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Biomedical subjects

P Smits

Publications and source records attributed to P Smits.

At least 109 records · Page 6Linked to original sources
PubMed1997

Long-term beta 1-adrenergic blockade restores adrenomedullary activity in primary hypertension.

In this study we examined the effects of long-term treatment of 19 patients with primary hypertension with the beta 1-adrenoceptor antagonist atenolol on norepinephrine and epinephrine kinetics, at rest and during sympathoadrenal stimulation by lower body negative pressure. Norepinephrine and epinephrine kinetics were measured by using the radioisotope-dilution technique by steady-state infusion of tritiated norepinephrine and epinephrine. The patients were studied before and at the end of 3 months of treatment with atenolol (50 or 100 mg daily). A control group of four normotensive subjects was studied before and after 3 months without any drug treatment. In this group, only arterial blood samples were collected without infusion of the tritiated catecholamines. Atenolol decreased blood pressure and heart rate, but forearm vascular resistance was not affected by atenolol. During atenolol, baseline arterial plasma epinephrine decreased from 0.23 +/- 0.02 to 0.17 +/- 0.01 nM (p < 0.05), and this was accompanied by a decrease in total body epinephrine spillover from 0.50 +/- 0.05 to 0.35 +/- 0.04 nmol/min (p < 0.05). In the control group, arterial plasma epinephrine had not decreased after 3 months. In addition, the increment of arterial plasma epinephrine during lower body negative pressure at -40 mm Hg was attenuated during atenolol. Atenolol had no effect on total body and forearm norepinephrine spillover rates, either at rest or during lower body negative pressure. Clearance rates of epinephrine and norepinephrine were not significantly affected by atenolol. These results suggest that treatment of patients with primary hypertension with the beta 1-adrenoceptor blocker atenolol inhibits the adrenomedullary secretion of epinephrine, but it does not affect the biochemical indices of sympathoneural activity. It remains speculative whether this selective effect of atenolol on epinephrine secretion contributes to its hypotensive action and to its cardioprotective effects in the long term.

Adrenergic beta-Antagonists↗
PubMed1997

Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives.

Familial combined hyperlipidemia (FCH) is a heterogeneous lipid disorder, caused by overproduction of VLDL and characterized by the occurrence of small, dense LDL particles, all features that are also associated with insulin resistance. Therefore, insulin sensitivity was examined directly by means of the euglycemic hyperinsulinemic clamp technique in male nonobese, normotensive FCH patients and compared with that of their nonaffected relatives, matched for age and body mass index (BMI). In addition, an oral 75-g glucose tolerance test (OGTT) was performed and lipid values, including the LDL subfraction profile, were determined. During the clamp, forearm blood flow (FBF) was measured by venous occlusion plethysmography. All participants had a normal glucose response after the glucose load, whereas FCH patients showed hyperinsulinemia after OGTT and higher fasting C-peptide levels. During the clamp, insulin concentrations increased equally in both groups. Mean whole-body glucose uptake (M) (120 to 180 minutes) was lower in FCH patients than in nonaffected relatives (6.89 +/- 0.31 versus 8.94 +/- 0.76 mg.kg-1.min-1; P = .01). In addition, the glucose uptake per unit insulin (I) was lower in FCH patients (insulin sensitivity index [M/I], 7.46 +/- 0.50 versus 9.51 +/- 0.53; P = .009). M significantly correlated with BMI, plasma cholesterol and triglyceride concentrations, and the individual LDL density. The FBF correlated with insulin sensitivity and increased significantly in nonaffected relatives (1.9 +/- 0.12 to 2.5 +/- 0.4 mL.min-1.dL-1; P = .025) but not in patients. Thus, FCH patients characterized by a predominance of small, dense LDL are insulin resistant compared with their nonaffected relatives. This insulin resistance may partly be explained by a decreased insulin-induced vasodilation in skeletal muscle.

