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Biomedical subjects

G A Rongen

Publications and source records attributed to G A Rongen.

At least 19 recordsLinked to original sources
PubMed2005

Methotrexate modulates the kinetics of adenosine in humans in vivo.

BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05). CONCLUSIONS: MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.

Adenosine↗
PubMed2004

Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans.

An increase in capillary blood flow and pressure in response to diabetes mellitus may lead to microangiopathy. We hypothesize that these haemodynamic changes are caused by a decreased activity of the sympathetic nervous system due to episodes of sustained hyperglycaemia. Twelve healthy volunteers consecutively underwent a hyperglycaemic experiment (HYPER), with the plasma glucose level maintained at 20 mmol.l(-1) for 6 h by combined infusion of somatostatin, insulin and glucose; and a normoglycaemic experiment (NORMO), with similar infusions but with the plasma glucose maintained at fasting level. During both experiments, sympathetic nervous system (SNS) activity was measured by assessing the plasma catecholamine levels, microneurography, power spectral analysis and forearm blood flow (FBF). In an age- and weight matched group, fasting and 6-h sympathetic activity was measured without infusion of somatostatin and insulin (CONTROL). During HYPER, forearm blood flow increased from 2.45 (0.21) to 3.10 (0.48) ml.dl(-1).min(-1) ( P <0.05), but did not change in NORMO or CONTROL. The HYPER conditions did not change the plasma noradrenaline levels or the muscle sympathetic nerve activity [42 (4), 50 (10) and 45 (5) bursts/100 beats, HYPER, NORMO and CONTROL respectively]. Also, the power spectral analysis was similar under all experimental conditions. All results are expressed as the mean (SEM). In conclusion, sustained hyperglycaemia in normal subjects induces moderate vasodilation in skeletal muscle, but this increased blood flow can not be attributed to a decreased sympathetic tone.

Adult↗
PubMed2004

ATP-induced vasodilation in human skeletal muscle.

1. The purine nucleotide adenosine-5'-triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2. Adenosine 5'-triphosphate (0.2, 0.6, 6 and 20 nmol dl(-1) forearm volume min(-1)) evoked a dose-dependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 microg dl(-1) min(-1), n=10), the blocker of Na(+)/K(+)-ATPase ouabain (0.2 microg dl(-1) min(-1), n=8), the blocker of K(Ca) channels tetraethylammonium chloride (TEA, 0.1 microg dl(-1) min(-1), n=10), nor by the K(ATP)-channel blocker glibenclamide (2 microg dl(-1) min(-1), n=10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and l-NMMA (n=6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 48+/-5, 67+/-3, 88+/-2, and 92+/-2% in the absence and 23+/-7, 62+/-4, 89+/-2, and 93+/-1% in the presence of the combination of TEA, indomethacin and l-NMMA (P<0.05, repeated-measures ANOVA, n=6). A similar inhibition was obtained for sodium nitroprusside (SNP, P<0.05 repeated-measures ANOVA, n=6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3. ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and l-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.

Adenosine Triphosphate↗
PubMed2004

Ischaemic preconditioning: from molecular characterisation to clinical application--part I.

Ischaemic preconditioning is defined as an increased tolerance to ischaemia and reperfusion induced by a previous sublethal period of ischaemia. Since this is the most powerful mechanism for limiting infarct size, other than timely reperfusion, an overwhelming number of studies have addressed the way in which this form of protection occurs. During the short preconditioning period of ischaemia, several trigger substances are released (adenosine, bradykinin, norepinephrine, opioids). By activation of membrane-bound receptors, these substances activate a complex intracellular signalling cascade, which converges on mitochondrial end-effectors, including the ATP-sensitive potassium channel and the mitochondrial permeability transition pore. Activation of this pathway protects cardiomyocytes against both necrosis and apoptosis during a subsequent more prolonged ischaemic episode. The protection afforded by preconditioning lasts only two to three hours, but reappears 24 hours after the preconditioning stimulus. This 'delayed preconditioning' requires synthesis of new proteins, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and heat shock proteins. Additionally, preconditioning is not confined to one organ, but can also limit infarct size in remote, non-preconditioned organs ('remote preconditioning'). Knowledge of these mechanisms mediating ischaemic preconditioning is essential to understand which drugs are able to mimic preconditioning or interfere with pre-conditioning in patients at risk for myocardial ischaemia. This review aims to summarise current knowledge regarding the different forms and mechanisms of ischaemic preconditioning.

