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PubMed2004

Liver injury after intermittent or continuous hepatic pedicle clamping and its protection by reduced glutathione.

BACKGROUND: The debate is still going on about selection of several clamping patterns during hepatectomy. The aim of this study was to assess the safety and preference of normothermic intermittent or continuous hepatic pedicle clamping and confirm the protective effect of reduced glutathione (GSH). METHODS: Thirty-two adult male healthy Sprague-Dawley (SD) rats were divided into groups of intermittent clamping and GSH absent (IA), continuous clamping and GSH absent (CA), intermittent clamping and GSH present (IP) and continuous clamping and GSH present (CP). The clamping manners were successively 40 minutes in continuous clamping groups and two cycles of 20 minutes with an interval of 5 minutes in intermittent clamping groups, and reperfusion periods were 60 minutes. Experimental parameters included levels of malonaldehyde (MDA) and Cu/Zn superoxide dismutase (SOD), pathological and ultrastructural changes in liver tissues, activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in sera. RESULTS: In the same group, the activities of ALT and AST were significantly higher in post-clamping rats than in pre-clamping rats (P<0.05), but no significant differences were noted in levels of MDA and Cu/Zn SOD (P>0.05). The differences of all values between post-reperfusion rats and pre-clamping rats were significant (P<0.05). Pathological and ultrastructural changes could be observed, but no irreversible injury was present. The comparison of the groups showed that the values at relevant time points between the intermittent and continuous groups were not significantly different (P>0.05). The values were significantly different between the GSH absent and present groups after reperfusion (P<0.05). The morphological damages were also obviously alleviated in the GSH present group. CONCLUSIONS: Normothermic intermittent or continuous hepatic pedicle clamping could cause reversible liver ischemia/reperfusion injury when the clamping time lasts 40 minutes. The injury extent seems to be similar. Continuous clamping should be regarded as a proper method in liver surgery. GSH has been confirmed as an effective agent in preventing post-clamping liver injury.

Animals↗
PubMed1988

Comparison of superoxide dismutase, thiopental, and nimodipine for maintenance of somatosensory evoked responses during aortic cross-clamping and declamping in dogs.

Paraplegia is a potential complication of aortic cross-clamping. The occurrence of this devastating sequela has caused increased interest in the use of somatosensory evoked responses (SER) to monitor spinal cord ischemia during aortic cross-clamping. This study was designed to examine changes in SERs during clamping and declamping of the canine aorta after injection of superoxide dismutase (SOD), thiopental (T), and nimodipine (N). In the control group, cross-clamping the aorta produced an increase in latency and a decrease in amplitude of the SER starting at two minutes. Isoelectric SERs were obtained after 16 minutes of aortic cross-clamping, but recovered with cross-clamp removal. When the aorta was clamped for more than 16 minutes in the control group, the isoelectric SERs obtained were irreversible. After the injection of SOD and T, SER latencies and amplitudes changed to a smaller degree with aortic cross-clamping and did not become isoelectric even after 20 minutes of clamping. During aortic cross-clamp removal in the control group, SERs initially improved and then showed signs of reperfusion ischemia, which disappeared after eight minutes. There were no significant SER changes due to reperfusion when SOD or T or the combination was given prior to aortic cross-clamping. There was no difference in SER changes from the control group during aortic cross-clamping and after release of cross-clamping when N was given. Nimodipine did not alter SER changes from aortic cross-clamping alone. In summary, SOD and T, alone or in combination, protect the spinal cord against ischemia during aortic cross-clamping and declamping.

Animals↗
PubMed2005

Biochemical and mutational analyses of a unique clamp loader complex in the archaeon Methanosarcina acetivorans.

