Fibrinolytic response during exercise and epinephrine infusion in the same subjects.

To determine whether exercise-induced increases in tissue plasminogen activator (t-PA) were related to plasma epinephrine concentration during exercise, 14 healthy men (aged 24 to 62 years) were studied during epinephrine infusions (10, 25 and 50 ng/kg per min) and graded supine bicycle exercise, beginning at 33 W and increasing in 33-W increments until exhaustion. Plasma epinephrine, active and total t-PA, active plasminogen activator inhibitor type 1 (PAI-1) and t-PA/PAI-1 complex concentrations were measured at each exercise and infusion level. During epinephrine infusion, active and total t-PA levels increased linearly with the plasma epinephrine concentration (respective slopes [+/- SEM] of 0.062 +/- 0.003 and 0.076 +/- 0.003 pmol/ng epinephrine). During exercise, t-PA levels did not increase until plasma epinephrine levels increased, after which both active and total t-PA levels again increased linearly with the plasma epinephrine concentration, but at twice the rate observed with epinephrine infusion (0.131 +/- 0.005 and 0.147 +/- 0.005 pmol/ng, respectively). The t-PA level in blood was directly proportional to the plasma epinephrine concentration during both exercise and epinephrine infusion, suggesting that epinephrine release during exercise stimulates t-PA secretion. In these healthy subjects, active plasminogen activator inhibitor type 1 and t-PA/PAI-1 complex levels were low (41 +/- 11 and 21 +/- 5 pmol/liter, respectively) and did not change significantly during exercise or epinephrine infusion. It is concluded that approximately 50% of the increase in t-PA during exercise is due to stimulated release of t-PA by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men

OBJECTIVES: The purpose of this study was to investigate in vivo the effects of acute systemic inflammation on the endogenous fibrinolytic capacity in men. BACKGROUND: Systemic inflammation and endogenous fibrinolysis play a major role in the pathogenesis of coronary artery disease. Although previous studies have shown impaired endothelium-dependent vasomotor function, the effects of inflammation on the endothelial release of the fibrinolytic factor tissue plasminogen activator (t-PA) are unknown. METHODS: In a double-blind randomized placebo-controlled crossover trial, we administered a mild inflammatory stimulus, Salmonella typhi vaccine, or saline placebo to eight healthy men on two separate occasions. Six hours after vaccination, blood flow and plasma fibrinolytic variables were measured in both arms during intrabrachial infusions of bradykinin (40 to 1,000 pmol/min), acetylcholine (5 to 20 microg/min), and sodium nitroprusside (2 to 8 microg/min). RESULTS: Compared with placebo, the S. typhi vaccination caused a rise in white cell count (11.1 +/- 0.5 x10(9)/l vs. 7.9 +/- 0.8 x10(9)/l; p = 0.004) and plasma interleukin-6 concentrations (6.9 +/- 1.4 pg/ml vs. 1.6 +/- 0.4 pg/ml; p = 0.01) in addition to a significant augmentation of t-PA antigen (45 +/- 9 ng/100 ml/min at peak dose vs. 24 +/- 8 ng/100 ml/min at peak dose; p = 0.016, analysis of variance) and activity (104 +/- 15 IU/100 ml/min vs. 54 +/- 12 IU/100 ml/min; p = 0.006, analysis of variance) release during bradykinin infusion. Forearm blood flow increased in a dose-dependent manner after bradykinin, acetylcholine and sodium nitroprusside infusions (p < 0.001), but this was unaffected by vaccination. CONCLUSIONS: Our results showed that acute systemic inflammation augmented local forearm t-PA release in men, which suggests that acute inflammation may invoke a protective response by enhancing the acute endogenous fibrinolytic capacity in healthy men. Further studies are needed to clarify whether this response is impaired in patients with cardiovascular disease.     