Adenosine↗
PubMed2004

Ischaemic preconditioning: from molecular characterisation to clinical application--part II.

Ischaemic preconditioning was originally described in animal hearts as histological infarct-size limitation by a previous brief episode of ischaemia. In humans, ischaemic preconditioning has been demonstrated in several in vitro and in vivo models, including coronary artery bypass grafting and percutaneous transluminal coronary angiograplasty, using surrogate markers of ischaemia and reperfusion injury. Increasing knowledge of the molecular signalling pathways mediating protection by ischaemic preconditioning has provided rational targets for pharmacological intervention. Several widely used drugs are able to mimic ischaemic preconditioning (e.g. adenosine, adenosine-uptake inhibitors, ACE inhibitors, angiotensin II antagonists, statins, opioids, volatile anaesthetics and ethanol), whereas others inhibit ischaemic preconditioning-induced protection (e.g. sulphonylureas and adenosine antagonists). The present review focuses on these different classes of drugs. Prudent use or avoidance of these drugs in patients who are at risk for myocardial infarction could theoretically limit ischaemia and reperfusion injury.

Animals↗
PubMed2002

Repeated ischaemic isometric exercise increases muscle fibre conduction velocity in humans: involvement of Na(+)-K(+)-ATPase.

This study was performed to test two hypotheses: (1) ischaemic preconditioning (development of tolerance to ischaemia) influences muscle fibre conduction velocity (MFCV) during repeated ischaemic isometric exercise and (2) the increase in MFCV to supranormal levels during recovery from ischaemic exercise is caused by activation of Na(+)-K(+)-ATPase. For this purpose, MFCV was measured with surface electromyography (sEMG) during repeated ischaemic isometric exercise of the brachioradial muscle (2 min at 30 % of maximal voluntary contraction). The involvement of ischaemic preconditioning was tested by changing the duration of ischaemia and by intra-arterial infusion of adenosine (brachial artery, 50 microg min(-1) dl(-1)). The role of Na(+)-K(+)-ATPase was explored using ouabain (0.2 microg min(-1) dl(-1)). During the exercise, MFCV decreased from 4.4 +/- 0.2 m s(-1) to 3.7 +/- 0.2 m s(-1) (P < 0.01, n = 13). Similar reductions in MFCV were observed during repeated exercise, irrespective of the reperfusion time (10 min vs. 18 min) or duration of the ischaemia (2 vs. 10 min). However, initial MFCV gradually increased for each subsequent contraction when contractions were repeated at 10 min intervals (4.4 +/- 0.2 m s(-1) vs. 4.9 +/- 0.2 m s(-1) for the first and fourth contraction respectively; P < 0.01; n = 13). This increase was not observed when contractions were performed at 18 min intervals, nor when additional ischaemia was applied. Intra-arterial adenosine did not affect MFCV. Intra-arterial ouabain did not affect the reduction in MFCV during exercise but completely prevented the increase in MFCV during recovery: from 4.7 +/- 0.2 m s(-1) to 5.2 +/- 0.2 m s(-1) vs. 4.5 +/- 0.1 m s(-1) to 4.5 +/- 0.1 m s(-1) in the absence and presence of ouabain respectively (P < 0.05 for ouabain effect; n = 6). In conclusion, ischaemic preconditioning is not involved in changes in MFCV during repeated ischaemic isometric exercise. The increase in MFCV during recovery from repeated ischaemic isometric exercise is caused by rapid activation of Na(+)-K(+)-ATPase.

Adult↗
PubMed2001

Effect of adenosine receptor blockade with caffeine on sympathetic response to handgrip exercise in heart failure.