Clamp loaders orchestrate the switch from distributive to processive DNA synthesis. Their importance in cellular processes is underscored by their conservation across all forms of life. Here, we describe a new form of clamp loader from the archaeon Methanosarcina acetivorans. Unlike previously described archaeal clamp loaders, which are composed of one small subunit and one large subunit, the M. acetivorans clamp loader comprises two similar small subunits (M. acetivorans replication factor C small subunit (MacRFCS)) and one large subunit (MacRFCL). The relatedness of the archaeal and eukaryotic clamp loaders (which are made up of four similar small subunits and one large subunit) suggests that the M. acetivorans clamp loader may be an intermediate form in the archaeal/eukaryotic sister lineages. The clamp loader complex reconstituted from the three subunits MacRFCS1, MacRFCS2, and MacRFCL stimulated DNA synthesis by a cognate DNA polymerase in the presence of its sliding clamp. We used site-directed mutagenesis in the Walker A and SRC motifs to examine the contribution of each subunit to the function of the M. acetivorans clamp loader. Although mutations in MacRFCL and MacRFCS2 did not impair clamp loading activity, any mutant clamp loader harboring a mutation in MacRFCS1 was devoid of the clamp loading property. Mac-RFCS1 is therefore critical to the clamp loading activity of the M. acetivorans clamp loader. It is our anticipation that the discovery of this unique replication factor C homolog will lead to critical insights into the evolution of more complex clamp loaders from simpler ones as more complex organisms evolved in the archaeal/eukaryotic sister lineages.

Amino Acid Sequence↗
PubMedDate not supplied

Dynamics of loading the Escherichia coli DNA polymerase processivity clamp.

Sliding clamps and clamp loaders are processivity factors required for efficient DNA replication. Sliding clamps are ring-shaped complexes that tether DNA polymerases to DNA to increase the processivity of synthesis. Clamp loaders assemble these ring-shaped clamps onto DNA in an ATP-dependent reaction. The overall process of clamp loading is dynamic in that protein-protein and protein-DNA interactions must actively change in a coordinated fashion to complete the mechanical clamp-loading reaction cycle. The clamp loader must initially have a high affinity for both the clamp and DNA to bring these macromolecules together, but then must release the clamp on DNA for synthesis to begin. Evidence is presented for a mechanism in which the clamp-loading reaction comprises a series of binding reactions to ATP, the clamp, DNA, and ADP, each of which promotes some change in the conformation of the clamp loader that alters interactions with the next component of the pathway. These changes in interactions must be rapid enough to allow the clamp loader to keep pace with replication fork movement. This review focuses on the measurement of dynamic and transient interactions required to assemble the Escherichia coli sliding clamp on DNA.

Adenosine Diphosphate↗
PubMed2001

Single-clamp technique does not protect against cerebrovascular accident in coronary artery bypass grafting.

OBJECTIVES: By potentially avoiding the embolic consequences of a side-biting aortic clamp, the single-clamp technique may decrease cerebrovascular accidents in coronary artery bypass grafting. However, this theoretical superiority in stroke prevention has not been conclusively demonstrated and use of this technique may lead to adverse myocardial effects due to longer cross-clamp times. In this study, we sought to determine if the single-clamp technique prevents postoperative stroke in clinical practice. METHODS: Of 607 consecutive isolated coronary bypass operations completed over a 3 year period, 301 (50%) were performed by one surgeon using exclusively the single-clamp technique and 306 (50%) were performed by a second surgeon using exclusively the two-clamp technique. Postoperative adverse events were retrospectively compared between these two groups. RESULTS: There were no differences between groups in terms of postoperative stroke (1.7% single-clamp vs. 2.0% two-clamp, P=0.78), hospital mortality (2.7% single-clamp vs. 1.6% two-clamp, P=0.38), or perioperative myocardial infarction (2.6% single-clamp vs. 0.7% two-clamp, P=0.052). The two-clamp technique was not a significant predictor of stroke by logistic regression analysis (P=0.72). CONCLUSIONS: We conclude that there are no statistically significant differences between clamp techniques with regard to stroke prevention or myocardial protection. We find no compelling evidence for surgeons successfully utilizing one technique to change to the other.