17Beta-estradiol increases basal but not bradykinin-stimulated release of active t-PA in young postmenopausal women

Angiotensin-converting enzyme inhibition potentiates basal and bradykinin-stimulated tissue-type plasminogen activator (t-PA) release to a greater extent in women than in men. This study tested the hypothesis that 17beta-estradiol enhances the effect of angiotensin-converting enzyme inhibition on t-PA release in young postmenopausal women. We conducted a double-blind, prospective, crossover study in 14 young postmenopausal women (mean age 48.2+/-2.3 years) who were randomized to receive 17beta-estradiol (1 mg/d) or matching placebo for 4 weeks. At the end of each treatment period, we measured the effect of intraarterial infusion of bradykinin, methacholine, and nitroprusside on forearm blood flow and net t-PA release, before and during intraarterial enalaprilat (0.33 microg/min/100 mL forearm volume). 17Beta-estradiol significantly reduced baseline venous plasminogen activator inhibitor-1 antigen (4.4+/-1.4 versus 10.4+/-2.5 ng/mL, P=0.001) and t-PA antigen (5.5+/-0.6 versus 7.5+/-1.3 ng/mL, P=0.022) compared with placebo. 17Beta-estradiol increased basal forearm vascular release of active t-PA compared with placebo (1.2+/-0.3 IU/mL/min versus 0.4+/-0.1 IU/mL/min respectively, P=0.032), without increasing t-PA antigen release (P=0.761). Enalaprilat significantly increased basal net t-PA antigen release (from -0.8+/-1.0 to 3.2+/-1.2 ng/min/100 mL, P=0.012), but not the release of active t-PA, during either placebo or 17beta-estradiol. Enalaprilat potentiated bradykinin-stimulated vasodilation and t-PA antigen and activity release similarly during placebo and 17beta-estradiol treatment. 17Beta-estradiol treatment does not alter the effect of angiotensin-converting enzyme inhibition on basal t-PA antigen or on bradykinin-stimulated t-PA antigen or activity release. 17Beta-estradiol increases basal release of active t-PA in young postmenopausal women, consistent with enhanced vascular fibrinolytic function.     

A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training

A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.     

Antianginal effects of intravenous nitroglycerin over 24 hours

To determine the constancy of hemodynamic and antianginal effects of the constant infusion of intravenous nitroglycerin (NTG) and their relationship to infusion rate and plasma NTG concentration, we administered maximal tolerated doses of intravenous NTG (range 10 to 120 micrograms/min, mean = 52 +/- 33 micrograms/min) and placebo to 10 patients with chronic stable angina for 25 hr each in a randomized, double-blind fashion. Sublingual NTG (0.4 mg) was given at 24.5 hr of infusion as a positive control. Bicycle exercise time (NIH protocol), blood pressure, heart rate, exercise ST response, and venous plasma NTG were determined before and at 1, 4, 8, 24, and 24.5 hr. Plasma NTG was linearly related to infusion rate, reached a steady state within 15 min and was unchanged over 24 hr (mean = 5.5 +/- 1.2 ng/ml). Mean plasma NTG clearance was 9.3 liters/min. However, during dose titration, patients demonstrated different relationships between plasma NTG and hemodynamic effects, with widely varying slopes and intercepts. Intravenous NTG produced a sustained reduction in blood pressure and a rise in heart rate at rest, and a reduction in blood pressure during submaximal exercise at as late as 24 hr, associated with reduced submaximal ST segment abnormality. In contrast, exercise tolerance to onset of angina showed a marked initial increase on intravenous NTG but fell progressively and did not differ from that with placebo at 24 hr. Increased exercise tolerance was associated with an increase in maximal heart rate and double product (heart rate X blood pressure), suggesting that direct coronary vasodilation and/or reduced left ventricular volume were the principal determinants of increased exercise tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man.

