Hypertensive stress increases dispersion of repolarization

Several electrocardiographic indices for repolarization heterogeneity have been proposed previously. The behavior of these indices under two different stressors at the same heart rate (i.e., normotensive gravitational stress, and hypertensive isometric stress) was studied. ECG and blood pressure were recorded in 56 healthy men during rest (sitting with horizontal legs), hypertensive stress (performing handgrip), and normotensive stress (sitting with lowered legs). During both stressors, heart rates differed <10% in 41 subjects, who constituted the final study group. Heart rate increased from 63 +/- 9 beats/min at rest to 71 +/- 11 beats/min during normotensive, and to 71 +/- 10 beats/min during hypertensive stress (P < 0.001). Systolic blood pressure was 122 +/- 15 mmHg at rest and 121 +/- 15 mmHg during normotensive stress, and increased to 151 +/- 17 mmHg during hypertensive stress (P < 0.001). The QT interval was larger during hypertensive (405 +/- 27) than during normotensive stress (389 +/- 26, P < 0.001). QT dispersion did not differ significantly between the two stressors. The mean interval between the apex and the end of the T wave (Tapex-Tend) of the mid-precordial leads was larger during hypertensive (121 +/- 17 ms) than during normotensive stress (116 +/- 15 ms, P < 0.001). The singular value decomposition T wave index was larger during hypertensive (0.144 +/- 0.071) than during normotensive stress (0.089 +/- 0.053, P < 0.001). Most indices of repolarization heterogeneity were larger during hypertensive stress than during normotensive stress. Hypertensive stressors are associated with arrhythmogeneity in vulnerable hearts. This may in part be explained by the induction of repolarization heterogeneity by hypertensive stress.     

The gain-of-function G389R variant of the beta1-adrenoceptor does not influence blood pressure or heart rate response to beta-blockade in hypertensive subjects.

Mutation scanning of the beta1-adrenoceptor gene has identified a polymorphism, G389R, that markedly affects G-protein coupling of the receptor and resulting cAMP production. We have investigated the effect of this functionally active polymorphism on clinical response to beta-adrenoceptor blockade. Two cohorts of untreated hypertensive patients randomly assigned to a beta1-selective beta-blocker at the start of antihypertensive therapy were studied retrospectively to see if the G389R polymorphism influenced the response in terms of blood pressure and heart rate. The blood pressure and heart rate responses to treatment were assessed 4 weeks later and compared with the G389R genotype, ascertained by PCR/restriction fragment length polymorphism. The falls in blood pressure and heart rate for the first group (n = 92) by genotype were: GG, 20.1 +/- 3.5/13.9 +/- 2.7 mmHg (systolic/diastolic blood pressure), 18.4 +/- 2.2 beats/min; GR, 20.0 +/- 2.2/15.0 +/- 1.3 mmHg, 16.5 +/- 1.5 beats/min; RR, 20.8 +/- 2.3/13.4 +/- 1.1 mmHg, 16.0 +/- 1.4 beats/min. For the second group (n = 55) the corresponding falls were: GG, 17.0 +/- 4.3/11.2 +/- 3.4 mmHg, 12.0 +/- 3.5 beats/min; GR, 16.6 +/- 1.8/14.4 +/- 1.1 mmHg, 13.1 +/- 2.1 beats/min; RR, 18.0 +/- 1.6/13.0 +/- 1.4 mmHg, 14.4 +/- 1.4 beats/min. The G389R genotype also failed to have a significant effect on pretreatment blood pressure or heart rate in either group. These data suggest that, despite clear functional differences between the G389R receptor variants expressed in vitro, the polymorphism does not affect the haemodynamic response of hypertensive subjects to chronic beta1-adrenoceptor blockade.     

