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Biomedical subjects

P Smits

Publications and source records attributed to P Smits.

At least 19 recordsLinked to original sources
PubMed2003

Hypoglycaemia downregulates endotoxin-induced production of tumour necrosis factor-alpha, but does not affect IL-1beta, IL-6, or IL-10.

The aim of the present study was to investigate the effect of hypoglycaemia on the production capacity of the proinflammatory cytokines tumour necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) in subjects with and without diabetes. Hyperinsulinaemic (360 pmolm(-2) x min(-1)) stepped hypoglycaemic (5.0-3.5-2.5 mmoll(-1)) glucose clamps were performed in eight diabetic patients and in six non-diabetic subjects, and hyperinsulinaemic normoglycaemia (5.0 mmoll(-1)) control experiments were performed in four non-diabetic subjects. Circulating levels of cytokines and endotoxin-induced production of TNFalpha, IL-1beta, IL-6, and IL-10 were assessed. The effects of insulin and adrenaline were measured in separate in vitro experiments. In non-diabetic subjects, hypoglycaemia downregulated the production capacity of TNFalpha in a concentration-dependent fashion (P=0.007), but not of IL-1beta, IL-6, or IL-10. Compared to controls, the production capacity of TNFalpha in diabetic patients was already suppressed at normoglycaemia (P=0.02) and only fell in response to hypoglycaemic nadir (P=0.04). The downregulation of TNFalpha could not be explained by increased insulin or adrenaline levels. We conclude that hypoglycaemia specifically downregulates TNFalpha production capacity. Diabetic patients already have a suppressed TNFalpha production capacity at non-hypoglycaemic levels.

Adult↗
PubMed2003

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.

Arm↗
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↗
PubMed2002

Sodium-lithium countertransport is increased in normoalbuminuric type 1 diabetes but is not related to other risk factors for microangiopathy.

BACKGROUND: It has been reported that sodium-lithium countertransport (Na/Li CT) activity is increased in patients with diabetes mellitus and that this increased Na/Li CT activity is associated with the development of diabetic nephropathy. It is unclear however, whether Na/Li CT is related to other pathophysiological factors in diabetic patients. We studied kinetic parameters of Na/Li CT activity together with other putative risk factors for microangiopathy in normoalbuminuric type 1 diabetic patients and matched control subjects. SUBJECTS AND METHODS: We measured maximum velocity (Vmax) and sodium affinity (Km) of Na/Li CT in 53 diabetic patients and 45 healthy controls. Endothelial function was assessed by monitoring forearm vascular response to intrabrachial infusion of acetylcholine. Blood samples were collected for measurement of HbA1c, glucose, insulin and lipids. Blood pressure was measured intra-arterially. Renal haemodynamics were measured by inulin/p-aminohippurate clearance. Urinary albumin was measured by enzyme-linked immunosorbent assay. Transcapillary escape of albumin (TERalb) was calculated by the disappearance curve of 125I-labelled albumin. RESULTS: Vmax was increased in diabetic patients (779 +/- 36 micromol Li+ h-1 L-1 erythrocytes vs. 623 +/- 35 in controls, P < 0.01), whereas Km was decreased (64 +/- 16 mmol L-1 vs. 76 +/- 27 in controls, P = 0.03). The ratio of Vmax : Km was 12.4 +/- 0.6 in diabetic patients and 8.9 +/- 0.9 in controls (P < 0.001). When comparing diabetic patients in the lowest and highest quartile of Vmax or Km there were no differences in blood pressure, renal haemodynamics, urinary albumin excretion, TERalb, endothelial function, HbA1c, glucose, insulin, or lipid profile. CONCLUSION: Na/Li CT is increased in uncomplicated type 1 diabetes and characterized by an increase in Vmax and a decrease in Km. The increase in Na/Li CT is not associated with changes in endothelial function, degree of metabolic control, blood pressure or renal haemodynamics.

Albuminuria↗
PubMed2002

Microcirculatory effects of KATP channel blockade by sulphonylurea derivatives in humans.