OBJECTIVE: Cigarette smoking impairs peripheral endothelium-dependent vasodilatation and acute tissue plasminogen activator (t-PA) release in man. The aim of the study was to determine if this endothelial dysfunction is, in part, mediated by the effects of nicotine. METHODS: Blood flow and plasma fibrinolytic factors were measured in both forearms of eight healthy male non-smokers during unilateral brachial artery infusion of the endothelium-dependent vasodilator, substance P (2 to 8 pmol/min). Endothelium-independent vasodilatation was assessed using intra-arterial infusion of sodium nitroprusside (2 to 8 microg/min). Subjects attended after 7 days treatment with transdermal nicotine or placebo in a double blind randomised crossover design. RESULTS: Plasma cotinine concentrations rose from 0.4+/-0.1 (placebo) to 125+/-25 ng/ml during nicotine administration (P<0.001). On both treatment days, substance P caused dose-dependent increases in blood flow and plasma t-PA antigen and activity concentrations (P<0.001 for all) but had no effect on plasma plasminogen activator inhibitor type 1 (PAI-1) concentrations. Compared with placebo, nicotine administration increased the substance-P-induced release of t-PA antigen and activity (P<0.05 for both) without an effect on endothelium-dependent or -independent vasodilatation. CONCLUSIONS: Short-term transdermal nicotine treatment does not affect endothelium-dependent vasomotion but does increase substance-P-induced t-PA release in vivo in man. This suggests that nicotine administration alters specific aspects of endothelial function and enhances the acute endogenous fibrinolytic capacity in vivo. The long-term effects of nicotine exposure, including the potential to cause depletion of endothelial t-PA stores, now needs to be assessed.     

Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology

This study was performed to characterize selected pharmacologic properties and effects on the fibrinolytic system of tissue-type plasminogen activator synthesized by recombinant DNA technology (rt-PA) in 12 patients treated for coronary thrombosis. rt-PA was infused parenterally (by the intracoronary route in four patients and intravenously in eight) in doses of 8.3, 12.5, or 16.7 micrograms/kg/min for 30 to 60 min, yielding a total dosage of 20 to 40 mg/patient. The drug induced coronary thrombolysis in 10 of the 12 patients treated (83%), including six of the eight given rt-PA intravenously. No bleeding complications were encountered. Serial blood samples were obtained before, during, and after infusion of rt-PA and analyzed for t-PA antigen (i.e., immunoassayable rt-PA protein), functional fibrinolytic activity attributable to rt-PA, fibrinogen, plasminogen, alpha 2-antiplasmin, fibrinogen degradation products, prothrombin time, activated partial thromboplastin time, and protamine-corrected thrombin time. Pretreatment plasma t-PA antigen levels averaged 16.5 +/- 5(SD) ng/ml. Peak plasma values were generally proportional to dose, averaging 3330 +/- 1201 ng/ml. Approximately 90% of peak level was reached in 30 min, with a plateau at peak reached within 40 min. Functional t-PA activity increased monotonically in a comparable fashion. Curves for disappearance of both t-PA antigen and functional activity from plasma were monoexponential for at least two half-lives (r = .99 for both) and were concordant. The observed half-lives were similar, averaging 8.3 and 9.1 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preserved tissue-type plasminogen activator release and endothelium-dependent vasodilation in postmenopausal women with NIDDM

We have recently shown that the net release of tissue-type plasminogen activator (t-PA) antigen can be rapidly enhanced by the muscarinic receptor stimulation in healthy males. Since diabetes mellitus has been associated with endothelial dysfunction, the aim of the present study was to compare the endothelium-derived local net release of t-PA with vasodilation in response to muscarinic receptor stimulation by metacholine (Mch) and fluid shear stress in a group of postmenopausal women with non-insulin-dependent diabetes mellitus (NIDDM), and to elucidate the influence of estrogen on this process. Six postmenopausal women with NIDDM were in randomized order exposed to step-wise intra-arterial infusions of Mch (0.1-0. 8-4.0 microg/min) and nitroprusside (SNP; 0.5-2.5-10.0 microg/min). Forearm blood flow (FBF) was assessed by plethysmography. The infusions with Mch and SNP were repeated during simultaneous intra-arterial infusion of 17-beta estradiol (E; 20 ng/min). During placebo infusion, FBF increased significantly in response to Mch and SNP (p<0.001), but no differences between Mch and SNP were found. In parallel to the blood flow increase in response to Mch stimulation, the t-PA net release was increased over 30 times (p<0.001). Estrogen did not produce any change in blood flow or net release of t-PA at baseline or in response to either drug (Mch or SNP). The present study demonstrates a preserved endothelium-dependent vasodilation and stimulated tissue-type plasminogen activator release in NIDDM postmenopausal women in response to Mch stimulation. Acute intra-arterial infusion of 17-beta estradiol did not affect the vasodilation or the t-PA net release.     