Effect of intravenous infusion of adrenaline on the cardiovascular responses to distal body subatmospheric pressure in man

1. On two separate occasions, at least 1 week apart, seven young healthy male subjects received intravenous infusions of either adrenaline [0.27 nmol (50 ng) min-1 kg-1] or saline (154 mmol/l NaCl), plus ascorbic acid (5.68 mmol/l), over 30 min. 2. On each occasion, the subjects were exposed to distal body subatmospheric pressure (DBSP), 0 to 50 mmHg (0 to 6.65 kPa) in 10 mmHg (1.33 kPa) steps, before infusion, during the final 15 min of the infusion, and at 15 min and 30 min after the cessation of the infusion. 3. Venous adrenaline concentrations of 2.85 +/- 0.22 nmol/l were achieved during the adrenaline infusion, compared with 0.49 +/- 0.07 nmol/l during the saline infusion (P less than 0.001). At 15 min and at 30 min after cessation of the adrenaline infusion, venous adrenaline concentrations had fallen to levels similar to those achieved after the cessation of the saline infusion. 4. Heart rate rose significantly from 58 +/- 4 beats/min to 67 +/- 4 beats/min during the adrenaline infusion (P less than 0.05), but there was no further significant change in response to 50 mmHg (6.65 kPa) DBSP. At 30 min after the cessation of the adrenaline infusion, heart rate rose from 60 +/- 4 beats/min to 78 +/- 7 beats/min in response to 50 mmHg DBSP. This increase was significantly greater than that observed before the adrenaline infusion [58 +/- 4 beats/min to 69 +/- 7 beats/min during 50 mmHg (6.65 kPa) DBSP; P less than 0.01].(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Forearm vasoconstriction in response to noradrenaline and NG-monomethyl-L-arginine in essential hypertension.

A role for abnormal NO production in essential hypertension remains controversial. Blunted vasoconstriction of forearm resistance vasculature in response to N(G)-monomethyl-L-arginine (L-NMMA; an inhibitor of NO biosynthesis), relative to the response to noradrenaline, has been reported in hypertensive patients and interpreted as evidence of reduced basal NO biosynthesis. We sought to determine whether reduced sensitivity of forearm vasculature to the vasoconstrictor action of L-NMMA relative to that of noradrenaline is a consistent finding in essential hypertension. We studied a group of patients (n=32; blood pressure 176+/-4/102+/-2 mmHg; means+/-S.E.M.) and a group of healthy normotensive controls (n=32; blood pressure 130+/-2/75+/-1 mmHg). Noradrenaline (60-240 pmol.min(-1)) and L-NMMA (1-4 micromol.min(-1)) were infused into the brachial artery, and forearm blood flow was measured by venous occlusion plethysmography. The effects of each vasoconstrictor were similar in hypertensive and control subjects. The highest dose of L-NMMA reduced forearm blood flow by 0.75+/-0.12 ml.min(-1).dl(-1) in the control group and by 0.89+/-0.10 ml.min(-1).dl(-1) in the hypertensive group. The study had 90% power (with P=0.05) to detect a 10% difference in forearm blood flow response between the hypertensive and control groups. We conclude that reduced sensitivity of forearm resistance vasculature to the vasoconstrictor action of L-NMMA is not a universal feature of essential hypertension. This argues against a primary role for reduced basal NO biosynthesis in skeletal muscle resistance vessels in the pathogenesis of essential hypertension.     

Should a VVIR Pacemaker Increase the Heart Rate with Standing?

To assess the usefulness of incorporating a posture sensor into a ventricular inhibited rate modulated pacemaker, the hemodynamic effects of increasing the ventricular pacing rate with standing were studied in 15 pacemaker dependent patients aged 55 +/- 3.5 years. In a randomized cross-over design, the pacing rate remained at 70 or was increased to 100 beats/min immediately prior to standing. Blood pressure was monitored continuously and forearm blood flow was measured by venous occlusion plethysmography. There was no difference in supine blood pressure (117 +/- 4/63 +/- 3 compared to 118 +/- 5/64 +/- 4 mmHg) or forearm blood flow (2.88 +/- 0.36 vs 2.94 +/- 0.32 mL/100 mL/min) before the 70 or 100 pacing rate intervention. With standing, blood pressure fell to an equivalent degree at the two pacing rates (fall in mean blood pressure at 70 beats/min 6 +/- 4 and at 100 beats/min 8 +/- 2 mmHg, P = 0.7). After 1 minute of standing differences in blood pressure were similar, but after 2.5 minutes of standing the increase in mean blood pressure was less at 70 than at 100 beats/min (increase from control 28 +/- 2 compared to 36 +/- 3 mmHg, P = 0.002). Forearm blood flow decreased after standing for 1 and 2.5 minutes but there was no difference between the 70 and 100 pacing rates (fall in forearm blood flow at 2.5 minutes 0.50 +/- 0.24 and 0.59 +/- 0.25 mL/100 mL/cm2).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hysteresis of the venous pressure-volume relationship in the forearm of borderline hypertensive subjects.