Adult↗
PubMed1996

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

Cardiovascular 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 micrograms. min-1. dl-1, both n = 12), 2) the new sulphonylurea derivative glimepiride (2.5 micrograms.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.

Adult↗
PubMed1996

Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans.

Experimental data show that ATP-sensitive potassium (KATP) channels not only occur in pancreatic beta cells, but also in the cardiovascular system, where they mediate important cardioprotective mechanisms. Sulphonylurea derivatives can block the cardiovascular KATP channels and may therefore interfere with these cardioprotective mechanisms. Therefore, it is of clinical importance to investigate whether sulphonylurea derivatives interact with vascular KATP channels in humans. Using venous-occlusion strain-gauge plethysmography, we investigated whether ischaemia-induced reactive hyperaemia is reduced by the sulphonylurea derivative glibenclamide in 12 healthy male non-smoking volunteers. Forearm vasodilator responses to three periods of arterial occlusion (2, 5 and 13 min) during concomitant infusion of placebo into the brachial artery were compared with responses during concomitant intra-arterial infusion of glibenclamide (0.33 microgram.min-1.dl-1). A control study (n = 6) showed that time itself did not change the vasodilator response to ischaemia. Glibenclamide significantly increased minimal vascular resistance (from 2.1 +/- 0.1 to 2.3 +/- 0.2 arbitrary units, Student's t-test: p = 0.01), and reduced mean forearm blood flow (from 37.5 +/- 2.0 to 35.4 +/- 2.0 ml min-1.dl-1 after 13 min occlusion, ANOVA with repeated measures: p = 0.006) and flow debt repayment during the first reperfusion minute (ANOVA with repeated measures: p = 0.04). In contrast, total flow debt repayment was not affected. Infusion of glibenclamide into the brachial artery resulted in local concentrations in the clinically relevant range, whereas the systemic concentration remained too low to elicit hypoglycaemic effects. Our results suggest that therapeutic concentrations of glibenclamide induce a slight but significant reduction in the early and peak vasodilation during reactive hyperaemia.

Adenosine Triphosphate↗
PubMed1996

Cardiovascular effects of sulphonylurea derivatives.

The classical sulphonylurea derivatives like glibenclamide and tolbutamide are widely prescribed in non-insulin dependent diabetes mellitus in order to stimulate insulin secretion. 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. Interestingly, the cardiovascular system also shares these KATP-channels. The open state probability of these channels is regulated by the intracellular concentration of ATP. During 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. Sulphonylurea derivatives like glibenclamide and tolbutamide have been reported to block the opening of KATP-channels in several types of tissues including myocardial and vascular smooth muscle cells. Since the opening of KATP-channels is regarded as an endogenous cardioprotective mechanism, the blocking effect of sulphonylurea derivatives in the cardiovascular system may have deleterious effects. Human studies on this issue have just been initiated, and preliminary results point towards a significant interaction between glibenclamide and cardiovascular KATP-channels at clinically relevant concentrations. In this regard, the introduction of more pancreas specific sulphonylurea derivatives like glimepiride, which do not interact with cardiovascular KATP-channels, is a promising development.

Adenosine Triphosphate↗
PubMed1996

The angio-Behçet syndrome.

Two man presented with recurrent venous thrombosis. One of them also suffered from arterial thrombosis and aneurysm. Additional history-taking revealed that both suffered from recurrent oral and/or genital ulcers, erythema nodosum and iritis. Consequently a diagnosis of 'angio-Behçet syndrome' was made. Related to the clinical observations in these patients, we discuss the complications and the management of angio-Behçet syndrome. Treatment includes anticoagulants and immunosuppressive drugs.

Adult↗
PubMed1996

Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion.