Adenosine (Ado) increases muscle sympathetic nerve activity (MSNA) reflexively. Plasma Ado and MSNA are elevated in heart failure (HF). We tested the hypothesis that Ado receptor blockade by caffeine would attenuate reflex MSNA responses to handgrip (HG) and posthandgrip ischemia (PHGI) and that this action would be more prominent in HF subjects than in normal subjects. We studied 12 HF subjects and 10 age-matched normal subjects after either saline or caffeine (4 mg/kg) infusion during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50%) HG exercise, followed by 2 min of PHGI. In normal subjects, caffeine did not block increases in MSNA during PHGI after 50% HG. In HF subjects, caffeine abolished MSNA responses to PHGI after both isometric and 50% isotonic exercise (P < 0.05) but MSNA responses during HG were unaffected. These findings are consistent with muscle metaboreflex stimulation by endogenous Ado during ischemic or intense nonischemic HG in HF and suggest an important sympathoexcitatory role for endogenous Ado during exercise in this condition.

Adenosine↗
PubMed2000

Comparison of two indices for forearm noradrenaline release in humans.

Although there is as yet no method which measures directly the neuronal release of noradrenaline in humans in vivo, the isotope dilution technique with [(3)H]noradrenaline has been applied to estimate forearm neuronal noradrenaline release into plasma. Two different equations have been developed for this purpose: one to estimate the spillover of noradrenaline into the venous effluent, and a modified formula (often referred to as the appearance rate) which may reflect more closely changes in the neuronal release of noradrenaline into the synaptic cleft, particularly during interventions that alter forearm blood flow. The present study was performed to compare the effects of two interventions known to exert contrasting actions on neuronal forearm noradrenaline release and forearm blood flow. Intra-arterial infusion of sodium nitroprusside at doses without systemic effect increases forearm blood flow, but not neuronal noradrenaline release. In contrast, lower-body negative pressure at -25 mm Hg causes forearm vasoconstriction by stimulating neuronal noradrenaline release. During sodium nitroprusside infusion, forearm noradrenaline spillover increased from 1.1+/-0.3 to 2.2+/-1.0 pmol x min(-1) x 100 ml(-1) (P<0.05), whereas the forearm noradrenaline appearance rate was unchanged. Lower-body negative pressure did not affect the forearm noradrenaline spillover rate, but increased the forearm noradrenaline appearance rate from 3.4+/-0.4 pmol x min(-1) x 100 ml(-1) at baseline to 5.0+/-0.9 pmol x min(-1) x 100 ml(-1) (P<0.05). These results indicate that the noradrenaline appearance rate provides the better approximation of changes in forearm neuronal noradrenaline release in response to stimuli which alter local blood flow.

Adult↗
PubMed1999

Effect of atrial natriuretic peptide on muscle sympathetic activity and its reflex control in human heart failure.

BACKGROUND: The purpose of this study was to determine if atrial natriuretic peptide (ANP) exerts a relative inhibitory effect on muscle sympathetic nerve activity (MSNA) at rest and during nonhypotensive lower body negative pressure (LBNP) in heart failure, as in healthy subjects. METHODS AND RESULTS: Fifteen men (age 39+/-2 years [mean+/-SE]) with dilated cardiomyopathy (ejection fraction 18+/-3%) received intravenous ANP (50 microgram bolus, then 50 ng. kg-1. min-1) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. During each infusion MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) were recorded before and during LBNP at -6 and -12 mm Hg. NTG and ANP caused similar and significant reductions in CVP and diastolic BP, but resting MSNA did not increase with either infusion. LBNP at -6 mm Hg lowered CVP (P<0.05), whereas LBNP at -12 mm Hg caused significant reductions in CVP, systolic BP, and diastolic BP. These effects of nonhypotensive and hypotensive LBNP on CVP and BP were similar during ANP and NTG infusions, yet MSNA was lower both before and with LBNP during ANP (P<0.02). Nonhypotensive LBNP increased MSNA during NTG (+133+/-68 Units; P<0.001) but not during ANP infusion (+24+/-23 Units; P=NS). CONCLUSIONS: These observations are consistent with the concept that ANP exerts a sympathoinhibitory action in heart failure. This is most evident in response to reductions in atrial pressures that do not affect systemic BP.