1. The forearm venous pressure-volume relationship was studied in 14 young men with borderline hypertension and in 16 control subjects of the same age and sex. Strain-gauge plethysmography was used to evaluate volume changes after slow increases and decreases in distention, in order to estimate the amplitude of the hysteresis curve. 2. Compared with normotensive control subjects, subjects with borderline hypertension had significantly higher values of blood pressure, heart rate and forearm blood flow. 3. Baseline forearm venous tone was slightly, but not significantly, increased in borderline hypertensive subjects (21.35 +/- 6.53 versus 18.75 +/- 5.95 mmHg ml-1 100 ml-1) and was significantly enhanced after a cold pressor test. The increase was no higher in the borderline hypertensive subjects than in the normotensive control subjects. 4. The area of the hysteresis curve was significantly decreased (7.58 +/- 3.58 versus 10.34 +/- 5.67 arbitrary units; P = 0.0092) as was the extent of isotonic relaxation (creep) (0.28 +/- 0.11 versus 0.39 +/- 0.22 ml/100 ml; P = 0.0098) in borderline hypertensive subjects compared with control subjects. Both parameters were unaffected by the cold pressor test. 5. The study suggests that the viscous component of the venous wall is altered in young patients with borderline hypertension, indicating intrinsic changes in vascular segments which are not exposed to increased intraluminal pressure.     

The renal and neurohumoral effects of the addition of low-dose dopamine in septic critically ill patients

OBJECTIVES: Dopamine exerts a complicated action on the cardiovascular-renal and neurohumoral systems. We evaluated the effects of the addition of different doses of dopamine on top of treatment with norepinephrine on the haemodynamics, renal function and neurohormones of septic shock patients. DESIGN: Open, uncontrolled, dose-finding study. SUBJECTS: Dopamine was administered, after fluid resuscitation, to septic shock patients who were more than 2 h haemodynamically and pulmonary stable with the use of a constant dose norepinephrine. Patients with a serum creatinine above 180 micromol x l were excluded. METHODS: Dopamine doses of 0, 2, 4, 6 and 0 microg x kg(-1) x min(-1) were given consecutively for 1 h each. Neurohormones were measured hourly after baseline levels had been taken. Systemic haemodynamics were measured using a pulmonary artery (PA) catheter every 30 min, whereas urine collections were examined every hour during the study period. RESULTS AND STATISTICAL ANALYSES: Eight patients (mean age 46 +/- 13 years, M/F 3/5) were included. The median norepinephrine dose at the start of the study was 0.29 microg x kg(-1) x min(-1) (range 0.07-0.48 microg x kg(-1) x min(-1)). Cardiac output (CO) rose during the dopamine infusion for all doses from 7.9 +/- 1.74 l/min to a maximum of 10.1 +/- 1.71 l/min, achieved at the 4 microg x kg(-1) x min(-1) dopamine dose, whereas systemic vascular rate (SVR) decreased slightly for all doses. Heart rate remained unchanged during the 2 microg x kg(-1) x min(-1) dose of dopamine but increased for the 4 and 6 microg x kg(-1) x min(-1) doses from 108 +/- 17 to a maximum of 124 +/- 24 beats/min. Filling pressures remained unchanged whereas the mean arterial blood pressure increased (from 83 +/- 7 to 93 +/- 11 mmHg). Plasma renin activity (PRA) was relatively high (but remained unchanged) as were aldosterone levels. Sodium excretion and diuresis increased for all doses, accompanied by an increase of fractional sodium excretion at the 4 and 6 microg x kg(-1) x min(-1) doses of dopamine. Creatinine clearances remained unchanged. All changed values returned to baseline values after cessation of the dopamine administration. CONCLUSION: During norepinephrine infusion, increasing doses of dopamine from 2 to 6 microg x kg(-1) x min(-1) augments CO, diuresis and sodium excretion in patients treated for septic shock, without changes in creatinine clearance. Higher doses of dopamine (4 and 6 microg x kg(-1) x min(-1)) also induce an increase in heart rate. PRA, aldosterone and norepinephrine levels remain unchanged during dopamine infusion.     