OBJECTIVES: The efficacy of high dose furosemide as a continuous infusion was compared with a bolus injection of equal dose in patients with severe heart failure. BACKGROUND: The delivery rate of furosemide into the nephron has been proved to be a determinant of diuretic efficacy in healthy volunteers. METHODS: In a randomized crossover study we compared the efficacy of a continuous infusion of high dose furosemide (mean daily dosage 690 mg, range 250 to 2,000) versus a single bolus injection of an equal dose in 20 patients with severe heart failure. The patients received an equal dosage, either as a single intravenous bolus injection or as an 8-h continuous infusion preceded by a loading dose (20% of total dosage). RESULTS: Mean (+/- SEM) daily urinary volume (infusion 2,860 +/- 240 ml, bolus 2,260 +/- 150 ml, p = 0.0005) and sodium excretion (infusion 210 +/- 40 mmol, bolus 150 +/- 20 mmol, p = 0.0045) were significantly higher after treatment with continuous infusion than with bolus injection, despite significantly lower urinary furosemide excretion (infusion 310 +/- 60 mg every 24 h, bolus 330 +/- 60 mg every 24 h, p = 0.0195). The maximal plasma furosemide concentration was significantly higher after bolus injection than during continuous infusion (infusion 24 +/- 5 micrograms/ml, bolus 95 +/- 20 micrograms/ml, p < 0.0001). Short-term, completely reversible hearing loss was reported only after bolus injection in 5 patients. CONCLUSIONS: We conclude that in patients with severe heart failure, high dose furosemide administered as a continuous infusion is more efficacious than bolus injection and causes less ototoxic side effects.

Aged↗
PubMed1996

Vascular effects of loop diuretics.

Although it is generally believed that the beneficial effect of loop diuretics is the result of a rapid increase in diuresis, substantial evidence, from a large number of in vitro and in vivo experiments, has accumulated showing that administration of furosemide causes direct vascular effects, which probably contribute to its acute clinical effects. Several mechanisms are involved in the vascular response to loop diuretics. The role of the renin-angiotensin-adolsterone axis, prostaglandins and the direct vascular effects of loop diuretics on both the arterial and venous parts of the vasculature are discussed.

Animals↗
PubMed1996

Differential effects of low- and high-intensity lower body negative pressure on noradrenaline and adrenaline kinetics in humans.

1. Lower body negative pressure provides a means to examine neurocirculatory reflexive responses to decreases in venous return to the heart. We assessed whether the pattern of catecholaminergic responses to lower body negative pressure depends on the intensity of the stimulus (-15 versus -40 mmHg). 2. In 14 healthy subjects, responses of forearm blood flow and noradrenaline spillover and of total body noradrenaline and adrenaline spillover were assessed during infusion of [3H]noradrenaline and [3H]adrenaline during -15 and -40 mmHg of lower body negative pressure. 3. During lower body negative pressure at -15 mmHg, heart rate and pulse pressure did not change, but forearm vascular resistance increased by 25-50%. Forearm noradrenaline spillover increased by about 50%, from 0.63 +/- 0.16 to 0.94 +/- 0.23 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline spillover did not change, and total body adrenaline spillover increased significantly by about 30%. Clearances of noradrenaline and adrenaline were unchanged. 4. During lower body negative pressure at -40 mmHg, heart rate increased and pulse pressure decreased. Forearm vascular resistance increased by about 100%, and forearm noradrenaline spillover increased by 80%, from 0.73 +/- 0.19 to 1.32 +/- 0.36 pmol min-1 100 ml-1 (P < 0.05). Total body noradrenaline spillover increased by 30%, and total body adrenaline spillover increased by about 50%. Clearances of both noradrenaline and adrenaline decreased. 5. The results are consistent with the view that selective deactivation of cardiopulmonary baroreceptors during low-intensity lower body negative pressure increases sympathoneural traffic to forearm skeletal muscle and increases adrenomedullary secretion without a concomitant generalized increase in sympathoneural outflows. Concurrent deactivation of cardiopulmonary and arterial baroreceptors during high-intensity lower body negative pressure evokes a more generalized increase in sympathoneural activity, accompanied by further increased adrenomedullary secretion and decreased plasma clearances of noradrenaline and adrenaline. The findings support differential increases in skeletal sympathoneural and adrenomedullary outflows during orthostasis, with more generalized sympathoneural responses to systemic hypotension.