BACKGROUND: Recent investigations have shown that glibenclamide inhibits the opening of vascular ATP-sensitive potassium channels during ischemia. This observation may implicate cardiovascular effects of sulphonylurea derivatives when used under conditions of ischemia in patients with Type 2 diabetes mellitus. In addition to resistance arteries, the (pre) capillary vessels also contain ATP-dependent potassium channels. Closure of these channels by sulphonylurea derivatives might affect the development of microvascular disease in Type 2 diabetes mellitus. Therefore, we investigated the microcirculatory effects of sulphonylurea derivatives in Type 2 diabetic patients as compared with healthy volunteers. MATERIALS AND METHODS: Arteriovenous blood flow (skin temperature and laser Doppler flux) and capillary blood cell velocity were measured before and during infusion of four doses of glibenclamide (0.1, 0.3, 1.0 and 3.0 microg min-1 dL-1) into the brachial artery of 14 Type 2 diabetic patients and 13 healthy controls. The experiments included appropriate time control studies. RESULTS: Both skin temperature and laser Doppler flux decreased in response to glibenclamide in healthy volunteers (-7 +/- 2%, P < 0.0005 and -31 +/- 11%, P = 0.001, respectively), but did not change in Type 2 diabetic patients (1 +/- 3%, P = 0.29 and 4 +/- 14%, P = 0.97). However, capillary blood cell velocity decreased in Type 2 diabetic patients (-38 +/- 18%, P = 0.04), but did not change in healthy volunteers (-1 +/- 11%, P = 0.28). CONCLUSIONS: The results of the present study indicate that glibenclamide indeed affects microvascular blood flow. Glibenclamide may induce redistribution of the microvascular skin flow from nutritive flow to arteriovenous shunt flow in Type 2 diabetic patients. Therefore, closure of ATP-dependent potassium channels by glibenclamide possibly plays a role in the development of microangiopathy in Type 2 diabetic patients.

Adenosine Triphosphate↗
PubMed2002

Vascular effects of glibenclamide vs. glimepiride and metformin in Type 2 diabetic patients.

AIMS: Glibenclamide attenuates the protective responses to opening of vascular ATP-sensitive potassium (K(ATP)) channels during ischaemia. Therefore, glibenclamide treatment of Type 2 diabetes mellitus may have hazardous cardiovascular effects when used under conditions of ischaemia. Glimepiride and metformin seem to lack such characteristics. Based on these data, we hypothesized that, in contrast to glibenclamide, chronic treatment of Type 2 diabetic patients with glimepiride or metformin will not impair the vasodilator function of K(ATP) opening in vivo. METHODS: Two groups of 12 Type 2 diabetes mellitus patients participated in a double-blind randomized cross-over study consisting of two 8-week periods, in which treatment with orally administered glibenclamide (15 mg/day) was compared with either glimepiride or metformin (6 mg and 1500 mg/day, respectively). At the end of each treatment period, the increase in forearm blood flow (FBF, venous occlusion plethysmography) in response to intra-arterial administered diazoxide (K(ATP) opener), acetylcholine (endothelium-dependent vasodilator) and dipyridamole (adenosine-uptake blocker) and to forearm ischaemia was measured. RESULTS: There were no significant differences in vasodilator responses to diazoxide, acetylcholine, dipyridamole and forearm ischaemia after glibenclamide compared with glimepiride and metformin. CONCLUSIONS: Chronic treatment of Type 2 diabetes mellitus with glimepiride or metformin has similar effects on vascular K(ATP) channels compared with chronic glibenclamide treatment.

Acetylcholine↗
PubMed2002

Routine intracoronary beta-irradiation. Acute and one year outcome in patients at high risk for recurrence of stenosis.

AIMS: Intracoronary radiation is a promising therapy potentially reducing restenosis following catheter-based interventions. Currently, only limited data on this treatment are available. The feasibility and outcome in daily routine practice, however, is unknown. METHODS AND RESULTS: In 100 consecutive patients, intracoronary beta-radiation was performed with a (90)Strontium system (Novoste Beta-Cathtrade mark) following angioplasty. Predominantly complex (73% type B2 and C) and long lesions (length 24.3+/-15.3 mm) were included (37% de novo, 19% restenotic and 44% in-stent restenotic lesions). Radiation success was 100%. Mean prescribed dose was 19.8+/-2.5 Gy. A pullback procedure was performed in 19% lesions. Geographic miss occurred in 8% lesions. Periprocedural thrombus formation occurred in four lesions, dissection in nine lesions. During hospital stay, no death, acute myocardial infarction, or repeat revascularization was observed. Major adverse cardiac events occurred predominantly between 6 and 12 months after the index procedure with major adverse cardiac event-free survival of 66% at 12 months (one death, 10 Q-wave myocardial infarctions, 23 target vessel revascularizations; ranked for worst event). CONCLUSION: Routine catheter-based intracoronary beta-radiation therapy after angioplasty is safe and feasible with a high acute procedural success. The clinical 1-year follow-up showed delayed occurrence of major adverse cardiac events between 6 and 12 months after the index procedure.