Enhanced dopamine renal responsiveness in patients with hypertension

The purpose of the study was to compare the renal effects of low doses of exogenous dopamine to assess the responsiveness of renal dopaminergic receptors in normotensive and hypertensive subjects. Eight hypertensive patients and seven normotensive volunteer subjects were studied. Inulin and para-aminohippuric (PAH) clearances, natriuresis, and fractional excretion of sodium increased significantly after intravenous dosing with dopamine (2 micrograms/min/kg) in both groups. These increases were significantly higher in hypertensive than in normotensive subjects: 31.8% +/- 3.7% vs. 16.2% +/- 1.2% for inulin clearance (P less than 0.01), 83.3% +/- 10.5% vs. 41.1% +/- 3.4% for PAH clearance (P less than 0.01), and 331% +/- 38% vs. 216% +/- 26% for natriuresis (P less than 0.01). These findings suggest hyperresponsiveness to dopamine during hypertension. This enhanced response to exogenous dopamine can be considered as a further argument favoring the existence of a deficit in dopaminergic activity during hypertension. Dopamine also induced a significant reduction in blood pressure and increased heart rate in hypertensive subjects but no significant change in blood pressure and heart rate occurred in normotensive subjects.     

Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.     

Influence of St John's wort on catecholamine turnover and cardiovascular regulation in humans

BACKGROUND: St John's wort (Hypericum perforatum) is a popular over-the-counter antidepressant. Its antidepressive effect has been attributed in part to inhibition of monoamine transporters and monoamine oxidase, on the basis of in vitro studies. METHODS: In a double-blind, randomized, placebo-controlled, crossover study, 16 healthy subjects (11 men and 5 women; mean age, 31 +/- 5 years) ingested either St John's wort (300 mg three times daily) or placebo for 7 days. Imipramine treatment (50 mg three times daily) in 7 subjects served as a positive control. After treatment, physiologic and biochemical tests included cardiovascular reflex testing, graded head-up tilt testing, and plasma catecholamine determinations. RESULTS: St John's wort had no effect on blood pressure, heart rate, heart rate variability, or blood pressure variability, regardless of the test condition. St John's wort had no effect on plasma concentrations of norepinephrine and its main metabolite, dihydroxyphenylglycol, whereas plasma dihydroxyphenylacetic acid (DOPAC; the main metabolite of dopamine) concentrations increased in every subject (1661 +/- 924 pg/mL versus 1110 +/- 322 pg/mL with placebo, P=.04). In contrast, imipramine increased resting blood pressure (124 +/- 10 mmHg/71 +/- 5 mmHg versus 110 +/- 8 mmHg/61 +/- 6 mmHg with placebo, P=.005 for systolic values and P=.003 for diastolic values) and heart rate (74 +/- 7 beats/min versus 62 +/- 6 beats/min with placebo, P=.005) and elicited a marked orthostatic tachycardia (increase in heart rate of 43 +/- 17 beats/min versus 26 +/- 8 beats/min with placebo, P=.006). CONCLUSIONS: Our findings challenge the concept that St John's wort elicits a major change in norepinephrine uptake or monoamine oxidase activity in vivo. The consistent increase in plasma DOPAC concentrations might suggest a novel mode of action or an inhibitory effect on dopamine beta-hydroxylase that should be followed up. We propose that a combination of physiologic and biochemical profiling may help better define the mode of action and potential side effects of herbal remedies.     

