P. Smits

Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans

SummaryCardiovascular adenosine-5′-triphosphate-sensitive potassium (KATP) channels have been reported to play an important role in endogenous cardioprotective mechanisms. Sulphonylurea derivatives can inhibit these cardioprotective mechanisms in animal models. We investigated whether therapeutic concentrations of sulphonylurea derivatives can block vascular KATP channels in humans. The forearm vasodilator responses to administration of the specific KATP channel opener diazoxide into the brachial artery of healthy male volunteers were recorded by venous occlusion plethysmography. This procedure was repeated with concomitant intraarterial infusion of: 1) the sulphonylurea derivative glibenclamide (0.33 or 3.3 Μg · min−1 · dl−1, both n=12), 2) the new sulphonylurea derivative glimepiride (2.5 Μg · min−1 · dl−1, n=12) or 3) placebo (n=12). The effects of glibenclamide on the vasodilator responses to sodium nitroprusside were also studied (n=12). Glibenclamide significantly inhibited the diazoxide-induced increase in forearm blood flow ratio (ANOVA with repeated measures: p<0.01). During the highest diazoxide dose this ratio (mean ± SEM) was lowered from 892±165 to 449±105%, and from 1044±248 to 663±114% by low- and high-dose glibenclamide, respectively. In contrast, neither glimepiride nor placebo attenuate diazoxide-induced vasodilation. Furthermore, glibenclamide did not affect nitroprusside-induced vasodilation. We conclude that therapeutic concentrations of the classical sulphonylurea derivative glibenclamide result in significant blockade of vascular KATP channels in humans. The newly developed glimepiride seems to be devoid of these properties.

Both body and arm position significantly influence blood pressure measurement

The position of both the body and the arm during indirect blood pressure (BP) measurement is often neglected. The aim of the present study was to test the influence of the position of the patient on BP readings: (1) sitting with the arms supported precisely at the right atrium level and (2) supine: (a) with the arms precisely at the right atrium level and (b) with the arms on the examination bed. In a first group of 57 hypertensive patients, two sessions of BP and heart rate (HR) measurements were performed in two positions: sitting and supine with the arms supported precisely at right atrium level in both positions. BP was measured simultaneously at both arms, with a Hawksley Random Zero sphygmomanometer at the right arm, and with an automated oscillometric device (Bosomat) at the left arm. BP and HR readings obtained in the two positions were then compared. In a second group of 25 normo- and hypertensive persons, two sessions of BP and HR readings were performed in supine with the arms in two different arm positions: (a) the arm placed precisely at right atrium level and (b) the other arm on the examination bed. The measurements were performed at both arms with two automated devices (Bosomat). The readings taken in the two positions were compared. Both systolic BP (SBP; by 9.5±9.0 (standard deviation, s.d.); right arm) and diastolic BP (DBP; by 4.8±6.0 mmHg; right arm) were significantly higher in the supine than in the sitting position. When the two different arm positions (body continously supine) were compared in the second part of the study, significantly higher SBP (by 4.6±6.1 mmHg) and DBP (by 3.9±2.8 mmHg) were obtained when the arm of the patient was placed on the bed (below the right atrium level), than when the arm was placed at the level of the right atrium. BP readings in sitting and supine positions are not the same. When according to guidelines the arm of the patient is meticulously placed at the right atrium level in both positions, the difference is even greater than when the arm rests on the desk or on the arm support of the chair. Moreover, in the supine position small but significant differences in BP are measured between arm on a 5 cm-high pillow and arm on the bed. In every study reporting BP values, the position of both the body and especially the arm should be precisely mentioned.

Cardiovascular effects of sulphonylurea derivatives : implications for the treatment of NIDDM?

