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Biomedical subjects

C B Nielsen

Publications and source records attributed to C B Nielsen.

14 recordsLinked to original sources
PubMed1992

Influence of osmolarity of solutions used for K+ contraction on relaxant responses to pinacidil, verapamil, theophylline and terbutaline in isolated airway smooth muscle.

Concentration-relaxation profiles for pinacidil, verapamil, terbutaline and theophylline were studied in guinea-pig trachealis contracted by two commonly applied techniques for K+ depolarization. All drugs were much less effective on contractions induced by hyperosmolar 124 mMn K+ solution (added KCl) than on contractions elicited by an isoosmolar 124 mM K+ Krebs solution (substituted KCl). The maximal relaxant responses were (isoosmolar K+/hyperosmolar K+): pinacidil 100%/40%, verapamil 100%/60%, theophylline 100%/0%, terbutaline 50%/0%. Addition of mannitol to establish the same hyperosmolarity as with 124 mM KCl also produced contraction of guinea-pig trachealis. Concentration-relaxation curves for the drugs on mannitol-induced contractions had close resemblance to those obtained in hyperosmolar 124 mM K+ solution. When contraction was elicited by 30 mM K+, pinacidil showed seven times higher relaxant potency in hyperosmolar compared to isoosmolar solution, whereas the relaxant responses to verapamil, theophylline and terbutaline were not influenced by osmolarity. When K+ depolarization is used as a tool for evaluation of drug action in airway smooth muscle, the two different techniques produce dissimilar results. The influence of hyperosmolarity per se appears to be an important and unwanted feature when K+ depolarization is produced by addition of KCl.

Animals↗
PubMed1990

Lack of effect of the vasodilator pinacidil on insulin secretion in healthy humans.

Pinacidil is a new antihypertensive vasodilator drug which is supposed to act by opening of ATP-sensitive and glibenclamide-sensitive K+ channels in vascular smooth muscle cell membranes. Similar K+ channels play an important role in insulin secretion from pancreatic islets cells. Inhibition of insulin secretion has been demonstrated with high concentrations of pinacidil in vitro. In the present study the insulin response to oral glucose were studied in six healthy subjects before and on the last day of 2 weeks treatment with pinacidil. The drug was given by the oral route 12.5 mg bid in the first week and 25 mg bid in the second. There were no significant changes in fasting blood levels of insulin or glucose, glucose-stimulated insulin secretion, or oral glucose tolerance during pinacidil administration. These results may suggest that pinacidil at therapeutic concentrations does not activate insulin regulating K+ channels in pancreatic islet cells.

Administration, Oral↗
PubMed1990

Myocardial accumulation kinetics and pharmacodynamics in the isolated rabbit heart of a new inhibitor of dopamine reuptake, GBR 12909.

Myocardial accumulation of GBR 12909 showed monophasic exponential kinetics with a half-life of 93 min. The disposition followed a three-phasic exponential time-course with half-lives of 1.1, 17 and 98 min., respectively, which was interpreted as three-compartment kinetics. The drug accumulated 430 times in the myocardium at steady-state with 8, 30 and 61% of the drug amount referable to a central, superficial and two deeper myocardial drug pools. GBR 12909 produced concentration dependent (range 0.01 to 12400 nM) biphasic negative inotropic and chronotropic effects. The inhibitory Em-values with regard to contraction velocity were 42 and 105% with corresponding EC50-values of 29 and 688 nM and the related Hill-exponents were 0.6 and 1.1, respectively. Frequency and contraction amplitude related inhibitory Em-values were of similar size. Apparent dynamic steady states developed within about 17 min. Very marked monophasic negative dromotropic effects were observed with computer-derived inhibitory Em-values related to the electrocardiographic PQ- and QRS-intervals exceeding 100%. The frequency-corrected QTc-interval showed an initial increase of 10% but decreased to about 20% below control level at the highest two drug concentrations. Coronary flow-rate increased about 30% and then gradually decreased to near the control value. Oxygen consumption only decreased at the three highest concentrations. Our findings seem compatible with the view that GBR 12909 may possibly act in the myocardium as a membrane-stabilizer which causes inhibition of Na(+)- and Ca+(+)-influx over sarcolemma. Intracellular inhibition of Ca+(+)-liberation from organelles and other calcium depots also seems possible.

Animals↗
PubMed1990

Lack of effect of pinacidil on theophylline pharmacokinetics and metabolism in man.