Aged↗
PubMed2002

Comparison of laparoscopic aortic clamps in a pulsatile circulation model.

PURPOSE: This study was designed to evaluate the fatigue characteristics and the safety and effectiveness of laparoscopic aortic clamps in a pulsatile circulation model. METHODS: A heart-lung machine was used to create a pulsatile circulation model with bovine aortas resembling the vessels being cross-clamped. Four different models (A-D) of laparoscopic aortic clamps were investigated, and three identical probes of each model underwent testing. Preliminary examinations were conducted to define the size and thickness of the bovine aortas that would allow effective cross-clamping and to detect gross material or functional deficits of the clamps. Then, the instruments were placed in the circulation model, which was set at a frequency of 82/min and a pressure of 200/120 mm Hg. Each clamp was subjected to these conditions for 120 hours and was opened and closed 40 times to stimulate real-life conditions. Clamping failures and mechanical defects were recorded, and the clamp parts were afterward examined with an electron microscope. RESULTS: Two clamp models had to be eliminated from the study after the preliminary examinations. All three probes of model B displayed mechanical defects after a few applications. All probes of model D were excluded because none effectively occluded the aortas. All probes of model A and one probe of model C provided effective cross-clamping during the 120-hour test phase and showed no signs of mechanical failure. Two probes of model C broke after 51 and 57 hours of testing, respectively. Both times, the defect occurred during application of the clamps. The detailed analysis of all instruments after the testing, including electron microscope imaging, revealed that several construction deficits and weak points were responsible for the mechanical failures. CONCLUSION: A surprisingly high incidence of clamping failures and mechanical deficits were encountered during the testing. Of the four clamps tested, only one (model A) seemed to be safe and effective enough for routine clinical use. These disappointing results demonstrate the need for further cooperation between vascular surgeons and instrument manufacturers to develop safe and effective laparoscopic vascular clamps.

Animals↗
PubMed2004

Protein trafficking on sliding clamps.

The sliding clamps of chromosomal replicases are acted upon by both the clamp loader and DNA polymerase. Several other proteins and polymerases also interact with the clamp. These proteins bind the clamp at the same spot and use it in sequential fashion. First the clamp loader must bind the clamp in order to load it onto DNA, but directly thereafter the clamp loader must clear away from the clamp so it can be used by the replicative DNA polymerase. At the end of replication, the replicase is ejected from the clamp, which presumably allows the clamp to interact with yet other proteins after its use by the replicase. This paper describes how different proteins in the Escherichia coli replicase, DNA polymerase III holoenzyme, coordinate their traffic flow on the clamp. The mechanism by which traffic flow on the beta clamp is directed is based on competition of the proteins for the clamp, where DNA structure modulates the competition. It seems likely that the principles will generalize to a traffic flow of other factors on these circular clamp proteins.

Binding, Competitive↗
PubMed1976

Limitations of the double sucrose gap voltage clamp technique in tension-voltage determinations on frog atrial muscle.

The purpose of this study was to evaluate the limitations of the double sucrose gap voltage clamp technique in the determination of tension-voltage relationships for frog atrial muscle. Tension-voltage relationships were determined under two conditions. In one case we determined both the tension response and slow inward current associated with an apparent step depolarization (step-clamp) as a function of the magnitude of the step depolarization. In the second case, an action potential was elicited, the voltage clamp was applied early during the plateau phase of the action potential, and the tension response was determined as a function of the clamp potential (action potential-clamp). Under both step-clamp and action potential-clamp conditions, the waveform of the tension response rose to a peak value (Tp) and then decayed with time to a tension that was maintained for the duration of the depolarization. The Tp-clamp potential relationships obtained under step-clamp and action potential-clamp conditions were similar. Microelectrode measurements of transmembrane potential of cells in the "voltage-clamped" region of the preparation demonstrated the lack of temporal and spatial voltage control under both step-clamp and action potential-clamp conditions, and also demonstrated that acquisition of spatial voltage control occurred at about the same time that the tension response reached its peak value. These data indicate that this voltage clamp technique does not allow an accurate determination of the so-called phasic tension-voltage relationship in frog atrial muscle because of a lack of temporal and spatial control of voltage during the rising phase of the tension response.