SummarySulphonylurea derivatives are widely used in the treatment of non-insulin-dependent diabetes mellitus. The mechanism of action of the insulinotropic effect of these agents is based on the closure of adenosine-5′-triphosphate (ATP)-sensitive potassium channels (KATP-channels) in the beta cells of the pancreas. In the last decade, these KATP-channels have been demonstrated in myocardial cells as well as in vascular smooth muscle cells. During myocardial ischaemia, the KATP-channels are thought to open by a fall in the cytosolic ATP concentration. The increase in the extracellular adenosine concentration, and the release of endothelium-derived hyperpolarizing factor (EDHF) during ischaemia may further contribute to the opening of cardiovascular KATP-channels. Independently from the mechanism of opening, sulphonylurea derivatives have been reported to block the opening of cardiovascular KATP-channels. Related to the role of KATP-channel-opening in the (patho)physiology of ischaemia, the use of sulphonylurea derivatives significantly modifies the outcome of experimental myocardial infarction. Sulphonylurea derivatives impair the recovery of the contractile function and increase the ultimate infarct size in animal models. In contrast, sulphonylurea derivatives have a beneficial effect on the incidence of ventricular fibrillation as occurs after ischaemic incidents of the myocardium. Based on these experimental observations, human studies are indicated to investigate whether the use of these drugs modifies the clinical outcome of cardiovascular events in patients with non-insulin dependent diabetes mellitus. [Diabetologia (1995) 38: 116–121]

Arm position is important for blood pressure measurement

Aim: To test the effect of positioning the arm on the arm-rest of a common chair, below the officially recommended right atrial level, on the blood pressure (BP) readings in a group of out-patients.Patients and methods: A group of 69 patients (58 hypertensives; 39 males; mean ± s.d. age 54.1 ± 16.0 years) participated in the present study. BP and heart rate values obtained in each of the following two positions were compared: (1) sitting with the arms supported on the arm-rests of the chair and (2) sitting with the arms supported at the level of the mid-sternum (the approximation of the right atrial level). BP was measured simultaneously at both arms, with a mercury sphygmomanometer at the right arm and with an automatic oscillometric device at the left arm.Results: Both the systolic and diastolic BPs were significantly higher (P < 0.0001) when the arm was placed on the arm-rest of the chair than at the right atrial level. the same differences ± s.d. in bp between the two positions were obtained with both measurement techniques: 9.7 ± 9.4 mm hg (systolic) and 10.8 ± 5.8 mm hg (diastolic) with the mercury sphygmomanometer and respectively 7.3 ± 8.9 mm hg and 8.3 ± 6.0 mm hg with the oscillometric device. no difference in the heart rate was found between the two positions.Conclusions: Placing the patient’s arms on the arm-rest of the chair instead of at the reference right atrial level, BP measurement will result in spuriously elevated BP values. This may be of great importance for the diagnosis and the subsequent treatment decisions for patients with hypertension.

Direct vasodilator effects of physiological hyperinsulin-aemia in human skeletal muscle

Systemic hyperinsulinaemia induces vasodilatation in human skeletal muscle. This effect is gradual in onset, and at low insulin levels not maximal until at least 3 h. To investigate whether the vasodilator response to insulin results from a direct vascular effect, we infused insulin directly into the cannulated brachial artery (perfused forearm technique) in a total of 30 experiments in 20 healthy, lean, normotensive volunteers. Local, intra‐arterial, infusion of insulin (180 min, 0.3 mU dL−1 forearm volume min−1, n = 15, forearm venous insulin concentration approximately 540 pmol L−1) induced a gradual increase in forearm blood flow (FBF; venous occlusion plethysmography) from 1.86  ±  0.17 to 3.64  ±  0.64 mL dL−1 min−1 after 180 min (anovaP < 0.001). Percentage increases in FBF after 60, 120 and 180 min averaged 14.4  ±  5.9, 59.4  ±  25.5 and 124.6  ±  51.2% respectively. Forearm glucose uptake increased from 0.24  ±  0.05 to a maximum of 1.98  ±  0.28 μmol dL−1 min  (P < 0.001). Furthermore, insulin infusion increased forearm lactate release and potassium uptake. In 10 out of these 15 individuals, the forearm glucose uptake was further increased in a second, separate, repeat experiment with concomitant intra‐arterial infusion of glucose 5% (0.2 mL dL−1 min−1), resulting in forearm venous glucose concentrations of approximately 15 mmol L−1. This combined infusion achieved a similar vasodilator response to the infusion of insulin alone. The individual vascular responses of the two paired experiments showed a strong correlation (r = 0.87, P < 0.01). In five subjects time and vehicle control experiments were performed, showing no changes in FBF or metabolism during the 180 min. We conclude that the slow vasodilator response to insulin (as observed during systemic infusion) can, at least partly, be explained by a direct vascular effect of insulin. Insulin‐mediated skeletal muscle glucose uptake precedes this effect, but seems not to be an important determinant of the vasodilator response to insulin.