Adult↗
PubMed1996

Preserved vasodilator response to adenosine in insulin-dependent diabetes mellitus.

Experimental data derived from animal models suggest that the endogenous nucleoside adenosine has important cardioprotective properties. The potent vasodilator effects of adenosine may contribute to this cardioprotection as ischaemia-induced release of endogenous adenosine has been suggested to adjust local blood flow to the metabolic demands of the tissue. Interestingly, the vascular effects of adenosine appeared to be impaired in animal models for diabetes mellitus. This observation may be of importance with respect to the increased cardiovascular mortality in diabetes. Therefore, the authors investigated the in vivo vasodilator effects of adenosine in insulin-dependent diabetic patients. In 12 uncomplicated insulin-dependent male diabetic patients and 12 healthy male age-matched subjects, the brachial artery was cannulated for infusion of adenosine (0 center dot 15, 0 center dot 5, 5, 15 and 50 mu g 100(-1) mL min-1) and for measurement of mean arterial pressure (MAP). Forearm blood flow (FBF) was measured by venous occlusion mercury-in-silastic strain gauge plethysmography. Maximal vasodilatation was assessed by standardized post occlusive reactive hyperaemia (PORH). Baseline forearm blood flow was 2 center dot 7 +/- 0 center dot 4 and 1 center dot 8 +/- 0 center dot 2 mL 100(-1) mL min-1 for the diabetic patients and control group respectively. In the diabetic patients, adenosine infusion raised forearm blood flow to 2 center dot 4 +/- 0 center dot 4, 2 center dot 6 +/- 0 center dot 4, 4 center dot 4 +/- 0 center dot 7, 6 center dot 3 +/- 1 center dot 0, 9 center dot 8 +/- 1 center dot 5 and 14 center dot 2 +/- 2 center dot mL 100(-1) mL min-1 for the respective dosages. In the control group these values were 1 center dot 7 +/- 0 center dot 2, 1 center dot 9 +/- 0 center dot 3, 3 center dot 2 +/- 0 center dot 8, 6 center dot 0 +/- 1 center dot 2, 10 center dot 9 +/- 2 center dot 1 and 17 center dot +/- 3 center dot 4 mL 100(-1) mL min-1 respectively (P > 0 center dot 1 for between group comparison). Forearm blood flow at the contralateral side was not significantly affected by the placebo and adenosine infusions. Similar results were obtained when results were expressed as changes in forearm vascular resistance or forearm blood flow ration (FBF infused arm/FBF control arm). Maximal vasodilatation did not differ between the two groups. The authors conclude that the forearm vasodilator response to adenosine is preserved in uncomplicated insulin-dependent diabetic patients. This observation argues against a primary role of a reduced adenosine responsiveness in the cardiovascular sequelae of diabetes.

Adenosine↗
PubMed1996

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 (ANOVA P < 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 micromol 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.

Adolescent↗
PubMed1996

Effects of tolbutamide on vascular ATP-sensitive potassium channels in humans. Comparison with literature data on glibenclamide and glimepiride.