Acute effects of angiotensin II on fibrinolysis in healthy volunteers.

Recent studies have suggested that angiotensin II may inhibit fibrinolysis. In order to further test this hypothesis, we investigated the acute effects of angiotensin II (intravenous infusion of 10 ng/kg per min over 15-20 min) on fibrinolytic function in 18 healthy men. Time-controls (n=11) and control experiments with a placebo infusion (n = 13) were also performed. The activities of plasmin activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA), as well as t-PA antigen levels, were determined in plasma before, during and 60 min after the infusion of angiotensin II. Angiotensin II caused a clear-cut elevation in blood pressure; heart rate and plasma noradrenaline levels tended to decrease during the infusion but increased afterwards, indicating reflexogenic adjustments. Plasma t-PA activity and antigen levels increased by 81+/-11 and 14+/-3%, respectively, during angiotensin II infusion (both P < 0.001), whereas t-PA activity was unchanged and t-PA antigen decreased (P < 0.05) in placebo experiments. PAI-1 activity decreased similarly in time-controls and during angiotensin infusion (P < 0.001). Thus, short-term infusion of angiotensin II enhances fibrinolysis by elevating plasma t-PA. It is not clear whether this is a direct angiotensin-receptor-mediated effect or if it is related to the hemodynamic effects of the infusion.     

Des-1-Asp-angiotensin II. Possible intrarenal role in homeostasis in the dog.

The relative effects of des-a-Asp-angiotensin 3I and angiotensin II on renal function, including renin secretion, were investigated in normal and sodium-depleted dogs. Intrarenal arterial infusion of the heptapeptide fragment into normal dogs at a rate which was calculated to increase blood levels by only 7 ng/100 ml decreased renal blood flow from 254 +/- 9 ml/min to 220 +/- 12 and 219 +/- 12 ml/min (P less than 0.01 for both values) after 10 and 30 minutes of infusion, respectively; renin secretion decreased from 502 +/- 214 ng/min to 253 +/- 109 and 180 +/- 53 ng/min (P less than 0.05 for both values). Infusion of angiotensin II at the same rate decreased renal blood flow from 251 +/- 26 ml/min to 224 +/- 22 and 220 +/- 16 ml/min (P less than 0.01 and 0.025, respectively) and decreased renin secretion from 374 +/- 25 ng/min to 166 +/- 76 and 131 +/- 37 ng/min (P less than 0.025 for both values). Neither peptide significantly changed mean arterial blood pressure, creatinine clearance, or excreted sodium in these dogs. Infusion of des-1-Asp-angiotensin II into sodium-depleted dogs decreased renin secretion from 1094 +/- 211 ng/min to 768 +/- 132 and 499 +/- 31 ng/min (P less than 0.025 for both values) after 10 and 30 minutes of infusion. Angiotensin II infusion decreased renin secretion from 1102 +/- 134 to 495 +/- 235 and 502 +/- 129 ng/min in these dogs (P less than 0.05 and 0.025, respectively). Neither peptide significantly altered renal blood flow, arterial blood pressure, creatinine clearance, or excreted sodium in the sodium-depleted dogs. The data demonstrated that these two peptides have similar effects on the renin secretory mechanism and the vascular receptor at the level of the renal arterioles.     

