Biomedical subjects

A Varro

Publications and source records attributed to A Varro.

At least 73 records · Page 4Linked to original sources

PubMed1993

Gastrin cell responses to acidification of the achlorhydric rat stomach.

In the rat, gastrin cells are normally exposed to the stimulatory effects of food and the inhibitory influences of acid in the gastric lumen. We have studied the effects of intragastric acid on gastrin cell function in animals in which the tonic inhibitory action of acid was removed by prior treatment with the proton pump blocker omeprazole. In fasted rats with gastric fistula treated with omeprazole, instillation of acid into the stomach produced a prompt decrease in plasma gastrin, but gastrin mRNA abundance showed a modest transient increase over a period of 2 h and thereafter no change; there was also a transient increase in tissue concentrations of the gastrin precursor progastrin that was compatible with increased gastrin synthesis. Concentrations of tissue gastrins, in general, increased after acid instillation, which can be attributed to continued synthesis in the presence of suppressed gastrin release. In rats fed ad libitum, a single dose of omeprazole (which produces achlorhydria for 24-30 h) produced an increase in plasma gastrin that peaked after 24 h and declined to control levels over the following 48 h; in contrast, gastrin mRNA abundance peaked 48 h after omeprazole before declining to control levels. The results indicate that whereas gastrin release might be promptly inhibited by intragastric acid, the changes in gastrin mRNA abundance are much slower: achlorhydria increases gastrin mRNA within 24 h, but acid takes longer to depress gastrin mRNA abundance. Over periods of a few hours, gastrin release and synthesis need not, therefore, change in parallel.

Animals↗

PubMed1992

Increased tissue concentrations of the gastrin precursor in patients treated with omeprazole.

The main form of gastrin in antral mucosa, the amidated heptadecapeptide G17, is generated from an inactive precursor, progastrin, by steps involving endopeptidase cleavage and amidation. Gastrin cells are normally inhibited by gastric acid and in this study we have examined how suppression of acid by treatment with omeprazole for 6-8 weeks influences gastrin production in patients with oesophagitis. Plasma concentrations of total amidated gastrins in the fasting state increased from 18 to 43 pmol l-1; assays specific for G17-immunoreactivity indicated that the plasma concentrations of this form increased from 6 to 12 pmol l-1. In endoscopic biopsies of antral mucosa there was no change with omeprazole treatment in the concentrations of total amidated gastrins, or their immediate precursors, the Gly-extended gastrins. However, assays using an antibody that reacts with progastrin, together with size exclusion chromatography, indicated that tissue progastrin concentration increased 6-fold. The data suggest a modest net increase in gastrin production with omeprazole-treatment; because the ratio of tissue concentrations of total amidated gastrins to Gly-extended gastrins did not change, it would seem that the amidating capacity of the gastrin cell was maintained. However, the increase in progastrin concentrations suggests a relative failure of the initial steps of post-translational processing, and consequently that in certain circumstances endopeptidase cleavage of progastrin may be rate limiting.

Amino Acid Sequence↗

PubMed1991

Substitution of phosphotyrosine for sulphotyrosine in biologically active peptides. Enzymatic phosphorylation of a progastrin peptide confers immunoreactivity reminiscent of the sulphated derivative.

The peptide SAEEEDQYN, corresponding to the carboxyl-terminal tryptic fragment of rat progastrin, whose penultimate tyrosyl residue is sulphated in the native peptide, is phosphorylated with Km values of 120 and 180 microM by two spleen tyrosine protein kinases, termed TPK-IIB and TPK-III, respectively. Another spleen tyrosine protein kinase related to the src family (TPK-I/lyn) is poorly active toward this peptide, displaying a Km 6.5 mM. The Tyr-phosphorylated peptide is recognized by an antibody (L304), which reacts with both sulphated and unmodified peptides, while it is not recognized by a second antibody (L303), which reacts with unmodified peptide yet not with the sulphated derivative. These data, in conjunction with previous observations (Hofsteenge, J., Stone, S.R., Donella-Deana, A. and Pinna, L.A. (1990) Eur. J. Biochem. 188, 55-59) support the view that phosphotyrosine is an effective surrogate for sulphotyrosine in a wide spectrum of biological activities.

