lesions treated with angiopeptin (12% vs 40%; p = 0.003). Late lumen loss also was significantly reduced after angiopeptin treatment (0.12 +/- 0.46 mm vs 0.52 +/- 0.64 mm; p = 0.003). In conclusion, continuous subcutaneous angiopeptin infusion for 5 days tended to decrease clinical events and restenosis after PTCA.

Absence of effect on exercise capacity of 12-weeks treatment with ramipril in patients with moderate congestive heart failure. Ramipril Study Group.

Pharmacological therapy in cases of chronic congestive heart failure (CHF) is usually evaluated by maximal exercise time. To assess the effect of an angiotensin converting enzyme inhibitor, ramipril, 223 patients with moderate CHF were studied in 24 centres in four Nordic countries in a randomized, double-blind, placebo-controlled, parallel group design. The study drug was titrated from 1.25 mg to a maximum of 10 mg once daily (o.d) over a period of 4 weeks (mean dose 8 mg). A symptom-limited bicycle exercise test, starting at 30 watts and increasing by 10 watts.min-1, was used to evaluate exercise capacity. Reproducible tests were required at baseline, and the test was repeated after 4, 8 and 12 weeks of treatment. Seven deaths were recorded in the placebo group and one death in the ramipril group. A total of 195 patients completed 12 weeks of treatment (placebo group n = 91, ramipril group n = 104). The groups had similar baseline characteristics. Maximal exercise time was increased by mean (SD) 35 s (9) and 41 s (8) in the placebo and ramipril groups, respectively. The adjusted difference between the groups at 12 weeks was 9 s (12) (ns). A significant decrease in blood pressure and rate-pressure product at rest and at end of exercise was obtained by ramipril as compared with placebo. Significantly fewer patients deteriorated in NYHA class from baseline to 12 weeks of ramipril treatment compared to placebo (P = 0.012). Concomitant medication for CHF increased significantly in the placebo group as compared with ramipril-treated patients (P = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Neurohormonal activation in patients with mild or moderately severe congestive heart failure and effects of ramipril. The Ramipril Trial Study Group.

OBJECTIVES: To describe neurohormonal activation in patients with mild or moderate heart failure and how it may be modified by treatment with ramipril. SETTING: Cardiology departments at 24 hospitals in Denmark, Finland, Norway, and Sweden. PATIENTS: 223 patients with mild or moderately severe congestive heart failure who were taking diuretics with or without digitalis. DESIGN: Randomised, double bind, multicentre, placebo controlled comparison of ramipril and placebo. Venous blood samples were drawn at rest, before blind treatment, and after 12 weeks of treatment with the study drug. A probability prediction score for mortality derived by stepwise linear discriminant from neurohormone data in the first cooperative north Scandinavian enalapril survival study (CONSENSUS I) was used to assess combined activity of the different neurohormonal systems. RESULTS: Plasma concentrations of atrial natriuretic peptide were raised at baseline but angiotensin II, aldosterone, and noradrenaline concentrations were within normal limits. There was, however, a wide interindividual variation. Plasma noradrenaline concentration and prediction score were higher among patients with class III congestive heart failure according to the New York Heart Association's classification than among patients with class II congestive heart failure (P < 0.05). There was a modest but significant inverse correlation between exercise duration at baseline and plasma noradrenaline concentration (r = -0.21, P = 0.0023), aldosterone concentration (r = -0.14, P = 0.04), and prediction score (r = -0.24, P = 0.0004). Prediction score at baseline was significantly higher among those who died (n = 10) than among survivors (P = 0.03). Angiotensin converting enzyme activity was suppressed and plasma concentrations of aldosterone and atrial natriuretic peptide were reduced after 12 weeks of treatment with ramipril compared with placebo. In patients with the most pronounced neurohormonal activation at baseline (highest third of noradrenaline concentration or prediction score), noradrenaline concentration and prediction score were significantly lower after 12 weeks of taking ramipril compared with placebo. Patients with a prediction score in the highest third at baseline had a higher heart rate than to those in the lowest third (P = 0.003). CONCLUSIONS: Neurohormonal activation is associated with the degree of symptoms and the severity of disease in mild or moderately severe congestive heart failure. Treatment with ramipril attenuates neurohormonal activation. This effect is most pronounced among patients with the highest circulating concentrations of neurohormones before the start of treatment.

Skeletal muscle vascular responses in human limbs to isometric handgrip.