Adult↗
PubMed1999

Flow ratios to express results obtained with the human in vivo 'perfused forearm technique'.

AIMS: To determine the accuracy of forearm blood flow (FBF) ratio (flow in infused arm/flow in control arm) to detect unilateral increases in forearm blood flow. METHODS: In nine healthy male volunteers, we measured the effect of infusion of saline into the brachial artery at a rate of 2 ml/100 ml forearm min-1 on FBF ratio during control, mental arithmetic (MAR) and lower body negative pressure (LBNP) at -40 mmHg. RESULTS: Saline infusion increased FBF ratio from baseline by 115.9+/-17.4, 82.0+/-19.0 and 159.6+/-53.3% for control, MAR and LBNP, respectively (P<0.05 for MAR vs control). CONCLUSIONS: FBF ratio may underestimate unilateral increases in forearm blood flow during simultaneous mental arousal.

Adult↗
PubMed1999

Resting muscle sympathetic nerve activity and peak oxygen uptake in heart failure and normal subjects.

AIMS: Exercise intolerance and increased efferent vasoconstrictor traffic to muscle are two characteristics of heart failure that have not been explicitly linked. We tested the hypothesis that peak oxygen consumption is inversely related to resting muscle sympathetic nerve activity in heart failure. METHODS AND RESULTS: We recorded peroneal muscle sympathetic nerve activity in 17 treated heart failure patients (16 men,1 woman; mean ejection fraction of 26. 0+/-3.2% (SE)) and 17 age-matched healthy subjects (16 men, 1 woman). Oxygen consumption was measured during cycle ergometry to maximal effort. In heart failure and normal subjects, mean peak oxygen consumption was 20.6+/-1.7 vs 32.2+/-2.6 ml x kg-1 x min-1(P<0.0001) and mean muscle sympathetic activity was 49.3+/-2.8 vs 33.0+/-3.3 bursts x min-1(P<.0007) respectively. When age was accounted for by multiple regression analysis, there was a significant relationship between peak oxygen consumption and burst frequency in heart failure (P<0.02) but not in healthy subjects. The percent of predicted peak oxygen consumption achieved (based on age, sex and body size) was inversely related to muscle sympathetic nerve burst frequency in heart failure (r=-0.71, P<0.0014) but not in normal subjects (r=-0. 44, P<0.08;P<0.0001 for this comparison). CONCLUSION: Reduced exercise capacity in heart failure is related to increased efferent sympathetic traffic to calf muscle. These observations are consistent with the concept of a peripheral neurogenic limit to exercise in heart failure.

Adult↗
PubMed1999

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.

Adenosine↗
PubMed1998

Caffeine abstinence augments the systolic blood pressure response to adenosine in humans.

Blood pressure and heart rate responses to adenosine infusion (35, 70, and 140 microg/kg/min, intravenously) were studied in 7 healthy men after 6, 30, 78, 150, and 318 hours of abstinence from regular caffeine use. The finding that caffeine abstinence augmented the systolic pressor response (from -1 +/- 2 mm Hg at 6 hours to +9 +/- 2 mm Hg at 318 hours; p = 0.01) but not the tachycardic response to adenosine has implications for current clinical and research applications of this purine.

Adenosine↗
PubMed1998

Angiotensin AT1 receptor blockade abolishes the reflex sympatho-excitatory response to adenosine.

We tested the hypothesis that endogenous angiotensin II participates in the direct and reflex effects of adenosine on the sympathetic nervous system. Nine healthy men were studied after 1 wk of the angiotensin II type I receptor antagonist losartan (100 mg daily) or placebo, according to a double-blind randomized crossover design. Bilateral forearm blood flows, NE appearance rates, and total body NE spillover were determined before and during graded brachial arterial infusion of adenosine (0.5, 1.5, 5, and 15 microg/100 ml forearm tissue) and nitroprusside. Adenosine increased total body NE spillover (P < 0.05) whereas nitroprusside did not. Losartan lowered BP (P < 0.05), had no effect on total body NE spillover at rest, or forearm vasodilation during either infusion, but reduced the systemic noradrenergic response to adenosine from 1.0+/-0.4 nmol/min on the placebo day to 0.2+/-0.3 nmol/min (P < 0.01), and forearm NE appearance rate in response to adenosine was lower in the infused, as compared with the contralateral arm (P = 0.04). The sympatho-excitatory reflex elicited by adenosine is mediated through pathways involving the angiotensin II type I receptor. Interactions between adenosine and angiotensin II may assume importance during ischemia or congestive heart failure and could contribute to the benefit of converting enzyme inhibition in these conditions.