Cimetidine does not reduce liver blood flow in cirrhosis

Cimetidine has been shown to reduce liver blood flow, as measured by indocyanine green clearance, in normal subjects. Concern over the potential deleterious effects of such reduction in cirrhosis led to the measurement of blood flow in 14 cirrhotics receiving oral or intravenous cimetidine. Liver blood flow was measured by the clearance of galactose at steady state during infusion of 40 mg per min. In six patients receiving 300 mg cimetidine by mouth each 6 hr for 4 days, basal flow (1,019 +/- 186 ml per min) was not significantly altered by cimetidine (1,087 +/- 156 ml per min). Intravenous infusion of cimetidine (300 mg) did not significantly alter flow in five patients between the basal (1,096 +/- 334 ml per min) and treatment periods (1,051 +/- 383 ml per min). Hepatic extraction of galactose in three patients (82 +/- 19%) was not significantly altered by cimetidine infusion (81 +/- 13%). The failure to reduce liver blood flow with cimetidine in this population may be due to their diminished proportion of portal venous flow, or alternatively suggests that histamine is not an important modulator of flow via H2 receptors. At a clinical level, the use of cimetidine in this population can continue without fear of further reduction in liver blood flow.     

Exercise training in patients with chronic heart failure delays ventilatory anaerobic threshold and improves submaximal exercise performance

We have recently demonstrated that exercise training can induce important hemodynamic and metabolic adaptations in patients with chronic heart failure due to severe left ventricular dysfunction. This study examines the accompanying changes in submaximal exercise performance and the ventilatory response to exercise in these patients. Before and after 16-24 weeks of exercise training, subjects underwent two symptom-limited bicycle exercise tests, one with an incremental graded workload, and one with a constant workload that represented 79 +/- 11% of the pretraining peak oxygen consumption. Breath-by-breath expired gas analysis was performed continuously during each test, and central hemodynamic, leg blood flow, and blood lactate measurements were obtained during the incremental protocol. The ventilatory anaerobic threshold was determined during the incremental exercise study from coplotted breath-by-breath ventilatory data with standard criteria by observers who were unaware of patient identity or training status. As previously reported, exercise training increased peak oxygen consumption by 23% from 16.8 +/- 3.8 to 20.6 +/- 4.7 ml/kg/min and reduced blood lactate levels during submaximal exercise. The training-induced decrease in lactate accumulation was accompanied by a decrease in carbon dioxide production, respiratory exchange ratio, and ventilation during submaximal exercise. The ventilatory anaerobic threshold was delayed from 284 +/- 43 to 352 +/- 91 seconds of exercise (p = 0.02), and it occurred at an increased oxygen consumption (10.1 +/- 1.2 vs. 12.1 +/- 2.6 ml/kg/min, p = 0.01). Exercise duration during the constant workload protocol increased from 938 +/- 410 to 1,429 +/- 691 seconds (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased galactose clearance after liver transplantation: a measure of increased blood flow through the denervated liver?

This study measured the liver blood flow-dependent index of galactose clearance in patients after liver transplantation, to test the hypothesis that liver blood flow is increased in the denervated liver. Eight normal subjects and 16 patients 1 to 8 months after liver transplant were studied. All patients were stable with no evidence of severe rejection at the time of study. Galactose clearance was measured at steady state during continuous infusion of 75 mg per min of 5% galactose. The results show a statistically significant (p less than 0.01) higher average galactose clearance in the transplant patients (1,187 +/- 316 ml per min per m2) compared to the control group (709 +/- 121 ml per min per m2). The major limiting factor in galactose clearance at low concentrations is liver blood flow, and we interpret these data as evidence for increased blood flow in the transplanted liver. Possible mechanisms for the increased galactose clearance are (i) loss of normal vasomotor tone in the denervated liver, or (ii) persistence of abnormal systemic hemodynamics after transplantation. Elucidation of these mechanisms awaits further study.     

The effect of exercise and heart rate on fibrinolytic activity.