Amino Acid Sequence↗

PubMed1991

Reversal by omeprazole of the depression of gastrin cell function by fasting in the rat.

1. Gastrin (G)-cell function is controlled by gastric acid, which has inhibitory effects, and food in the gastric lumen, which has stimulatory effects. We have examined the role of acid in mediating the depression of G-cell function that occurs in fasting in the rat. 2. Rats were fasted for 48 h, and received either the H(+)-K(+)-ATPase inhibitor omeprazole, to reduce acid secretion, or vehicle. Basal acid secretion was not significantly different after fasting for 24 or 48 h. Fasted rats which received omeprazole were achlorhydric. 3. In rats treated with vehicle and fasted for 48 h, plasma and tissue gastrin concentrations were significantly depressed. The fall in both parameters suggests an inhibition of gastrin synthesis and consistent with this a decrease was observed in tissue gastrin mRNA abundance and in phosphorylation of progastrin-derived peptides. 4. In fasted rats treated with omeprazole, tissue gastrin concentrations were not significantly different from those of rats fed ad libitum, but plasma gastrin concentrations were significantly higher than in rats fed ad libitum. Gastrin mRNA abundance and the phosphorylation of progastrin-derived peptides in omeprazole-treated rats was not significantly different from rats fed ad libitum. 5. The data suggest that the depression of G-cell function which occurs in fasted rats can be attributed to the inhibitory action of intraluminal acid on the G-cell. Gastric acid appears to regulate several different aspects of G-cell function, including gastrin synthesis, post-translational processing and secretion.

Animals↗

PubMed1991

The secretory kinetics of the G cell in omeprazole-treated rats.

Prolonged achlorhydria leads to hypergastrinemia which must be matched by increased gastrin production. The extent to which the balance between synthesis and storage or secretion is shifted in achlorhydria remains uncertain. In the present study, rats were treated for 14 days with the hydrogen-potassium-stimulated ATPase inhibitor omeprazole, and the effects on plasma and tissue gastrin concentrations and on the abundance of gastrin messenger RNA were examined. To calculate the fractional release rates of gastrin, the metabolic clearance rate of synthetic unsulfated rat heptadeca peptide gastrin in anesthetized rats was also measured. Treatment with omeprazole for 14 days led to a profound hypergastrinemia, a twofold increase in antral gastrin stores, and a tenfold increase in messenger RNA. Calculations based on the metabolic clearance rate for rat heptadecapeptide gastrin suggested that in control rats, about 0.08% of stored gastrin was released per minute compared with about 0.4% in omeprazole-treated rats. No evidence was observed to suggest that changes in the efficiency of conversion of Gly-extended gastrins to amidated peptides were of any significance in accounting for the increased production of amidated gastrin. The increased gastrin synthesis in achlorhydria is therefore attributable to increased messenger RNA levels; most of the increase in gastrin production is directly secreted as changes in the stores of gastrin appear to be of lesser importance.

Animals↗

PubMed1990

Processing of the gastrin precursor. Modulation of phosphorylated, sulfated, and amidated products.

Post-translational processing of the precursor for rat gastrin yields products that include peptides phosphorylated at Ser96, amidated at Phe92, and sulfated at Tyr87 or Tyr103. The phosphorylation site is immediately adjacent to the processing point that gives rise to the biologically active amidated gastrins. We have examined changes in post-translational processing which occur in gastrin cells from rats that are physiologically stimulated (by feeding) or unstimulated (by fasting). Peptides were identified using site-directed radioimmunoassays and chromatographic systems that resolve phosphorylated, amidated, and sulfated progastrin products, including intermediates generated prior to amidation (i.e. C-terminal glycine-extended variants). Assays for Phe92-amidated peptides and for the C-terminal tryptic fragment of progastrin indicated decreases in the total tissue concentrations of immunoreactive peptide with fasting; in contrast, the tissue concentrations of glycine-extended biosynthetic intermediates were similar in fasted and fed rats. Taken together the data suggest a relative failure in amidation mechanisms in unstimulated cells. The endopeptidase cleavage of progastrin was not influenced significantly by fasting. However, the phosphorylation of peptide products containing Ser96 was depressed significantly in fasted rats. The proportions of amidated peptides sulfated at Tyr87 were generally lower than their corresponding glycine-extended biosynthetic precursors, but in both cases the proportion of peptide in the sulfated form was lower than for peptides sulfated at Tyr103. Feeding did not change the sulfation of amidated heptadecapeptide gastrin or its glycine-extended variant. The results suggest that the mechanisms determining phosphorylation and amidation of progastrin-related peptides depend on the patterns of stimulation of gastrin cells. The observation that decreased phosphorylation is associated with a failure to produce active amidated products is consistent with a regulatory function for phosphorylation in gastrin production.