Action Potentials↗
PubMed2001

Dissection of the ATP-driven reaction cycle of the bacteriophage T4 DNA replication processivity clamp loading system.

Processive DNA replication requires the loading of a multisubunit ring-shaped protein complex, known as a sliding or processivity clamp, onto the primer-template (p/t) DNA. This clamp then binds to the replication polymerase to form a processive polymerase holoenzyme. The processivity of the holoenzyme derives from the topological properties of the clamp, which encircles the DNA without actually binding to it. Multisubunit complexes known as clamp-loaders utilize ATP to drive the placement of this ring around the DNA. To further understand the role of ATP binding and hydrolysis in driving clamp-loading in the DNA replication system of bacteriophage T4, we report the results of a series of presteady-state and steady-state kinetic ATPase experiments involving the various components of the reconstituted system. The results obtained are consistent with a mechanism in which a slow step, which involves the binary ATP-bound clamp-clamp loader complex, activates this complex and permits p/t DNA to bind and stimulate ATP hydrolysis. ATP hydrolysis itself, as well as the subsequent (after clamp-loading) dissociation of the clamp-loader and the slippage of the loaded clamp from the p/t DNA construct, are shown to be fast steps. A second slow step occurs after ATP hydrolysis. This step involves the dissociated clamp loader complex and may reflect ADP release. Only one molecule of ATP is hydrolyzed per clamp-loading event. Rate constants for each step, and an overall reaction mechanism for the T4 clamp-loading system, are derived from these data and from other results in the literature. The principles that emerge fit into a general framework that can apply to many biological processes involving ATP-driven reaction cycles.

Adenosine Triphosphatases↗
PubMed2002

[Injury of polyester grafts by vascular clamps].

UNLABELLED: Protected vascular clamps are not new. Clamp associated damage of human arteries has already been published over 20 years ago. The necessity of protective clamps seems to have been forgotten. In our explant archive (230 explants) we have observed an accumulation of graft ruptures in the groin (13 of 25 ruptures). We presume a multifactorial process. Clamp damage could be part of it. The aim of this study is to prove the clamp induced damage of polyester vascular grafts and to examine whether protected clamps can reduce this. METHOD: Five unprotected (Aesculap(R) FB512R, FB502, FB517, Ulrich CC1235, CV3535) and 5 protected vascular clamp types (Aesculap(R) FB667, FB668, Edwards(R) - formally Baxter(R) - Fogarty(R) CV5050, CV5201, Edwards(R) Cosgrove(R) CV1033) were tested. A longitudinal burst test was performed after maximal clamp closure on 6 different, multifilament polyester yarns of 2 different vascular grafts manufacturers (B. Braun(R), Edwards(R)). RESULTS: The yarn tests with protected clamps showed no difference to those of the unclamped yarns. After clamping with unprotected vascular clamps the stress-strain-diagrams differed significantly. The mean, maximum burst strength was up to 75 % lower. Video documentation revealed filament ruptures. Damage of the yarn surface was seen on a simple woven graft in scanning electron microscopy (SEM). DISCUSSION: The application of unprotected vascular clamps on polyester vascular grafts is common in Germany (56 %). The observed damage of multifilament polyester yarns makes it necessary to re-consider the use of unprotected vascular clamps. The benefit for biological vessels has already been shown.

Blood Vessel Prosthesis↗
PubMed2005

Out-of-plane motions in open sliding clamps: molecular dynamics simulations of eukaryotic and archaeal proliferating cell nuclear antigen.