Angiotensin II augments sympathetically mediated arteriolar constriction in man.

1. In animal studies, angiotensin II facilitates adrenergic neurotransmission by both pre- and post-synaptic mechanisms. We have investigated whether this interaction occurs in forearm resistance vessels in man. 2. The effect of arterial infusion of angiotensin II (320 fmol/min) on sympathetic vasoconstriction produced by lower-body negative pressure (15 mmHg) was studied in six subjects, and that on the response to exogenous noradrenaline (37.5-150 pmol/min) was studied in a further eight subjects. Forearm blood flow was measured by strain-gauge plethysmography. 3. The dose of angiotensin II was chosen to produce no alteration in resting blood flow, and those of noradrenaline were selected to provide a reduction in blood flow equivalent to that produced by lower-body negative pressure. 4. Lower-body negative pressure produced no change in heart rate or diastolic blood pressure, but caused an initial 5 mmHg fall in systolic blood pressure (P less than 0.01). Blood flow was reduced by 21 +/- 6% in both forearms by lower-body negative pressure during saline infusion. During angiotensin II infusion, there was a marked difference in the response to lower-body negative pressure, with blood flow being reduced by 40 +/- 7% in the infused arm, but only by 21 +/- 4% in the control arm (P less than 0.05). Angiotensin II infusion had no effect on resting blood flow or the responses to noradrenaline. 5. We conclude that angiotensin II augments sympathetic vasoconstriction in forearm resistance vessels in man at a concentration that has no direct effect on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of adenosine on heart rate variability in humans.

By stimulating afferent nerve endings in skeletal muscle, heart, kidney and the carotid body, adenosine infusion evokes a receptor-specific sympatho-excitatory reflex in humans that overrides its direct negative chronotropic effect. We tested the hypothesis that adenosine increases heart rate by suppressing parasympathetic and augmenting sympathetic components of heart rate variability. High-frequency (PH; 0.15-0.50 Hz) and low-frequency (PL; 0.05-0.15 Hz) components of heart rate variability total power (PT) were determined by spectral analysis. The ratios PH/PT and PL/PH respectively were used to estimate parasympathetic and sympathetic input to the sino-atrial node. Heart rate was recorded before and during a 5 min intravenous infusion of adenosine (140 micrograms.min-1.kg-1) in seven healthy men. Adenosine did not affect blood pressure, but increased heart rate by 33+/-6 beats/min, and reduced PT, PH, PL and PH/PT. In contrast, there was an increase in PL/PH. In a second experiment in nine men, brachial artery infusion of adenosine (15 micrograms.min-1.100 ml-1 forearm tissue) increased heart rate by 3 beats/min, had no effect on PT, PH, PL or PH/PT, yet increased PL/PH. Intra-arterial adenosine exerts a modest effect on heart rate by modulating cardiac sympathetic indices, without affecting parasympathetic indices, of heart rate variability, whereas intravenous infusion of adenosine reduces heart rate variability and raises heart rate by decreasing parasympathetic and increasing cardiac sympathetic tone. These reflex effects may become clinically relevant during adenosine stress testing, or when endogenous adenosine is increased, such as during ischaemia, exercise or vasodepressor reactions, or in heart failure.     

Acute haemodynamic effects of lipolysis-induced increase of free fatty acids in healthy men