Amides↗

PubMed1990

Modulation of posttranslational processing of gastrin precursor in dogs.

The precursor of the acid-stimulating hormone gastrin is processed in pyloric antral gastrin cells by steps involving sulfation, phosphorylation, cleavage, and amidation. We describe here changes in posttranslational processing in dogs with a surgically excluded antrum; in the preparation we used there was an intact pylorus but antral mucosa was excluded from the normal influence of the luminal contents. Three to five months after the operation, basal plasma gastrin increased from 30.1 +/- 4.0 to 66.1 +/- 16.1 pmol/l, and concentrations of gastrin in the excluded mucosa were 9.23 +/- 1.75 compared with 3.2 +/- 0.56 nmol/g in control antral mucosa. Calculations based on the metabolic clearance rate and plasma and tissue gastrin concentrations suggest two-fold lower fractional release rates from the excluded G-cells compared with normal G-cells. Radioimmunoassay of tissue extracts using antisera specific for the extreme COOH-terminus of progastrin, for glycine-extended G-17, and for the COOH-terminus of G-17, combined with gel filtration and ion exchange chromatography, indicated normal endopeptidase cleavage of progastrin. However there was significantly reduced phosphorylation of the COOH-terminal tryptic fragment of progastrin, and there was also decreased conversion of Gly-extended intermediates to the biologically active COOH-terminally amidated forms of gastrin. Thus, in spite of hypergastrinaemia, the excluded antral mucosa showed evidence of decreased secretory rates associated with decreased progastrin phosphorylation and amidating enzyme activity. The results suggest that contact of antral mucosa with the luminal contents is able to modulate the posttranslational processing of progastrin and so determine the production of biologically active hormone.

Amino Acid Sequence↗

PubMed1989

In vivo studies on the enhancement of cholecystokinin release in the rat striatum by dopamine depletion.

The release of cholecystokinin-8-like (CCK) immunoreactivity from the rat striatum has been studied in vivo using brain microdialysis. A basal efflux of CCK-like immunoreactivity was not detectable in the majority of experiments. Intrastriatal infusion of veratrine (100 micrograms/ml) increased striatal dialysate levels of CCK-like immunoreactivity above detection limits, representing an overflow into the interstitial fluid. High concentrations of potassium caused similar but less consistent effects. Extracellular dopamine depletion using alpha-methyl-p-tyrosine or reserpine also increased the dialysate content of CCK-like immunoreactivity. In contrast, inhibition of peptidases reported to hydrolyse CCK in vitro did not affect either basal or evoked efflux of CCK-like immunoreactivity. These data demonstrate that CCK-like immunoreactivity may be released from neuronal elements within the striatum by depolarizing stimuli in vivo, and suggest that increased overflow of CCK-like immunoreactivity is associated with dopamine depletion.

Animals↗

PubMed1989

The isolation and chemical characterization of phosphorylated enkephalin-containing peptides from bovine adrenal medulla.

There is increasing evidence that the opioid peptide precursor, proenkephalin A, and its products undergo extensive post-translational modification, in addition to the cleavage at dibasic amino acid sites. We have used an antiserum directed toward the C terminus of Met-enkephalin Arg6-Phe7 in a radioimmunoassay to monitor the purification to homogeneity of four peptide B variants from bovine adrenal medulla, using gel filtration, anion exchange chromatography, and reverse phase high performance liquid chromatography. Amino acid sequence analysis, together with immunochemical data, confirmed that each comprised the primary sequence, proenkephalin A-(209-239). In addition, three of the four variants were shown to be phosphorylated by alkaline phosphatase digestion, microphosphate analysis, and ethanethiol derivatization coupled with amino acid sequence analysis; these variants were shown to have 1, 2, or 3 phosphate groups per peptide chain, which corresponded to their increasing acidic nature. The phosphorylation sites were clustered together at positions Ser7, Ser13, and Ser15 and were in close association with acidic residues. The clustering of phosphorylated residues is unique among regulatory peptide precursors. This region of proenkephalin A is well conserved, which suggests that it constitutes an important novel functional domain.