Sliding clamps are ring-like multimeric proteins that encircle duplex DNA and serve as mobile DNA-bound platforms that are essential for efficient DNA replication and repair. Sliding clamps are placed on DNA by clamp loader complexes, in which the clamp-interacting elements are organized in a right-handed spiral assembly. To understand how the flat, ring-like clamps might interact with the spiral interaction surface of the clamp loader complex, we have performed molecular dynamics simulations of sliding clamps (proliferating cell nuclear antigen from the budding yeast, humans, and an archaeal species) in which we have removed one of the three subunits so as to release the constraint of ring closure. The simulations reveal significant structural fluctuations corresponding to lateral opening and out-of-plane distortions of the clamp, which result principally from bending and twisting of the beta-sheets that span the intermolecular interfaces, with smaller but similar contributions from beta-sheets that span the intramolecular interfaces within each subunit. With the integrity of these beta-sheets intact, the predominant fluctuations seen in the simulations are oscillations between lateral openings and right-handed spirals. The tendency for clamps to adopt a right-handed spiral conformation implies that once opened, the conformation of the clamp can easily match the spiraling of clamp loader subunits, a feature that is intrinsic to the recognition of DNA and subsequent hydrolysis of ATP by the clamp-bound clamp loader complex.

Archaeal Proteins↗
PubMed1997

The biomechanical effect and clinical application of a Ni-Ti shape memory expansion clamp.

STUDY DESIGN: The study involves three phases: a clinical study of 30 patients, a biomechanical study to assess the expansion force of a recovering-shape memory expansion clamp, and a biomechanical study using cadaveric specimens to assess the pullout strength of the shape memory expansion clamp as a function of the shape of the clamp. OBJECTIVE: To evaluate the biomechanical effect and clinical application of the shape memory expansion clamp. SUMMARY OF BACKGROUND DATA: The major complication of anterior cervical decompression and fusion was graft dislodgement and pseudarthrosis. Improvement of the shape of bone graft and fusion technique could not eliminate the problem completely. The authors designed the shape memory expansion clamp by using the characteristic of Ni-Ti shape memory alloy and first applied it in an anterior cervical operation. METHODS: The expansion force of recovering of the shape memory expansion clamp was measured in a biomechanical study. Eight fresh human cadaver cervical spine specimens were used to assess the pullout strength of the shape memory expansion clamp as a function of the shape of the clamp. The shape memory expansion clamp had been used to fix rotated circular grafts in 30 cases with cervical spine injuries or cervical spondylosis after anterior decompression. RESULTS: The expansion force of the shape memory expansion clamp in recovery was 4.65-27.96 N, and the pullout strength was 8.82-20.58 N. Bone fusion was achieved in all 30 cases. Dislocation of bone graft, loosening of clamp, or kyphotic deformity had not occurred. CONCLUSION: The expansion force and the pullout strength of the partially recovered shape memory expansion clamp were determined biomechanically. The clinical study demonstrated that the shape memory expansion clamp is safe and effective.

Adult↗
PubMed1992

Impaired relaxation of the human mammary artery after temporary clamping.

Internal mammary artery specimens from 17 patients were each divided into three separate rings. One ring (control) remained in Krebs solution and the other two were clamped for 30 minutes with either a soft or hard jaw clamp. Isometric tensions were measured in an organ chamber by contracting the rings twice with a thromboxane A2 mimetic, U46619, and relaxing the rings first with the endothelium-dependent agent acetylcholine followed by the endothelium-independent agent sodium nitroprusside. Endothelium-dependent maximal relaxation of the rings was impaired from control after both soft (20% versus 91%; p < 0.01) and hard (1% versus 91%; p < 0.01) jaw clamps were used. However, relaxation after use of hard jaw clamps was significantly less than after use of soft jaw clamps (1% versus 20%; p < 0.05). Endothelium-independent maximal relaxation was not impaired from control after soft jaw clamps (89% versus 97%) were applied but was significantly impaired after use of the hard jaw clamps compared with control (73% versus 97%; p < 0.01) and compared with soft jaw clamps (73% versus 89%; p < 0.05). Rings of internal mammary artery specimens from 10 patients from each experimental group were silver stained. The percentage of intact endothelial cells was significantly greater after soft jaw clamping than after hard jaw clamping (39% versus 15%; p < 0.02). These data suggest that soft jaw clamps significantly reduce the degree of vasoactive dysfunction compared with hard jaw clamps. In addition, soft jaw clamps produce fewer morphologic changes in the human mammary artery after temporary occlusion.