Effect of Long-term Angiotensin-converting Enzyme Inhibition on Endothelial Function in Patients with the Insulin-resistance Syndrome

Cardiovascular risk factors such as hypertension, diabetes, and dyslipemia are associated with an impaired endothelium-dependent vasodilation. In patients with type 2 diabetes mellitus, these risk factors are frequently clustered. We investigated whether long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril can improve endothelium-dependent vasodilation in this particular group of patients. We selected 10 patients with type 2 diabetes and hypertension (age 59.4 +/- 3.2 years, body mass-index 29.7 +/- 1.5 kg.m-2, blood pressure 169 +/- 6/92 +/- 1 mm Hg, total cholesterol 6.6 +/- 0.3 mM). Using venous occlusion plethysmography, we recorded the increases in forearm blood flow (FBF) in response to three vasodilator stimuli: (a) 5 min of forearm ischemia, (b) infusion of the endothelium-dependent vasodilator methacholine (Mch) into the brachial artery (0.03, 0.3, and 1.0 micrograms/min/100 ml), and (c) intraarterial infusion of the endothelium-independent vasodilator sodium nitroprusside (SNP 0.06, 0.2, 0.6 microgram/min/100 ml). This procedure was repeated after 6 months of treatment with perindopril 4-8 mg/day. Forearm vascular resistance (FVR) was calculated by the quotient of the mean arterial pressure (MAP) and the FBF. Perindopril reduced blood pressure (BP) by 19/10 mm Hg (p < 0.05) and increased baseline FVR, but improved neither the maximal percentage decrease in vascular resistance induced by Mch (from -80 +/- 2 to -82 +/- 2%) nor that induced by SNP (from -73 +/- 3 to -72 +/- 3%). Perindopril decreased the FVR reached after the ischemic stimulus from 6.5 +/- 1.2 to 4.8 +/- 0.6 U (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of innate immunity by adenosine receptor stimulation

In the past decades, increased concentrations of the signaling molecule adenosine have been shown to play an important role in the prevention of tissue damage evoked by several stressful circumstances. During systemic inflammation, the circulating adenosine concentration increases rapidly, even up to 10-fold in septic shock patients. By binding to specific adenosine receptor subtypes, designated A1, A2a, A2b, and A3, adenosine exerts a wide variety of immunomodulating and (cyto)protective effects. Only recently, several specific adenosine receptor agonists and other drugs that modulate adenosine metabolism have been developed for human use. Importantly, correct interpretation of the effects of adenosine is highly related to the model of inflammation used, e.g., administration of endotoxin or live bacteria. This review will discuss the potential role for adenosine as an immunomodulating and cytoprotective signaling molecule and will discuss its potential role in the treatment of the patient suffering from sepsis.ABBREVIATIONS-AMP-adenosine monophosphate; 5NT-5&vprime;-nucleotidase; ADA-adenosine deaminase; AK-adenosine kinase; ENT-equilibrative nucleoside transporter; cAMP-5&vprime; cyclic adenosine monophosphate; CLP-cecal ligation and puncture; NF-&kgr;B-nuclear factor &kgr;B

Influence of the arm position on intra- arterial blood pressure measurement

The reference level for the measurement of blood pressure (BP) is the level of the right atrium. In practice this is regularly disregarded, as the patient’s arm is usually placed lower than the right atrial level. The aim of the study was to determine the influence of first, different arm positions and second, different transducer positions on the intra-arterially (i.a.) recorded BP. In 16 healthy men (age 28.1 ± 8.0 (s.d.) years), i.a. BP was recorded at the left arm in supine position, using a 5–7 cm long cannula. The baseline position was with the tip of the cannula placed precisely at the level of the right atrium. Subsequently, the following changes were made: 5, 10, 15 and 20 cm above and 5, 10, 15, and 20 cm below the baseline position. A 2-min rest period was allowed in each position before the BP was measured. The whole procedure was done either with the transducer connected to the arm at the place of the cannula (n = 7), or with the transducer placed next to the subject and continuously kept at the right atrial level during the BP measurement (n = 9). Simultaneously, baseline BP was measured indirectly, with a standard mercury sphygmomanometer, in the opposite arm maintained with the cubital fossa at the right atrial level during the whole procedure. This resulted in the first group of seven volunteers for both the i.a. systolic (SBP) and diastolic BP (DBP) values to significantly decrease (P < 0.001) when the arm together with the transducer were elevated above the level of the right atrium, and returned to the initial value when the arm and the transducer were placed back at the right atrial level. intra-arterial sbp and dbp significantly (P < 0.001) increased as the arm, together with the transducer, were lowered below the right atrial level and returned to the initial value when the arm and the transducer were placed back at the right atrial level. in both directions, each 5 cm change in the arm level was accompanied by a 3–4 mm hg change in the i.a. bp value. the baseline bp, measured sphygmomanometrically at the contralateral arm, remained constant during the whole duration of the procedure. the changes in the i.a. bp were minimal in the second group of nine subjects in which only the arm but not the transducer was placed at different levels. we conclude that small deviations in arm position above or below the ‘gold standard’, ie, the fossa cubiti at the right atrial level, will result in largely erroneous bp values. the correct positioning of the arm during bp measurement is therefore mandatory for the diagnosis and follow-up of hypertensive subjects.