Adrenal Medulla↗

PubMed1989

The constitution and properties of phosphorylated and unphosphorylated C-terminal fragments of progastrin from dog and ferret antrum.

Antibodies to the extreme C-terminal tryptic (nona-) peptide fragment of porcine progastrin have been used in radioimmunoassay to identify progastrin fragments in dog, ferret and pig antral mucosa extracts and to monitor their purification. In addition to previously characterised phosphorylated and unphosphorylated C-terminal tryptic peptides of porcine progastrin a minor form corresponding to the C-terminal octapeptide (i.e. des-Ser C-terminal nonapeptide) was isolated and characterised. The latter form together with phosphorylated and unphosphorylated forms of the nonapeptides were also isolated and chemically characterised from dog antrum, and the unphosphorylated nonapeptide was characterised from ferret antrum. The primary amino acid sequences of the dog, ferret and pig nonapeptides were identical. In ferret the unphosphorylated nonapeptide predominated, and in dog the phosphorylated form predominated; in pig both forms of the nonapeptide were well represented. Intact progastrin was identified in gel filtration eluates of extracts of all 3 species, but occurred only in relatively low concentrations. The nonapeptides did not stimulate acid secretion in the conscious gastric fistula rat and they did not modify the acid response to G17. Phosphorylation of progastrin-derived peptides is evidently well conserved across a range of species even though there appear to be differences in the relative proportions of phosphorylated and unphosphorylated forms.

Animals↗

PubMed1989

Visceral and somatic afferent origin of calcitonin gene-related peptide immunoreactivity in the lower thoracic spinal cord of the rat.

The origin of calcitonin gene-related peptide in the thoracic spinal cord of the rat was investigated by radioimmunoassay and immunohistochemistry. In transverse sections from normal animals there was a dense staining of calcitonin gene-related peptide-immunoreactivity in laminae I, II and V of the dorsal horn. In parasagittal sections this was found to consist of rostrocaudally orientated fibres in laminae I and II and longitudinal bundles of fibres interspersed with a plexus of immunoreactivity in lamina V. After sectioning the thoracic spinal nerves there was a significant reduction in immunoreactivity in the dorsal horn of the spinal cord which was seen as a marked reduction of staining in lamina II and in the bundles of fibres in lamina V. Section of the splanchnic nerve slightly reduced staining in lamina I and virtually abolished the plexuses of immunoreactivity in lamina V. However, measurement of calcitonin gene-related peptide in samples from coeliac-ganglionized rats revealed an increase in immunoreactivity in regions of the spinal cord containing lamina V. These results provide evidence of a visceral and somatic afferent origin of calcitonin gene-related peptide in the thoracic spinal cord of the rat.

Animals↗

PubMed1989

Effect of altered repolarization course induced by antiarrhythmic drugs and constant current pulses on duration of premature action potentials in canine cardiac Purkinje fibers.

The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5-14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 +/- 1.8% (n = 60) to 47.4-60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p less than 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (less than or equal to 2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p less than 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.

Action Potentials↗

PubMed1988

The human gastrin precursor. Characterization of phosphorylated forms and fragments.