Circulating free fatty acids (FFA) are elevated in subjects with insulin resistance and Type II diabetes, and increase during myocardial ischaemia, but their haemodynamic effects are incompletely understood. During an investigation of the effects of FFA on endothelial function, we administered lipid emulsion (150 mg x min(-1) of soybean oil) with heparin (0.2 unit x kg(-1) x min(-1)) intravenously to eight healthy men for 2 h. This increased circulating FFA to 3.1+/-0.5 mmol/l. Forearm blood flow was measured by venous occlusion plethysmography during brachial artery infusions of saline, acetylcholine and nitroprusside before, and at 1 and 2 h. Lipid/heparin infusion had no significant effect on vasodilation to nitroprusside but progressively increased responses to acetylcholine (from 6.3+/-2.0 during 30 microg x min(-1) before-lipid infusion to 7.9+/-1.3 at 1 h and 12.2+/-1.1 ml x min(-1) x 100 ml(-1) at 2 h, P<0.001). Basal flow increased from 2.7+/-0.7 to 4.7+/-0.8 ml x min(-1) x 100 ml(-1) from 0 to 2 h. We performed a second study to clarify this effect on basal blood flow. Healthy men (n=8) received, on separate occasions, 4 h intravenous infusions of lipid emulsion with heparin and, as a control, saline with heparin. Lipid with heparin increased mean arterial blood pressure (maximum increment 8.2+/-2.7 mm Hg, P<0.01 compared with saline/heparin control) and forearm blood flow (from 1.7+/-0.2 to 2.9+/-0.3 ml x min(-1) x 100 ml(-1), P<0.01) without a significant effect on heart rate, and reduced calculated forearm vascular resistance (from 49.1+/-5.4 to 31.3+/-3.9 arbitrary units, P<0.01). In conclusion, acute elevation of FFA in healthy men increases arterial blood pressure and reduces vascular resistance. These haemodynamic changes could be clinically relevant.     

Endothelin plays an important role in the endothelium-dependent vasodilatation in the human forearm

Endothelium-dependent vasodilatation (EDV) in humans has been evaluated mainly by local infusion of a muscarinic-receptor agonists in the forearm. It has been postulated that the function of the vasodilator nitric oxide (NO) can be evaluated with this technique. However, the role of the vasoconstrictor endothelin in this model has not been investigated. METHODS: Ten male hypertensive and seven male normotensive subjects were subjected to measurements of forearm blood flow (FBF) by venous occlusion plethysmography during local intra-arterial infusion of metacholine (4 microg/min) or nitroprusside (10 microg/min). In parallel, forearm venous plasma endothelin (ir-ET) was determined. RESULTS: Metacholine and nitroprusside increased FBF 2.3 and 2.2 times the baseline level (6.6+/-2.8 SD ml/min/100 ml tissue) in hypertensive subjects and 5.1 times the baseline level (2.7+/-3.0 ml/min/100 ml tissue) for both drugs in the normotensive subjects. None of the drugs induced any significant changes in ir-ET levels in any of the groups (baseline 1.5+/-0.4 pmol/l in hypertensive and 1.1+/-1.2 pmol/l in normotensive subjects). However, in the hypertensive subjects, the individual change in venous ir-ET levels during infusion with metacholine, but not with nitroprusside, was inversely related to the degree of vasodilatation induced by this agent (r = -0.71, p < 0.02). A similar correlation coefficient (r=-0.69) was found in healthy subjects. CONCLUSION: Muscarinic-receptor-agonist-stimulated vasodilatation in the human forearm, thought mainly to reflect NO synthesis, was inversely related to the change in endothelin levels, suggesting an important role for this endothelium-derived vasoconstrictor in this model of EDV.     

Disparities in circulatory adjustment to standing between young and elderly subjects explained by pulse contour analysis.

1. The circulatory adjustment to standing was investigated in two age groups. Young subjects consisted of 20 healthy 10-14-year-old girls and boys. Elderly subjects consisted of 40 70-86-year-old healthy and active females and males. Continuous responses of blood pressure and heart rate were recorded by Finapres. A pulse contour algorithm applied to the finger arterial pressure waveform was used to assess stroke volume responses. 2. During the first 30s (initial phase), an almost identical drop in mean blood pressure was found in both age groups (young, 16 +/- 10 mmHg; old, 17 +/- 10 mmHg), but the initial heart rate increase was attenuated in the elderly subjects (young, 29 +/- 7 beats/min; old, 17 +/- 7 beats/min). 3. During the period from 30 s to 10 min of standing, mean blood pressure increased from 96 +/- 12 to 106 +/- 12 mmHg in the elderly subjects compared with almost no change in the young subjects (from 82 +/- 8 to 84 +/- 7 mmHg). In the elderly subjects a progressive increase in total peripheral resistance (from 114 +/- 14% to 146 +/- 29%) was found, compared with an initial rapid increase in total peripheral resistance (126 +/- 18% after 30 s) with no further change during prolonged standing (124 +/- 17% after 10 min) in the young subjects. In this age group the decrease in stroke volume and the increase in heart rate after 10 min of standing were large (young, -37 +/- 11% and 27 +/- 11 beats/min; old, -31 +/- 9% and 7 +/- 6 beats/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a specific antidiuretic agonist on cardiac output and its distribution in intact and anephric dogs