Studies of whole limb blood flow have shown that static handgrip elicits a vasodilatation in the resting forearm and vasoconstriction in the resting leg. We asked if these responses occur in the skeletal muscle vascular bed, and if so, what is the relative contribution of local metabolic versus other mechanisms to these vascular responses. Blood flow recordings were made simultaneously in the skeletal muscle of the resting arm and leg using the Xenon-washout method in ten subjects during 3 min of isometric handgrip at 30% of maximal voluntary contraction. In the arm, skeletal muscle vascular resistance (SMVR) decreased transiently at the onset of exercise followed by a return to baseline levels at the end of exercise. In the leg SMVR remained unchanged during the 1st min of handgrip, but had increased to exceed baseline levels by the end of exercise. During exercise electromyography (EMG) recordings from nonexercising limbs demonstrated a progressive 20-fold increase in activity in the arm, but remained at baseline in the leg. During EMG-signal modelled exercise performed to mimic the inadvertent muscle activity, decreases in forearm SMVR amounted to 57% of the decrease seen with controlateral handgrip. The present study would seem to indicate that vascular tone in nonexercising skeletal muscle in the arm and leg are controlled differently during the early stages of static handgrip. Metabolic vasodilation due to involuntary contraction could significantly modulate forearm skeletal muscle vascular responses, but other factors, most likely neural vasodilator mechanisms, must make major contributions. During the later stages of contralateral sustained handgrip, vascular adjustments in resting forearm skeletal muscle would seem to be the final result of reflex sympathetic vasoconstrictor drive, local metabolic vasodilator forces and possibly neurogenic vasodilator mechanisms.

The exercise pressor response to sustained handgrip does not augment blood flow in the contracting forearm skeletal muscle.

Previous studies have advanced the concept that during sustained handgrip (SHG) reflex increases in blood pressure are able to partially offset increases in tissue pressure and thus effectively maintain increases in muscle blood flow during mild to moderate levels of sustained handgrip. However, this concept is based upon measurements of blood flow to the entire forearm. The aim of this study was to evaluate this concept by simultaneously measuring time-dependent changes in systemic arterial pressure and blood flow in an active muscle during the actual period of exercise. To accomplish this aim, we measured 133Xenon washout from the extensor carpi radialis longus muscle over 3 min of SHG at 15, 30 and 45% of maximal voluntary contraction (MVC). During sustained handgrip at 15% MVC, muscle blood flow increased more than 20 fold from rest to exercise (P < 0.05), even though mean arterial pressure increased by only 12 +/- 4 mmHg. This large exercise-induced hyperaemia was abolished during SHG at both 30 and 45% MVC, despite large and progressive increases in mean arterial pressure of 29 +/- 3 and 54 +/- 5 mmHg, respectively. We conclude that at levels of handgrip above 15% MVC blood pressure ceases to be an important determinant of blood flow in the active skeletal muscle. Importantly, the increases in forearm blood flow that have been reported previously with such levels of static handgrip do not appear to be directed to the most active muscle.

Effect of prolonged alveolar hypoxia on pulmonary arterial pressure and segmental vascular resistance.

The time course of hypoxic pulmonary vasoconstriction and its segmental distribution were studied during prolonged (150 min) alveolar hypoxia in in vivo dog lungs at constant-flow perfusion. With the pulmonary and the systemic circulations separated by two extracorporeal circuits, adequate systemic oxygenation was achieved throughout the experiments. The pulmonary circulation exhibited a time-related biphasic hypoxic vasoconstrictor response: an initial rapid contraction [79 +/- 11% (SE) above control level] was followed by a partial relaxation when a second slow and sustained vasoconstriction (92 +/- 13% above control level) superseded. We partitioned the pulmonary circulation into two segments by arterial occlusion: an upstream arterial segment and a downstream segment consisting of a middle and a venous segment. Measurements were performed at baseline and during the late sustained vasoconstrictor response. Prolonged alveolar hypoxia increased pulmonary capillary pressure by 90 +/- 18%, the site of pulmonary vasomotion being the arterial upstream and downstream middle and venous segments.

Effects of orthostatic stress on peripheral capillary filtration in mild congestive heart failure after healing of myocardial infarction.