Sulfonylurea (SU) derivatives exert their hypoglycemic effect by blockade of adenosine-5'-triphosphate-sensitive potassium (KATP) channels in the beta-cell of the pancreas. Interestingly, KATP channels also occur in the cardiovascular system, where they are thought to play an important role in cardioprotective mechanisms against ischemia. We have recently shown that the classical second generation SU-derivative glibenclamide is able to block vascular KATP channels in man, whereas the newly developed second generation derivative glimepiride was devoid of this property. The aim of this study was to determine whether the first generation SU derivative tolbutamide has KATP channel blocking properties in humans. In a group of 12 healthy male non-smoking volunteers, we investigated whether therapeutic concentrations of tolbutamide were able to inhibit the forearm vasodilation in response to the infusion of the KATP channel opening drug diazoxide into the brachial artery. Changes in forearm blood flow were recorded by venous occlusion mercury-in-silastic strain-gauge plethysmography. Diazoxide alone increased the forearm blood flow ratio dose-dependently by ultimately 691 +/- 198%. A second diazoxide infusion in the presence of tolbutamide revealed a comparable vasodilator response with a percentage increase in forearm blood flow ratio of ultimately 542 +/- 111%. This response did not differ from the vasodilator response to diazoxide alone. The present study shows that therapeutic concentrations of tolbutamide are not able to attenuate the vasodilation caused by the KATP channel opener diazoxide in man. When compared with published data on second generation SU derivatives, tolbutamide shows an intermediate position between glibenclamide (with significant blockade of vascular KATP channels) versus glimepiride (with no blockade at all). It remains to be determined whether these acute effects of SU derivatives on pharmacological opening of forearm vascular KATP channels can be extrapolated to the chronic effects of these drugs on ischemia-mediated opening of myocardial KATP channels during treatment of NIDDM patients.

Adenosine Triphosphate↗
PubMed1996

Effect of atrial natriuretic factor on skin microcirculation versus skeletal muscle blood flow.

The response of the skin microcirculation and of forearm skeletal muscle blood flow to infusion of alpha-human (99-126) atrial natriuretic factor (ANF) into the brachial artery was investigated in 15 young (18-25 years) healthy volunteers in a double-blind, randomized, placebo-controlled study. The forearm blood flow (FBF) was measured with venous occlusion plethysmography, and the skin flux was measured by using laser Doppler fluxmetry (LDF). Dose-response curves were made using increasing dosages of ANF: 1, 10, and 100 ng/min/dl forearm volume. The FBF showed a significant, dose-dependent increase during ANF infusion, averaging 107 + 22% during the highest ANF dosage, as compared with -5 +/- 9% during placebo (p < 0.001). For the LDF, these numbers were 34 +/- 21 and -6 +/- 10%, respectively (NS). In two subgroups of subjects, the effect of ANF on microvascular reactivity was assessed by registering the vasoconstrictor response to cold exposure (n = 7) and the vasodilator response to arterial occlusion (n = 7). ANF did not change the microvascular response to these stimuli. ANF induces a dose-dependent increase in skeletal muscle BF without a relevant response in the skin microcirculation. ANF does not play an important role in the regulation of skin perfusion.

Adult↗
PubMed1996

Regional hyperinsulinemia induces vasodilation but does not modulate adrenergic responsiveness in humans.

The relation between insulin resistance/ hyperinsulinemia and cardiovascular disease may be related to one of the cardiovascular effects of insulin. In acute experiments in humans, systemic euglycemic hyperinsulinemia induced vasodilation in skeletal muscle. Furthermore, the sympathetic nervous system is activated, although this does not lead to increase in blood pressure (BP). We hypothesized that insulin could induce vasodilation either by reduction of alpha- or by augmentation of beta-adrenergic responsiveness. The effect of insulin infusion into the brachial artery (regional forearm hyperinsulinemia; venous insulin concentration approximately 500 pM) on forearm blood flow (FBF: plethysmography) was studied. Responses to the alpha-adrenoceptor-mediated vasoconstrictor norepinephrine (NE: once with and once without the beta-adrenoceptor antagonist propranolol, 2 x n = 12; 9 participated in both), and to the beta-adrenoceptor-mediated vasodilator isoproterenol (n = 12) were measured before and during local hyperinsulinemia. Time/control studies (n = 6) were performed. Insulin alone induced vasodilation, as indicated by an increase in FBF-ratio (infused/ control arm) from 1.2 +/- 0.1 to 1.6 +/- 0.2, p = 0.009. Increasing dosages of NE (1.25 to 240 ng.dl-1.ml-1) induced vasoconstriction that was more pronounced during concomitant propranolol infusion (p < 0.001), indicating a dose-dependent vasodilatory component in the effect of NE. Isoproterenol (ISO 0.03 to 10 ng.dl-1.ml-1), a pure beta-adrenoceptor agonist, induced vasodilation. The percentage changes of FBF-ratio during NE+propranolol were similar and not significantly different before and during hyperinsulinemia. The same was true of the response to NE alone and the response to ISO. Neither was the intrinsic beta-agonist component of NE influenced by insulin. Repeated NE infusion showed no time- or vehicle effect. We conclude that regional hyperinsulinemia in the physiological range induces local vasodilation in the skeletal muscle vascular bed, but this vasodilation is not mediated through modulation of alpha- or beta-adrenergic responsiveness.