The effect of heart rate on plasma fibrinolytic activity was investigated in nine patients with dual chamber cardiac pacemakers before and after 10 min of stimulated tachycardia to 123 beats/min. The results were compared to seven volunteers who performed submaximal exercise to 90% target heart rate and to five of the seven who underwent a second period of exercise to a heart rate of 120 beats/min. During submaximal exercise (mean heart rate 152 beats/min) the median ECLT fell from 248 min (interquartile range 147.5-305) to 90 (55-202) P less than 0.01 and t-PA:Ag increased from 6.1 ng/ml (3.92-7.95) to 9.3 (8.45-12.7), P less than 0.025. PAI and PAI-1:Ag fell from 12.0 IU/ml (5.85-15.5) to 4.1 (1.85-11.67), P less than 0.01, and 9.7 ng/ml (2.8-10.6) to 6.7 (2.1-9.9), P less than 0.01 respectively. A lower level of exercise to 120 beats/min resulted in a reduction in ECLT from 215 min (167.5-228.5) to 135 (116-154), P = 0.05 and an increase in t-PA:Ag from 4 ng/ml (3.07-4.45) to 5.0 (3.3-5.22) P less than 0.05. PAI and PAI-1:Ag fell from 7.6 IU/ml (3.27-8.5) to 7.1 (2.77-7.4) and from 7.7 ng/ml (6.0-7.92) to 6.4 (4.8-7.3) respectively but these changes were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Splanchnic extraction and clearance of tissue plasminogen activator (t-PA) after injection of recombinant t-PA (Actilyse) in resting healthy subjects is proportional to the arterial concentration.

The purpose of the study was to evaluate the splanchnic extraction of tissue plasminogen activator (t-PA) in normal healthy fasting subjects after the injection of recombinant t-PA (rt-PA; Actilyse). In nine healthy volunteers (five male, four female), 21-29 years of age, the concentration of t-PA was determined in plasma samples taken simultaneously from a femoral artery and a large liver vein after a bolus injection (5, 10 or 20 mg) of rt-PA. The splanchnic plasma flow rate, the plasma volume, and the splanchnic extraction fraction of t-PA were determined. After the rt-PA injection, the measured arterial concentration of t-PA decreased from 36 750 to 45 pmol/l for t-PA antigen and from 50 700 to 17 pmol/l for active t-PA. The splanchnic extraction fraction decreased from 0.95 to 0.02 for t-PA antigen and from 0.78 to 0.08 (n = 3) for active t-PA. The extraction fraction was proportional to the arterial concentration of t-PA when the arterial concentration of t-PA was above about 300 pmol/l (both t-PA antigen and active t-PA). The median splanchnic plasma flow rate was 911 ml/min (range, 651-1149 ml/min). In the individual subject, the splanchnic plasma flow rate remained constant during the experimental period. The main conclusion of the study is that the splanchnic clearance and extraction fraction of t-PA, following an injection of rt-PA in the resting fasting steady state, depends on the arterial concentration of t-PA. The higher the arterial concentration of t-PA, the higher the extraction fraction of t-PA.     

Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure

We studied the central hemodynamic, leg blood flow, and metabolic responses to maximal upright bicycle exercise in 30 patients with chronic heart failure attributable to severe left ventricular dysfunction (ejection fraction, 24 +/- 8%) and in 12 normal subjects. At peak exercise, patients demonstrated reduced oxygen consumption (15.1 +/- 4.8 vs. 32.1 +/- 9.9 ml/kg/min, p less than 0.001), cardiac output (8.7 +/- 3.2 vs. 18.6 +/- 4.4 l/min, p less than 0.001), and mean systemic arterial blood pressure (116 +/- 15 vs. 135 +/- 13 mm Hg, p less than 0.01) compared with normal subjects. Leg blood flow was decreased in patients versus normal subjects at rest and matched submaximal work rates and maximal exercise (2.1 +/- 1.9 vs. 6.4 +/- 1.4 l/min, all p less than 0.01). Mean systemic arterial blood pressure was no different in the two groups at rest or at matched submaximal work rates, whereas leg vascular resistance was higher in patients compared with normal subjects at rest, submaximal, and maximal exercise (all p less than 0.01). Although nonleg blood flow was decreased at rest in patients, it did not decrease significantly during exercise in either group. Peak exercise leg blood flow was related to peak exercise cardiac output in patients (r = 0.66, p less than 0.01) and normal subjects (r = 0.67, p less than 0.01). In patients, leg vascular resistance was not related to mean arterial blood pressure, pulmonary capillary wedge pressure, arterial catecholamines, arterial lactate, or femoral venous pH at rest or during exercise. Compared with normal subjects during submaximal exercise, patients demonstrated increased leg oxygen extraction and lactate production accompanied by decreased leg oxygen consumption. Thus, in patients with chronic heart failure compared with normal subjects, skeletal muscle perfusion is decreased at rest and during submaximal and maximal exercise, and local vascular resistance is increased. Our data indicate that nonleg blood flow and arterial blood pressure were preferentially maintained during exercise at the expense of leg hypoperfusion in our patients. This was associated with decreased leg oxygen utilization and increased leg oxygen extraction when compared to normal subjects, providing further evidence that reduced perfusion of skeletal muscle is important in causing early anaerobic skeletal muscle metabolism during exercise in subjects with this disorder.(ABSTRACT TRUNCATED AT 400 WORDS)     