Pinacidil, a pyridyl cyanoguanidine derivative, is a new antihypertensive vasodilator drug. It shares structural similarities with the histamine H2-receptor blocker cimetidine, an imidazole cyanoguanidine derivative, which is a potent inhibitor of cytochrome P-450 and of theophylline metabolism. In the present study the pharmacokinetics and metabolism of theophylline were determined in six healthy volunteers before and on the last day of oral pinacidil administration for two weeks. The dosage of pinacidil was 12.5 mg twice a day in the first week and 25 mg in the second. There were no significant changes in theophylline plasma clearance, terminal half-life or volume of distribution during pinacidil administration. Also the renal and metabolic clearance of theophylline and the formation clearances of the major theophylline metabolites in the urine (DMU, 1MU, 3MX) did not change significantly during administration of therapeutic doses of pinacidil.

Administration, Oral↗
PubMed1990

Differential relaxant responses to pinacidil of smooth muscle preparations contracted by a high concentration of potassium in isoosmolar and hyperosmolar solutions.

Contractions were produced in guinea-pig trachealis, aorta and pulmonary artery by depolarization with 124 mM K+ using two commonly applied techniques. Addition of KCl to the organ bath solution making it hyperosmolar induced slowly developing contractions, which were only weakly inhibited by pinacidil. Hyperosmolar mannitol-induced contractions showed similar characteristics. In contrast, contractions elicited by isoosmolar K+ Krebs solution developed more rapidly and could be completely suppressed by pinacidil (10(-6)-10(-3) M) in a concentration-dependent manner. The findings explain previously published discrepant results on the relaxant response to pinacidil of smooth muscle preparations contracted by high concentrations of K+, and indicate other mechanisms of action for pinacidil in addition to K+ channel opening, in the concentration range 10(-6)-10(-3) M.

Animals↗
PubMed1989

A comparison of the relaxant effects of pinacidil in guinea-pig trachea, aorta and pulmonary artery.

The relaxant activity of pinacidil, a proposed K+ channel opener, was compared in isolated guinea-pig trachea, aorta and pulmonary artery. In preparations precontracted by histamine or PGF2 alpha, pinacidil produced complete tracheal relaxation but only partial relaxation of vascular tissues. The order of responsiveness was: pulmonary artery greater than trachea greater than aorta. The slope of the pinacidil concentration-effect (C/E) curve was much steeper in the tracheal than in the vascular preparations. The pinacidil C/E curves for relaxation were similar when the three types of preparations were precontracted by 124 mM K+. Pretreatment with pinacidil caused a parallel shift of the tracheal histamine C/E curve to the right, whereas the maximal response to histamine was markedly depressed in the pulmonary artery.

Animals↗
PubMed1989

Pinacidil uptake and effects in the isolated rabbit heart.

The myocardial accumulation of pinacidil showed one-compartment characteristics with a half-time of 1.11 min., whereas the disposition followed three-compartment kinetics with half-times for the relevant two redistributory and the terminal phases of 0.39, 1.51 and 5.44 min., respectively. At a steady-state drug concentration in the perfusate of 6.12 nmol ml-1, the average concentration of pinacidil in the myocardium was 20.6 nmol g-1. The accumulated amount could predictically be referred with 57% to a central and 31 and 12% to two peripheral (deeper) drug pools. The pharmacodynamic effects of pinacidil in the isolated perfused rabbit heart were studied at stepwise increasing concentrations from 0.15 to 100 microM. Coronary flowrate increased initially up to 24.5% at 1.5 microM pinacidil and then gradually decreased. Amplitude and velocity of contraction were both inhibited in a biphasic way up to 92.7 and 94.1%, respectively. Apparent dynamic steady states developed within 13-15 min. The computer-derived inhibitory Em-values related to the first phase were 49.2 and 52.4% and those related to the second phase were 111.7 and 108.3%, respectively. Heart frequency decreased monophasically and exhibited an inhibitory Em-value of 19.6%. Oxygen consumption decreased at pinacidil concentrations higher than 15 microM and the Em-value was 69.7%. The frequency-corrected QT-interval decreased biphasically and the related inhibitory Em-values were 8.6 and 58.7%. The QRS-interval did not change and the PQ-interval only showed a minor increase at the highest pinacidil concentration. Our findings are compatible with the concept of pinacidil being a potassium channel opener.

Animals↗
PubMed1988

Effects of pinacidil on guinea-pig airway smooth muscle contracted by asthma mediators.

Pinacidil is a new antihypertensive, direct vasodilator drug which has been classified as a K+ channel opener. The present study demonstrated a concentration-dependent relaxant activity of pinacidil in guinea-pig tracheal preparations. The potency and efficacy of pinacidil depended on the agent used to induce tracheal tone. Tracheal preparations with spontaneous tone or precontracted by different asthma mediators were completely relaxed by pinacidil. A high potency was found in spontaneously contracted preparations (EC50 = 7.8 x 10(-7) M). The EC50 values ranged from 2.3 to 5.4 x 10(-6) M in histamine-, PGF2 alpha- or LTC4-contracted preparations. When tone was induced by carbachol, the EC50 was 2.1 x 10(-5) M. In contrast, pinacidil produced incomplete relaxation and had a low potency in preparations contracted by 30 or 124 mM K+ Krebs solutions. This effect profile differed from that seen with beta 2-receptor agonists, xanthines and Ca2+ antagonists in guinea-pig trachealis and seems compatible with K+ channel opening as a primary mode of relaxation for pinacidil in airway smooth muscle.