Aged↗
PubMed2002

Metformin improves cardiac functional recovery after ischemia in rats.

The biguanide, metformin, is widely used for the treatment of type 2 diabetes mellitus. In the recently published United Kingdom Prospective Diabetes Study (UKPDS), it was shown that the use of metformin was associated with a reduction of macrovascular complications compared to other blood glucose-lowering strategies. The present study was aimed at determining whether metformin has direct beneficial effects on the heart. We tested the effects of metformin on cardiac functional recovery after a mild ischemic incident (stunning) in our isolated, erythrocyte perfused, rat working-heart model. Three groups were tested: vehicle, 50 and 500 micromol/l metformin (total n = 6). In diabetic rats, a concentration of 50 microM has been shown to reduce the blood glucose concentration. Slight metformin-induced increases in coronary blood flow during normoxia (pre-ischemically) and during reperfusion (post-ischemically) were observed and compared to vehicle (p < 0.05). Both metformin concentrations significantly reduced cardiac functional loss induced by the 12-min global ischemic incident compared with vehicle (3.4 +/- 1.0 % and 3.5 +/- 0.6 % loss during metformin versus 10.7 +/- 0.8 % during vehicle, p < 0.001). This study clearly shows that metformin acutely improves cardiac function after a mild ischemic incident (stunning) in rats.

Animals↗
PubMed2002

Vascular K(ATP) channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes.

Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (K(ATP)) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of K(ATP) opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to K(ATP) channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10 mg x day(-1)) followed by 8 weeks of treatment with acarbose (300 mg x day(-1)), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290 +/- 58% and 561 +/- 101% respectively; P<0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to K(ATP) opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of K(ATP) channel activation.

Acarbose↗
PubMed2002

Abstract!

With the availability of electronic databases, it has become crucial to provide informative abstracts to published papers. Articles published without an abstract run a great risk of being neglected by readers and authors. The Netherlands Journal of Medicine will provide informative abstracts of all future papers, including editorials and letters.

Abstracting and Indexing↗
PubMed2001

Effects of sulfonylurea derivatives on ischemia-induced loss of function in the isolated rat heart.

This study determined whether sulfonylurea derivatives affect cardiac function prior to and after a mild ischemic incident (stunning). This was investigated using an isolated, erythrocyte-perfused, working rat heart model. In total, 11 groups were studied: five increasing (clinically relevant) concentrations of the classical glibenclamide (range 0.005-4 micromol l(-1)), five increasing concentrations of the newly developed glimepiride (range 0.005-0.8 micromol l(-1)), and one control group. Pre-ischemically, glibenclamide and glimepiride reduced coronary blood flow concentration dependently to 55.2+/-4.5% and 58.5+/-5.5%, respectively (P<0.001). Twenty minutes after a 12-min ischemic incident, these reductions of flow were even more pronounced (to 38.3+/-6.7% and 45.8+/-5.8%, P<0.001). This shows that both sulfonylureas reduce coronary blood flow at concentrations slightly higher than therapeutic ones. In the control group, the ischemic incident significantly lowered cardiac function by 22.2+/-2.9%. In the therapeutic range, glimepiride, but not glibenclamide, significantly reduced this ischemia-induced cardiac functional loss to 4.9+/-1.2% (P<0.01). Therefore, we suggest that both sulfonylureas and in particular glimepiride can be used safely in patients with type 2 diabetes mellitus, as long as the coronary vascular system is not compromised. Because of the obvious vasocontrictor response to sulfonylurea derivatives, these drugs must be used with caution in patients with a reduced coronary reserve.

Animals↗
PubMed2001

The transcription factors L-Sox5 and Sox6 are essential for cartilage formation.

L-Sox5 and Sox6 are highly identical Sry-related transcription factors coexpressed in cartilage. Whereas Sox5 and Sox6 single null mice are born with mild skeletal abnormalities, Sox5; Sox6 double null fetuses die with a severe, generalized chondrodysplasia. In these double mutants, chondroblasts poorly differentiate. They express the genes for all essential cartilage extracellular matrix components at low or undetectable levels and initiate proliferation after a long delay. All cartilages are thus extracellular matrix deficient and remain rudimentary. While chondroblasts in the center of cartilages ultimately activate prehypertrophic chondrocyte markers, epiphyseal chondroblasts ectopically activate hypertrophic chondrocyte markers. Thick intramembranous bone collars develop, but the formation of cartilage growth plates and endochondral bones is disrupted. L-Sox5 and Sox6 are thus redundant, potent enhancers of chondroblast functions, thereby essential for endochondral skeleton formation.