Response of upper limb blood flow to handgrip exercise after Blalock-Taussig operation (for tetralogy of Fallot) or subclavian flap operation (for aortic isthmic coarctation)

To evaluate the effects of long-term reductions in perfusion pressure on blood flow responses to increased functional demand, 5 patients (aged 12 to 26 years) without normal aortic to subclavian artery blood flow to 1 arm as a result of surgery to treat congenital heart disease were studied. Five age- and sex-matched healthy (control) subjects were also studied. In the patients, forearm blood flow was not different in the surgical and normal arms at rest (3.6 +/- 0.6 vs 4.0 +/- 0.7 ml/min/100 ml, respectively, mean +/- standard error, difference not significant) despite lower systolic blood pressure in the surgical arm (87 +/- 2 vs 115 +/- 2 mm Hg, p less than 0.05). The increases in heart rate, systolic blood pressure, forearm electromyographic activity (index of muscle fatigue) and postexercise forearm blood flow (index of muscle oxygen deficit) were not different in response to 2.5 minutes of submaximal rhythmic handgrip exercise (50% of maximal force) performed with the surgical versus the normal arms. Peak forearm blood flow elicited by combined ischemia and maximal isometric handgrip exercise was not significantly different in surgical and normal arms in the group as a whole (39 +/- 4 vs 43 +/- 3 ml/min/100 ml, difference not significant), although some bilateral deficit (20 to 38%) was observed in 2 patients. No bilateral differences were observed in the control subjects under any condition. The finding of normal physiologic adjustments to submaximal rhythmic handgrip exercise with the surgical arm suggests that oxygen delivery during exercise was adequate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired forearm vasodilation to hyperosmolal stimuli in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy.

Patients with congestive heart failure (CHF) have impaired peripheral vasodilation during exercise. Hyperosmolality is one local stimulus that produces vasodilation during exercise in normal subjects. This study addressed the hypothesis that vasodilation to hyperosmolal stimuli is impaired in patients with CHF. Forearm blood flow responses to intrabrachial artery infusions of isoosmolar (280 mosm/kg) and hyperosmolal (480 and 660 mosm/kg) solutions of saline and glucose were compared in 9 patients with CHF and 13 normal subjects. Forearm blood flow was measured by strain gauge plethysmography. In the normal subjects, hyperosmolal infusions of 480 and 660 mosm/kg increased forearm blood flow by 3.12 +/- 0.40 and 6.80 +/- 0.67 ml/min/100 ml forearm volume, respectively (both p < 0.001 compared with isoosmolal infusions). In contrast, in the patients with CHF, these infusions increased forearm blood flow by 2.19 +/- 0.44 and 4.06 +/- 0.92 ml/min/100 ml forearm volume (p < 0.05 normal vs CHF). The impaired forearm blood flow responses in heart failure occurred despite significantly greater (p < 0.05, normal vs CHF) increases in venous osmolality (17.3 +/- 6.5 vs 9.6 +/- 1.3 mosm/kg for the 660 mosm/kg infusion). There were no differences between groups in forearm venous hematocrit, calcium, and sodium or potassium changes during hyperosmolal infusions. It is concluded that peripheral vasodilation to hyperosmolal stimuli is impaired in patients with CHF.     