Animals↗
PubMed1985

Diabetic retinopathy after one year of improved metabolic control obtained by continuous subcutaneous insulin infusion (CSII).

Twenty-four insulin dependent juvenile diabetics, with no or minimal background retinopathy, were randomly allocated to conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII) administrated by means of a portable pump. The metabolic control was significantly improved in the CSII group as compared to the CIT group. After one year, a progression of diabetic retinopathy (criterion: development of more than 2 microaneurysms) was observed in 3 of 12 patients in the CSII group and in 4 of 12 patients in the CIT group (P greater than 0.05). A tendency to more severe progression was observed in the CIT group. None developed soft exudates or retinal proliferations. Although no significant beneficial effect of pump treatment could be demonstrated, it seems safe to conclude that pump treatment does not accelerate progression of diabetic retinopathy in patients with no or minimal background retinopathy.

Adolescent↗
PubMed1985

Effect of alpha- and beta-receptor active drugs on corneal thickness.

Phenylephrine (10 mg/ml), phentolamine (10 mg/ml), isoprenaline (0.5 mg/ml) and timolol (5 mg/ml) were applied topically to one eye of volunteers with normal corneas, the other eye serving as a control. One drop of each drug was given twice a day for 3 or 4 days. Timolol was found to increase corneal thickness in both the medicated and the control eye. A significantly greater effect was noted on the eye receiving the drug directly. When isoprenaline was given for 3 days, a slight significant decrease in corneal thickness was found in both the medicated and the control eye, with the two eyes exhibiting a similar CCT change. The present results are suggestive of endothelial beta-receptor importance in the regulation of corneal thickness.

Adult↗
PubMed1979

The influence of ionic strength, albumin and incubation time on the sensitivity of the indirect Coombs' test.

The sensitivity of the indirect Coombs' test was investigated using saline, albumin, or low ionic strength (LIS) in the incubation phase and an incubation time varying from 5 to 120 min. Titration of 41 antibodies showed that LIS always resulted in a higher or almost the same mean scores as the other solutions after the same incubation time. The maximum mean score was always higher with LIS than with saline and was reached after a shorter period of incubation, only 20--40 min even with the weakest antibodies. With LIS, a longer incubation time than 40 min resulted in a sudden decrease in mean score. The maximum mean score using saline or albumin was reached after 40--60 min incubation. The same mean score was obtained after only 15--20 min, when LIS was used. Albumin gave only slightly higher mean scores than saline.

Antibodies↗
PubMedDate not supplied

Effect of insulin pump treatment for one year on renal function and retinal morphology in patients with IDDM.

The effect of strict metabolic control for 1 yr on renal function and retinal morphology was estimated in 24 insulin-dependent diabetic individuals (age 29 +/- 8 yr, diabetes duration 10 +/- 6 yr) with Albustix negative urine and minimal or no background retinopathy before the study. They were randomized to conventional insulin treatment (CIT) or continuous subcutaneous insulin infusion (CSII) with a portable pump. During CSII treatment the metabolic status was significantly improved and glomerular filtration rates (GFR) were found to decline (from 130 +/- 18 to 116 +/- 15 ml/min/1.73 m2, P less than 0.01). The mean value of urinary albumin excretion (UAE) was not statistically significantly reduced (from 15.3 +/- 24.1 to 6.8 +/- 1.5 mg/24 h, P greater than 0.1). In the CIT group both GFR and UAE values were unchanged. In all subjects before treatment we found a positive correlation between the metabolic status, estimated by the HbA1c values, and GFR as well as UAE values, respectively (r = 0.64, P less than 0.01 and r = 0.42, P less than 0.05). We conclude that elevated GFR values can be reduced toward normal level by insulin pump treatment for 1 yr. Retinal morphology was found to deteriorate in four of 12 CIT subjects and in three of 12 CSII subjects. However, the progression was mild and in most individuals only due to a slight increase in the number of microaneurysms. Pump treatment did not induce proliferation and "cotton-wool" exudates were not detectable in any pump subject after 1 yr of treatment. We conclude that CSII treatment for 1 yr was unable to stop the progression of retinopathy in individuals with minimal or no retinopathy on entering the study. On the other hand, pump treatment did not induce cotton-wool exudates or proliferation in these subjects as previously reported in subjects with more severe retinopathy before CSII treatment.

Adult↗