Acetylcholine↗
PubMed1998

Loss of endothelium mediated vascular relaxation as a response to various clamping pressure. Part I. A pharmacological study.

BACKGROUND: The contraction/relaxation response of thoracic aortal rings clamped with two clamping pressures to KCl, noradrenaline and carbachol was studied. METHODS: Clamp A had the tip pressure PA = 0.60 N/mm2 and clamp B PB = 5.16 N/mm2. In fifteen Wistar albino rats, weighing 328 +/- 19 g (mean +/- SD) the thoracic aorta was occluded for 15 minutes and then three vascular rings (2 mm wide) were excised. The proximal unclamped ring served as a control. From distal rings the diameter of the aorta was calculated from their circumference 1.61 +/- 0.01 mm (n = 15, dmin = 1.51 mm, dmax = 1.70 mm). The rings were challenged with cumulative additions of KCl (10-80 mmol/l) to measure the contraction. Then cumulative relaxation to carbachol (0.01-100 mumol/l) as a response to noradrenaline precontraction (0.1 mumol/l) was determined. RESULTS: A significant loss (p < 0.05) of vascular relaxation in all clamped rings (clamped with PA and PB clamping pressures) was seen. No significant differences (p > 0.05) were observed for contraction between clamped and control rings clamped with clamp A, however the rings clamped with clamp B showed a significant reduction in contraction (p < 0.05). No significant differences were seen from control rings between groups A and B (p > 0.05), or from clamped rings between groups A and B (p > 0.05) for both the contraction and relaxation part of experiments. CONCLUSIONS: Endothelial vascular layers are much more susceptible to pressure injuries than was previously believed.

Animals↗
PubMed2026

Mechanistic diversity of clamp loading at small DNA gaps.

DNA sliding clamps, including PCNA (proliferating cell nuclear antigen) and the 9-1-1 (RAD9-RAD1-HUS1 in humans) complex, are ring-shaped protein complexes that encircle DNA and serve as central interaction platforms in DNA replication, repair, and checkpoint signaling. While clamp loading at canonical primer-template junctions by AAA+ (ATPases associated with diverse cellular activities) clamp loaders is well established, how clamps are loaded onto physiologically relevant but geometrically constrained DNA intermediates, such as nicks and single-stranded gaps, has remained unclear. Recent cryo-electron microscopy studies reveal that clamp loaders have evolved distinct strategies to overcome these constraints and to specialize for different genomic contexts. At gapped DNA, the eukaryotic clamp loader RFC (replication factor C) engages both 3'- and 5'-recessed DNA ends and can locally unwind DNA, enabling PCNA loading across a wide range of gap sizes. In contrast, the bacterial DnaX clamp loader lacks a 5'-DNA-binding site and does not unwind DNA, instead loading the &#x3b2;-clamp at small gaps (<6 nt) by sharply bending DNA. The checkpoint clamp loader Rad24-RFC (RAD17-RFC in humans) similarly lacks DNA unwinding activity, restricting loading of 9-1-1 clamp to larger gaps (&#x2265;6 nt). In a distinct specialization, Ctf18-RFC interacts with the leading-strand DNA polymerase &#x3b5;, positioning it as a dedicated loader for leading-strand synthesis, whereas Elg1-RFC (ATAD5-RFC in humans) excludes DNA from its chamber and functions as a PCNA unloader. Together, these mechanisms illustrate how clamp loaders are diversified to accommodate DNA structure and replisome context, ensuring coordinated control of genome replication and maintenance.

9-1-1 clamp↗
PubMed1997

Beta cell response to oral glimepiride administration during and following a hyperglycaemic clamp in NIDDM patients.