1. The specific antidiuretic agonist [4-valine, 8-D-arginine]vasopressin (VDAVP) was administered intravenously to seven conscious dogs at a rate of 10 ng min-1 kg-1. Cardiac output (aortic electromagnetic flowmeter), mean arterial pressure and regional blood flows (radioactive microspheres) were measured before and after 30 min of infusion. 2. Mean arterial pressure fell from 89.9 +/- 4.5 (mean +/- SEM) to 82.3 +/- 5.9 mmHg and cardiac output increased from 115.4 +/- 8.7 to 163.0 +/- 14.4 ml min-1 kg-1. Total peripheral resistance decreased from 41.6 +/- 3.7 to 27.8 +/- 3.6 units and heart rate increased from 79.2 +/- 5.9 to 123.2 +/- 5.9 beats/min. Blood flow increased significantly in the myocardium, fat and skeletal muscle vascular bed. 3. In another group of six dogs subjected to a similar protocol 24 h after bilateral nephrectomy, mean arterial pressure fell from 102.2 +/- 5.3 to 82.7 +/- 3.4 mmHg and cardiac output increased from 125.6 +/- 3.0 to 171.2 +/- 4.0 ml min-1 kg-1. Total peripheral resistance decreased from 39.3 +/- 3.4 to 23.4 +/- 1.3 units and heart rate increased from 84 +/- 4.9 to 113.3 +/- 4.3 beats/min. The increase in cardiac output and the fall in total peripheral resistance did not differ significantly between intact and anephric dogs. Regional blood flow responses differed in some respects in the two groups studied, but there was no evidence that the vasodilatory action of VDAVP depended on the presence of the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancing liver blood flow after cardiopulmonary bypass: the effects of dopamine and dopexamine

Liver blood flow is reduced after cardiopulmonary bypass (CPB) and both dopamine and dopexamine are used to overcome this. This study compares the effects of these agents on liver blood flow. Thirty patients undergoing elective coronary artery bypass graft surgery were randomized into three groups (n = 10 per group). Six hours after surgery baseline liver blood flow was determined by the percentage disappearance rate of indocyanine green measured by dichromatic auricular densitometery. Patients then received infusions of either: (1) placebo (dextrose 5%); (2) dopamine (4 micrograms/kg/min); (3) dopexamine (1 microgram/kg/min increasing to 2 micrograms/kg/min). One hour after infusion, liver blood flow measurements were repeated. In the dopexamine group the infusion was increased and the measurements repeated another hour later. We found that patient-specific variables and operative details were similar for all groups. Postoperative cardiac index and heart rate were increased significantly by dopamine (cardiac index 2.82 +/- 0.46 l/m/m2 vs 3.28 +/- 0.67 l/m/m2: p < 0.001 and heart rate 87.5 +/- 13.2 vs 96 +/- 16: p < 0.05) and dopexamine at 2 micrograms/kg/min (cardiac index 2.71 +/- 0.53 l/m/m2 vs 3.45 +/- 0.67 l/m/m2: p < 0.05 and heart rate 89.0 +/- 18.9 vs 107.4 +/- 13.6: p < 0.001) compared to placebo (cardiac index 2.97 +/- 0.8 l/m/m2 vs 3.18 +/- 0.9 l/m/m2: p > 0.05 and heart rate 77.2 +/- 7.4 vs 77.3 +/- 8: p > 0.05) despite similar atrial and systemic arterial pressures. The disappearance rate of indocyanine green was not altered during infusion of placebo group (9.0 +/- 3.2%/min vs 7.9 +/- 3.0%/min: p > 0.05) or dopexamine at 1 microgram/kg/min (9.7 +/- 3.1%/min vs 11.2 +/- 4.1%/min: p > 0.05). The disappearance rate was increased with dopamine (6.7 +/- 3.7%/min vs 11.8 +/- 3.0%/min: p < 0.05) and dopexamine 2 micrograms/kg/min (9.7 +/- 3.1%/min vs 13.5 +/- 3.2%/min: p < 0.05). This indicates a 76% increase in liver blood flow with dopamine and a 38% increase with dopexamine. We conclude that dopamine 4 micrograms/kg/min and dopexamine 2 micrograms/kg/min increase liver blood flow, although this may, in part, be related to an increase in cardiac output. Dopexamine shows no advantage over dopamine in enhancing liver blood flow after CPB.     