Patients with heart failure have impaired baroreflex control of the peripheral circulation with attenuated vasoconstrictor response during orthostatic stress. The aim of this study was to test if this impaired baroreflex control not only affects the arterial, but also the capillary bed. Blood flow and capillary filtration were measured in the forearm (plethysmography) in 7 normal subjects and 7 patients with mild congestive heart failure (New York Heart Association functional class II). Measurements were done with the subjects supine and during head-up tilt at 45 degrees. While supine, forearm vascular resistance and capillary filtration coefficient did not differ significantly between the groups. In the control subjects, tilt decreased capillary filtration coefficient by 14 +/- 3% (p < 0.02), and increased forearm vascular resistance by 88 +/- 37% (p < 0.02); in contrast, patients with heart failure had an increase in capillary filtration coefficient of 26 +/- 5% (p < 0.02) and only increased the forearm vascular resistance by 10 +/- 1%, (p = NS, p = 0.26). Our data provide evidence that patients with mild heart failure, in contrast to normal subjects, increase the peripheral capillary filtration during orthostatic stress. The data indicate that impaired baroreflex mechanisms might influence the capillary filtration and it is suggested that impaired baroreflex control of the peripheral circulation can contribute to formation of edema in patients with heart failure.

Absence of pre-dose rebound phenomena with once daily 5-ISMN in a controlled-release formulation.

To avoid the development of nitrate tolerance secondary to relatively constant elevated plasma nitrate concentrations, intermittent nitrate dosing has been advocated. However, a nitrate-free interval may induce a rebound increase in myocardial ischaemia, and thus increase anginal symptoms during the latter portion of the dosing interval. This was suggested by the results of recent studies in which nitroglycerin patches were administered intermittently with a 12 h nitrate-free interval. The present investigation was carried out to determine whether a controlled-release formulation of 60 mg isosorbide-5-mononitrate (5-ISMN) would produce such a rebound phenomenon. Seventy-nine patients, who had participated in four crossover, placebo-controlled studies in which the treatment arms lasted for between 1 and 2 weeks, were reviewed. These studies had assessed the efficacy of this nitrate preparation by exercise testing and each had included exercise testing at the end of each treatment phase, 24 h after the last medication had been administered. There were no differences noted in the time to onset of angina, the time to onset of 1 mm ST segment depression or the total exercise duration between the two treatment phases, indicating an absence of rebound phenomena at the end of the dosing interval. The reason for the absence of a detectable pre-dose rebound is unclear, but the plasma concentration profile of 5-ISMN produced by the presently used preparation, resulting in a nitrate-low instead of nitrate-free interval, may have contributed.

Subcutaneous and skeletal muscle vascular responses in human limbs to lower body negative pressure.

Cardiopulmonary baroreceptor unloading in humans comparably increases sympathetic discharge to skeletal muscle in the forearm and calf, but blood flow studies have disclosed differential rather than uniform vasomotor responses in the extremities. The aim of the present study was to address the issue of differential effects of orthostatic stress on forearm and calf vascular adjustment and to extend previous studies by determining changes in vascular responses separately in various vascular beds of the limbs. The local [133Xenon] washout method was used for recording blood flow rates in subcutaneous tissue and skeletal muscle. Simultaneous recordings from the forearm and calf were performed in 11 healthy young males during lower body negative pressure at -10 mmHg. Heart rate, arterial mean and pulse pressures did not change during lower body negative pressure. In the forearm blood flow rates decreased significantly, in subcutaneous tissue by 16 +/- 2% (mean +/- SEM) and in skeletal muscle by 16 +/- 1%. In the calf lower body negative pressure induced a significant decrease in blood flow rates of 17 +/- 3% in subcutaneous tissue and of 30 +/- 2% in skeletal muscle. This vasoconstriction in calf skeletal muscle was consistently disclosed in both legs and was about the same magnitude in each calf when studied with the one leg exposed to lower body negative pressure and the other outside the lower body negative pressure chamber. These findings suggest that during unloading of cardiopulmonary afferents, reflex sympathetic activation as an important autonomic adjustment to orthostatic stress is accompanied by uniform vasoconstriction in subcutaneous and skeletal muscle vascular beds of human limbs.

Effects of Felodipine on the dog kidney: a lithium clearance study.

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorption rate increased significantly from 2.1 +/- 0.3 to 2.7 +/- 0.4 mmol min-1. Sodium clearance (C-Na) increased from 0.22 +/- 0.08 to 0.40 +/- 0.07 ml min-1. The alpha-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After alpha-adrenergic blockade felodipine caused an increase in C-Na from 0.28 +/- 0.06 ml min-1 to 0.63 +/- 0.04 ml min-1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after alpha-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local alpha-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.