Adult↗
PubMed1996

Glomerular filtration and saturable absorption of iohexol in the rat isolated perfused kidney.

1. The renal handling of iohexol was examined in the rat isolated perfused kidney (IPK) over a perfusate concentration range of 5-20 micrograms ml-1. 2. At a concentration of 5 micrograms ml-1, a ratio of renal clearance over clearance by glomerular filtration (ClR/GF) of 0.63 +/- 0.06 could be determined. This ratio increased until 1.02 +/- 0.06 at 20 micrograms ml-1, indicating that a saturable mechanism is involved in the luminal disappearance of the drug. 3. Pretreatment of the kidneys with polylysine, probenecid or diatrizoate resulted in a significantly enhanced clearance of iohexol, probably due to inhibition of membrane binding. Renal clearance data were fitted to a kinetic model including filtration into the primary urine followed by saturable absorption at the luminal membrane. An absorption constant, KA, of 7.3 +/- 1.3 micrograms ml-1, and a maximum rate of absorption, VA,Max, of 1.4 +/- 0.1 micrograms min-1 were determined. 4. Iohexol accumulated in kidney tissue, reaching a concentration of 2 to 7.5 times the perfusate concentration. In freshly isolated proximal tubular cells and kidney cortex mitochondria, iohexol reduced the uncoupled respiratory rate at a concentration comparable to the highest tissue concentration found in the IPK. 5. In conclusion, iohexol is not only filtered by the kidney but also reabsorbed via a saturable mechanism, which results in tubular accumulation. Intracellularly sequestered iohexol may affect mitochondrial oxidative metabolism. Our results indicate that iohexol is not a true filtration marker.

Animals↗
PubMed1996

Activation of ATP-sensitive potassium channels contributes to reactive hyperemia in humans.

Activation of ATP-sensitive potassium (KATP) channels present on vascular smooth muscle cells causes membrane hyperpolarization and vasodilation. The purpose of this study was to determine whether KATP channels contribute to reactive hyperemia in humans. Accordingly, we studied the effect of tolbutamide, a KATP channel inhibitor, on reactive hyperemic forearm blood flow. Forearm blood flow was measured by venous occlusion plethysmography. Forearm ischemia was produced by inflating a sphygmomanometric cuff on the arm to suprasystolic pressures for 5 min. After cuff release, forearm blood flow was measured during the reactive hyperemic phase for 5 min. Tolbutamide (1 mM blood concentration, n = 6) did not affect basal (2.4 +/- 0.2 to 2.2 +/- 0.1 ml.100 ml-1.min-1) or peak reactive hyperemic forearm blood flow (21.9 +/- 3.8 to 22.6 +/- 2.9 ml.100 ml-1.min-1, each P = NS), but it significantly attenuated total hyperemic volume (12.6 +/- 1.7 vs. 9.2 +/- 1.8 ml/100 ml, P < 0.02). Vehicle (n = 6) did not affect basal flow, peak reactive hyperemic flow, or total hyperemia. To determine whether adenosine or endothelium-derived nitric oxide contribute to reactive hyperemia via KATP channels, adenosine (1.5-500 micro grams/min, n = 6) and acetylcholine (30 micrograms/min, n = 6) were infused before and during tolbutamide coinfusion. Tolbutamide did not significantly alter the forearm blood flow response to either adenosine or acetylcholine. In conclusion, KATP channels contribute to vasodilation during reactive hyperemia in humans.

Acetylcholine↗