Cardiovascular effects of two xanthines and the relation to adenosine antagonism

We hypothesize that the hemodynamic effects of xanthine derivatives depend on their ability to antagonize the vasodilating effects of endogenous adenosine. In a randomized, double-blind, and placebo-controlled study of 10 normotensive volunteers caffeine, a xanthine with in vitro adenosine antagonistic properties, increased mean arterial pressure by 5.6 +/- 0.9 mm Hg and lowered heart rate by 5.3 +/- 1.1 beats/min. After administration of enprofylline, a xanthine without adenosine antagonism, forearm vascular resistance decreased by 5.6 +/- 3.4 IU, heart rate increased by 10.6 +/- 2.6 beats/min, and plasma adrenaline, plasma noradrenaline, and renin activity increased by 178 +/- 86%, 14 +/- 8%, and 36 +/- 13%, respectively. Adenosine infusion alone induced a dose-related increase in pulse pressure and heart rate, and it increased plasma adrenaline and noradrenaline by 186 +/- 77% and 132 +/- 55%, respectively. This response to adenosine was reduced by pretreatment with caffeine but not enprofyline. Thus opposite circulatory responses to caffeine and enprofylline occurred, with signs of vasoconstriction and vasodilation, respectively. In addition, caffeine, but not enprofylline, reduced the cardiovascular response to exogenous adenosine.     

Altered renal response to enhanced endogenous 5-hydroxytryptamine after tryptophan administration in essential hypertension.

1. To examine the pathophysiological significance of 5-hydroxytryptamine (serotonin) in essential hypertension, we compared the renal response to intrarenally formed 5-hydroxytryptamine by oral dosing with its precursor, L-tryptophan (2 g), in nine patients with essential hypertension and in six subjects with normotension. 2. Before tryptophan administration, urinary excretion of 5-hydroxytryptamine was significantly higher in the hypertensive group than in the normotensive group (66 +/- 8 versus 36 +/- 6 ng/min, P less than 0.05), whereas renal plasma flow and glomerular filtration rate did not differ between the two groups. After dosing with tryptophan, urinary excretion of 5-hydroxytryptamine significantly increased to the same plateau level in both groups (366 +/- 55 ng/min in the hypertensive group and 365 +/- 64 ng/min in the normotensive group). Significant and equivalent decreases in renal plasma flow were observed in the early phase after tryptophan administration in both groups (-8.5 +/- 3.4% in the hypertensive group and -8.2 +/- 1.7% in the normotensive group). Thereafter, renal plasma flow increased to above the baseline value in normotensive subjects, whereas this late vasodilatation was absent in the hypertensive group. Glomerular filtration rate significantly decreased at the time of the fall in renal plasma flow in the normotensive group (106.8 +/- 7.8 to 92.7 +/- 8.5 ml min-1 1.73 m-2, P less than 0.05), whereas it remained unchanged in the hypertensive group (108.2 +/- 6.2 to 110.4 +/- 6.3 ml min-1 1.73 m-2, not significant).(ABSTRACT TRUNCATED AT 250 WORDS)