The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia.

Administration, Oral↗
PubMed1994

Evidence by a voltage clamp study of an electrically mediated block to polyspermy in the egg of the ascidian Phallusia mammillata.

Eggs of the ascidian Phallusia mammillata were voltage clamped (from -100 to +60 mV) and inseminated with a low or heavy sperm concentration. From inseminations with low sperm concentration (1 x 10(6) sp/ml), we found that fertilization currents occurred between -100 and +40 mV: they were always inward and displayed an analogous pattern whatever the clamped voltage. We established that the percentages of inseminated eggs that produced a fertilization current varied as a function of the clamped voltage. These percentages were not statistically different from 100% at clamped voltages between -100 and -30 mV, they decreased to 68 and 56% at clamped Vm of -10 and 0 mV, respectively, but were not statistically different from 0% at clamped Vm between +10 and +40 mV. We never obtained any egg electrical response at a clamped voltage of +50 mV. Almost all eggs (96%) which responded electrically were penetrated by one or several spermatozoa. These eggs were resuming meiosis (81 to 50%) at values of clamped Vm between -100 and 0 mV, respectively. At clamped Vm between +10 and +50 mV, the percentages of eggs resuming meiosis were not statistically different from 0. These results indicate that in P. mammillata eggs, the occurrence of an electrical response is voltage dependent and consequently that the initial depolarizing shift of the fertilization potential constitutes a fast block to polyspermy. However, in this species, the sperm penetration is not voltage dependent, since it occurred at clamped Vm from -100 to +40 mV. On the other hand, when eggs were clamped from -100 to +60 mV and inseminated with a heavy sperm concentration (2 x 10(7) sp/ml), the curves expressing, respectively, the percentages of eggs which responded electrically, the percentages of eggs which were penetrated by one or several spermatozoa, and the percentages of eggs resuming meiosis, as functions of the clamped Vm, were shifted by approximately 35 mV toward more positive voltages, compared to the corresponding curves obtained from eggs inseminated with a low sperm concentration. This last result means that the critical value of the membrane potential which characterizes the electrical block to polyspermy is dependent on the sperm concentrations used for inseminations.

Animals↗
PubMed2001

Effects of a four-day hyperinsulinemic-euglycemic clamp in early and mid-lactation dairy cows on plasma concentrations of metabolites, hormones, and binding proteins.

The effects of insulin, using a 4 d hyperinsulinemic-euglycemic clamp, on plasma concentrations of hormone, metabolites, and binding proteins were evaluated in four Holstein dairy cows during wk 4 and 17 of lactation. Insulin was infused at 1 microg/kg/hr for 96 hr during the clamp period. Compared with the pre-clamp period, plasma insulin concentrations increased 7-fold and 4-fold during the clamp periods in early and mid-lactation, respectively. The total amount of glucose infused was higher (P < 0.05) during the clamp in early lactation. The clamp decreased plasma concentrations of non-esterified fatty acids (P < 0.001) during early lactation while differences in mid-lactation were minor. The clamp also decreased plasma concentration of beta-hydroxybutyrate (P < 0.001), plasma urea nitrogen (P < 0.001), and true protein (P < 0.01) although the patterns of decline differed between early and mid-lactation. Growth hormone (GH) concentrations decreased (P < 0.001) and insulin-like growth factor-1 (IGF-1) increased (P < 0.01) during the clamp period suggesting a direct effect of insulin on the un-coupling of the GH/IGF-1 axis. Levels of IGF binding protein-2 (IGFBP-2) decreased (P < 0.01) during the clamp period. The relative proportion of IGFBP-2 decreased (P < 0.001) and that of IGFBP-3 increased (P < 0.001) during the clamp period. There were no interactions between the clamp period and stage of lactation on GH, IGF-1, or IGFBPs. Overall, most plasma variables measured were affected in the same way during the two clamps, but the pattern of change often varied with stage of lactation.

3-Hydroxybutyric Acid↗