Neurohumoral antecedents of vasodepressor reactions

Abstract. Vasodepressor (vasovagal) syncope, the most common cause of acute loss of consciousness, can occur in otherwise vigorously healthy people during exposure to stimuli decreasing cardiac filling. Antecedent physiological or neuroendocrine conditions for this dramatic syndrome are poorly understood. This study compared neurocirculatory responses to non‐hypotensive lower body negative pressure (LBNP) in subjects who subsequently developed vasodepressor reactions during hypotensive LBNP with responses in subjects who did not. In 26 healthy subjects, LBNP at ‐15 and ‐40mmHg was applied to inhibit cardiopulmonary and arterial baroreceptors. All the subjects tolerated 30min of LBNP at ‐15 mmHg, but during subsequent LBNP at ‐40 mmHg 11 subjects had vasodepressor reactions, with sudden hypotension, nausea, and dizziness. In these subjects, arterial plasma adrenaline responses to LBNP both at ‐15 and at ‐40 mmHg exceeded those in subjects who did not experience these reactions. In 16 of the 26 subjects, forearm noradrenaline spillover was measured; in the eight subjects with a vasodepressor reaction, mean forearm noradrenaline spillover failed to increase during LBNP at ‐15mmHg (Δ= ‐0.06±(SEM) 0.04pmol min‐1 100mL‐1), whereas in the eight subjects without a vasodepressor reaction, mean forearm noradrenaline spillover increased significantly (Δ=0.31±0.13pmolmin‐1100mL‐1). Plasma levels of β‐endorphin during LBNP at ‐15 mmHg increased in some subjects who subsequently had a vasodepressor reaction during LBNP at ‐40 mmHg. The findings suggest that a neuroendocrine pattern including adre‐nomedullary stimulation, skeletal sympathoinhibition, and release of endogenous opioids can precede vasodepressor syncope.

Mechanisms of adenosine-induced renal vasodilatation in hypertensive patients.

Background Adenosine is an endogenous nucleoside with potent vasodilatory capacities, released under ischaemic conditions in particular. Its mechanisms of action, however, remain elusive. Objective To evaluate the role of adenosine, using a non-selective purinergic receptor antagonist, and the possible involvement of nitric oxide in this mechanism. In addition, the production of renin and catecholamines was studied during infusion of adenosine, caffeine, or both. Methods Thirty-three hypertensive patients who underwent diagnostic renal angiography received intrarenal infusions of adenosine either alone or in combination with caffeine or the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). The effects on renal blood flow (RBF) were assessed by the xenon-133 washout technique and both arterial and renal venous blood samples were taken for measurement of renin and catecholamine concentrations. Intra-arterial blood pressure and heart rate were monitored continuously. Results Adenosine induced a dose-dependent vasodilatation. Caffeine alone did not change RBF, but shifted the dose–response curve of adenosine to the right during concomitant infusion of caffeine. RBF during combined infusion of L-NMMA and adenosine was not different from that during adenosine alone, but the decrease in renal vascular resistance was less pronounced during this combination. Renin secretion did not change during the infusion of either adenosine alone or adenosine in combination with caffeine. Catecholamine concentrations also did not change during any of the experiments. Conclusions Adenosine induces vasodilatation in the human hypertensive kidney and this effect is mediated by the adenosine receptor. Nitric oxide plays, at most, a minor part in the adenosine-induced vasodilatation. Furthermore, renin secretion is not affected by adenosine and caffeine.