Adenosine↗
PubMed1998

Neural and hypotensive effects of angiotensin II receptor blockade.

Angiotensin II participates in the neural regulation of the heart and circulation at both central and peripheral sites. To explore the role of endogenous angiotensin II in blood pressure regulation, we conducted a randomized double-blind crossover trial in nine young healthy men (aged 33+/-3 [mean+/-SE] years) studied in the absence of salt restriction, comparing the effect of 1 week treatment with the angiotensin II receptor antagonist losartan (100 mg daily) against placebo with respect to the following variables, recorded during supine rest: intra-arterial blood pressure (BP), heart rate (HR), forearm vascular resistance and norepinephrine appearance rate, total body norepinephrine spillover, variability of BP and HR (spectral analysis), and baroreflex sensitivity for HR (gain of the transfer function from systolic BP to HR). Blood pressure was 119+/-7/66+/-4 mm Hg (systolic BP/diastolic BP) after 1 week of placebo and 112+/-6/61+/-3 mm Hg after 1 week of losartan (P<.05). Forearm vascular resistance tended to fall, from 42.3+/-6.9 U on placebo to 32.8+/-5.0 U with losartan treatment (P=.07). Losartan had no effect on HR (60+/-3 on placebo versus 59+/-2 beats per minute with losartan), total body norepinephrine spillover (3.0+/-0.8 versus 3.3+/-1.2 nmol/min), forearm norepinephrine appearance rate (3.8+/-1.1 versus 5.3+/-1.1 pmol/100 mL forearm tissue per minute), power in the high- or low-frequency components of the HR variability and BP variability spectra or on baroreflex sensitivity for HR. Endogenous angiotensin II contributes to the maintenance of supine BP in normal subjects, studied in the absence of sodium restriction. The fall in BP caused by losartan is accompanied by a resetting of the baroreflex regulation of HR and sympathetic outflow, but baroreflex sensitivity for heart rate is not altered. Therefore, the reduction in BP observed after short-term angiotensin type 1 receptor antagonism may be achieved through a direct effect on vascular tone rather than through a primary reduction in sympathetic outflow.

Adult↗
PubMed1997

Cardiovascular pharmacology of purines.

1. This review focuses on the extracellular actions of ATP and adenosine, and in particular their role in cardiovascular regulation. 2. ATP serves as a co-transmitter within the sympathetic nervous system, and is also released from endothelium and aggregating thrombocytes. ATP acts on P2x purinoceptors on vascular smooth muscle cells to induce vasoconstriction. Stimulation of P2y purinoceptors on endothelial cells releases endothelium-derived relaxing factors and causes vasodilatation. This dual action of ATP may have pathophysiological importance by inducing vasospasm at sites of impaired endothelial function and thrombus formation. 3. Adenosine is generated by enzymic degradation of ATP. Its formation is enhanced during ischaemia. Adenosine inhibits noradrenaline release from sympathetic nerve endings, causes vasodilatation via endothelium-dependent and endothelium-independent actions, has important anti-arrhythmic properties and prevents deleterious sequelae of ischaemia. In humans, adenosine evokes a sympatho-excitatory reflex mediated by chemically sensitive receptors and afferent nerves in the kidney, heart and forearm. This reflex may be active during exercise and ischaemia and, because of its potential adverse consequences, it should be considered when developing new therapies to potentiate the anti-ischaemic actions of endogenous adenosine in humans. Adenosine appears to mediate ischaemia-induced pain; a reduced sensitivity to adenosine may underlie silent ischaemia. 4. New drugs that interact with adenosine formation or degradation or with adenosine receptors are under development. These have potential therapeutic application in the treatment of ischaemia and other circulatory disorders.

Adenosine↗