Comparison of vasodilator effects of substance P in human forearm vessels of normoalbuminuric Type 1 diabetic and non-diabetic subjects.

AIMS: To compare the vasodilatory responses to substance P in human forearm vessels in Type 1 normoalbuminuric diabetic and non-diabetic subjects. METHODS: Forearm blood flow (FBF) was measured using a plethysmography technique in 12 normoalbuminuric Type 1 diabetic subjects (six males, six females) (HbA(1c) 8.2 +/- 0.3% (mean +/- SEM)) and 12 non-diabetic healthy control subjects in response to the infusion of the vasodilators substance P (SP), acetylcholine (ACh) and nitroprusside. RESULTS: There was no significant difference in baseline FBF between the two groups (2.80 +/- 0.29 ml/min per 100 ml forearm tissue (diabetic group) vs. 2.85 +/- 0.37 ml/min per 100 ml (non-diabetic group), P = 0.45). Infusion of SP was associated with an incremental increase in FBF in the diabetic (0.6, 2 and 6 ng/min - 6.08 +/- 1.07, 7.82 +/- 1.08 and 9.48 +/- 1.14 ml/min per 100 ml, respectively) and the non-diabetic group (0.6, 2 and 6 ng/min - 5.41 +/- 0.80, 6.93 +/- 0.96 and 9.25 +/- 1.11 ml/min per 100 ml, respectively). Similarly, an incremental rise in FBF was observed during infusion of ACh (diabetic group: 7.5, 15 and 30 microg/min - 7.14 +/- 1.22, 8.91 +/- 1.40 and 11.67 +/- 1.93 ml/min per 100 ml, respectively; non-diabetic group: 7.5, 15 and 30 microg/min - 5.87 +/- 0.81, 7.49 +/- 0.96 and 10.74 +/- 1.29 ml/min per 100 ml, respectively). When FBF was expressed as percentage change from baseline, there was no significant difference in vasodilatory responses between the two groups for SP (0.6 ng/min, P = 0.21; 2 ng/min, P = 0.19; 6 ng/min, P = 0.19) or ACh (7.5 microg/min, P = 0.20; 15 microg/min, P = 0.20; 30 microg/min, P = 0.35). CONCLUSIONS: This study suggests that endothelium-dependent vasodilatory responses to SP (and ACh) are not impaired in Type 1 diabetic subjects with normal urinary albumin excretion.     

Prevention of coronary thrombosis with subthrombolytic doses of tissue-type plasminogen activator

To determine whether tissue-type plasminogen activator (t-PA) may prevent coronary thrombosis or accelerate the lysis of clot formed under conditions in which increased concentration of the activator is present before thrombosis, clot lysis studies were undertaken in vitro and in vivo. In vitro, exogenous t-PA (6 to 100,000 ng/ml) accelerated the lysis of clot in a dose-dependent fashion when the clot was formed either from whole plasma or from euglobulin fractions (n = 316 determinations). Adding t-PA before clot formation shortened the time to lysis by at least threefold with euglobulin fractions and by at least 10-fold with whole plasma clots, which is consistent with the presence of inhibitors of fibrinolysis in whole plasma and with the binding of t-PA to nascent fibrin. In an intact dog preparation of coronary thrombosis (n = 25), occlusive thrombus formation was prevented when t-PA was present in subthrombolytic concentrations (430 to 1200 ng/ml, n = 5). Occlusive thrombus formation occurred after only discontinuation of the t-PA infusion and clearance of t-PA. Lower concentrations of t-PA (147 to 427 ng/ml, n = 6) significantly delayed occlusion (26 +/- 6.5 vs 7.8 +/- 2.8 min for controls). In animals with t-PA concentrations of less than 140 ng/ml (n = 4), the time to occlusion was unaltered (7.7 +/- 4.5 min). The present study demonstrates that t-PA present before clot formation inhibits thrombosis or accelerates thrombolysis depending on concentration, and that subthrombolytic doses of t-PA can prevent thrombus formation in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)