Animals↗
PubMed2001

Recombinant human extracellular matrix protein 1 inhibits alkaline phosphatase activity and mineralization of mouse embryonic metatarsals in vitro.

Two mRNAs are transcribed from the extracellular matrix protein 1 gene (Ecm1): Ecm1a and an alternatively spliced Ecm1b. We studied Ecm1 mRNA expression and localization during endochondral bone formation and investigated the effect of recombinant human (rh) Ecm1a protein on organ cultures of embryonic mouse metatarsals. Of the two transcripts, Ecm1a mRNA was predominantly expressed in fetal metacarpals from day 16 to 19 after gestation. Ecm1 expression was not found in 16- and 17-day-old metatarsals of which the perichondrium was removed. In situ hybridization and immunohistochemistry demonstrated Ecm1 expression in the connective tissues surrounding the developing bones, but not in the cartilage. Biological effects of rhEcm1a protein on fetal metatarsal cultures were biphasic: at low concentrations, Ecm1a stimulated alkaline phosphatase activity and had no effect on mineralization, whereas at higher concentrations, Ecm1a dose dependently inhibited alkaline phosphatase activity and mineralization. These results suggest that Ecm1a acts as a novel negative regulator of endochondral bone formation.

Alkaline Phosphatase↗
PubMed2001

In vivo evidence for K(Ca) channel opening properties of acetazolamide in the human vasculature.

1. The selective carbonic anhydrase inhibitor acetazolamide is known to increase blood flow in several organs. Acetazolamide directly dilates isolated resistance arteries associated with activation of calcium-activated potassium (K(Ca)) channels. We examined both the presence and mechanism of the direct vascular action of acetazolamide in vivo in humans. 2. Forearm vasodilator responses of 30 healthy volunteers to infusion of placebo and increasing doses of acetazolamide (1-3-10 mg min(-1) dl(-1)) into the brachial artery were recorded by venous occlusion plethysmography, before and after local administration of L-NMMA (0.2 mg min(-1) dl(-1), an inhibitor of NO-synthase, n=6), indomethacin (5.0 microg min(-1) dl(-1), an inhibitor of prostaglandin synthesis, n=6), glibenclamide (10 microg min(-1) dl(-1), an inhibitor of K(ATP) channels, n=6), tetraethylammonium (0.1 mg min(-1) dl(-1), an inhibitor of K(Ca) channels, n=6) or placebo (NaCl 0.9%, n=6). Lower dosages of acetazolamide did not affect vascular tone (n=6). 3. Acetazolamide infusions increased forearm blood flow from 2.41+/-0.17 to 2.99+/-0.18, 4.09+/-0.26 and 6.77+/-0.49 ml min(-1) dl(-1) in the infused forearm (P:<0.001), with no significant changes in the non-infused forearm, blood pressure or heart rate. Acetazolamide-induced vasodilation was not inhibited by L-NMMA, indomethacin, or glibenclamide but was significantly attenuated by TEA (vasodilation: 23+/-6, 82+/-19, 241+/-38% versus 27+/-8, 44+/-22, 42+/-35%). 4. We conclude that acetazolamide exerts a direct vasodilator effect in vivo in humans mediated by vascular K(Ca) channel activation. This makes acetazolamide the first drug known that specifically modulates this channel.

Acetazolamide↗
PubMed2001

Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells.

Tumor growth and metastasis are critically dependent on the formation of new blood vessels. The present study found that extracellular matrix protein 1 (ECM1), a newly described secretory glycoprotein, promotes angiogenesis. This was initially suggested by in situ hybridization studies of mouse embryos indicating that the ECM1 message was associated with blood vessels and its expression pattern was similar to that of flk-1, a recognized marker for endothelium. More direct evidence for the role of ECM1 in angiogenesis was provided by the fact that highly purified recombinant ECM1 stimulated the proliferation of cultured endothelial cells and promoted blood vessel formation in the chorioallantoic membrane of chicken embryos. Immunohistochemical staining with specific antibodies indicated that ECM1 was expressed by the human breast cancer cell lines MDA-435 and LCC15, both of which are highly tumorigenic. In addition, staining of tissue sections from patients with breast cancer revealed that ECM1 was present in a significant proportion of primary and secondary tumors. Collectively, the results of this study suggest that ECM1 possesses angiogenic properties that may promote tumor progression.

Angiogenesis Inducing Agents↗