There is a potential phosphorylation site in the C-terminal region of the precursor for the acid-stimulating hormone gastrin, which is immediately adjacent to an important cleavage point. In the present study we have sought to identify, separate, quantify and characterize phosphorylated and unphosphorylated forms of human progastrin and its fragments. Identification was made by two radioimmunoassays: (a) a novel assay employing an antibody raised to intact human progastrin; and (b) an assay using antibody reacting with the C-terminal tryptic fragment of human progastrin, as well as progastrin itself. Two forms of human progastrin isolated from a gastrinoma were separated by ion-exchange h.p.l.c., and had similar elution positions on reverse-phase h.p.l.c. and on gel filtration. The more acidic peptide contained close to equimolar amounts of phosphate. On trypsinization, peptides were released that co-eluted on ion-exchange h.p.l.c. with, and had the immunochemical properties of, naturally occurring C-terminal fragments of progastrin. One of the latter was isolated and shown by Edman degradation after derivatization with ethanethiol to have the sequence Ser (P)-Ala-Glu-Asp-Glu-Asn. Similar peptides occur in antral mucosa resected from ulcer patients. The unphosphorylated forms of progastrin predominated, whereas the phosphorylated forms of the C-terminal fragments were predominant. This distribution could be explained by preferential cleavage of phosphorylated progastrin. We conclude that in human progastrin, Ser-96 can occur in the phosphorylated form; this residue immediately follows a pair of basic residues (Arg-Arg) that are cleaved during synthesis of the biologically active product.

Amino Acid Sequence↗

PubMed1988

Calcitonin gene-related peptide in visceral afferent nerve fibres: quantification by radioimmunoassay and determination of axonal transport rates.

An antibody specific for the C-terminus of rat alpha calcitonin gene-related peptide has been used in radioimmunoassay to measure concentrations of immunoreactive peptide in the upper gastrointestinal tract of capsaicin-treated and coeliac ganglionectomized rats, and to measure axonal transport velocities in the vagus and splanchnic nerves. In adult rats that had been treated soon after birth with capsaicin, immunoreactive calcitonin gene-related peptide in the stomach and duodenum was undetectable (less than 0.1 pmol/g) compared with 4-10 pmol/g in control rats. Removal of the coeliac ganglion also reduced concentrations of immunoreactive calcitonin gene-related peptide by 5-fold, but Leu-enkephalin and Met-enkephalin Arg6Gly7Leu8-immunoreactivities (which are thought to occur in intrinsic gut neurons) were unchanged by coeliac ganglionectomy. Concentrations of calcitonin gene-related peptide immunoreactivity in coeliac ganglia were depressed by 90% in capsaicin-treated rats but concentrations of opioid peptide immunoreactivity were similar to control. The results suggest calcitonin gene-related peptide-immunoreactivity in the upper gastrointestinal tract in the rat is predominantly of extrinsic afferent origin. Chromatographic separation on Sephadex G50, or high-performance liquid chromatography revealed that the major immunoreactive form in stomach extracts corresponded to intact calcitonin gene-related peptide, although there was evidence of smaller, less hydrophobic C-terminal fragments. Direct evidence of transport of calcitonin gene-related peptide toward the gut was obtained by ligation of the cervical vagus and greater splanchnic nerves. There was accumulation on the central side of ligatures, which suggested axonal transport velocities in the vagus of about 1.5 mm/h and 0.7 mm/h in splanchnic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Electrophysiological effects of the antiarrhythmic agent GYKI-23107 in dogs.

Cardiac electrophysiological properties of GYKI-23107, a new membrane stabilizing antiarrhythmic agent were studied in anaesthetized open-chest dogs. Epi- end endocardial electrograms (for sinus potential and for His bundle recording) were obtained during sinus rhythm and following atrial and ventricular pacing. The registration were performed under control conditions as well as five minutes after drug administration of 8 mg/kg slow i.v. or 20 minutes after 20 mg/kg intraduodenal administration respectively. GYKI-23107 did not influence significantly either the sinus cycles, PA-intervals, sinus node potentials, or the classical electrophysiological parameters of sinoatrial function as the corrected recovery time of the sinus node, sino-atrial conduction time or the secondary post-stimulation sinus cycles before and after vegetative blockade. Neither the AH intervals, anterograde Wenckebach period, nor ventriculo-atrial conduction time changed significantly. QRS duration, configuration and HV-intervals remained also unchanged after drug administration in doses which used in this study, and which seemed to be in therapeutic range. The agent did not influence significantly the effective refractory periods of the atrium and ventricle during sinus rhythm. This study suggest that the GYKI-23107 is not depressive on the anterograde (AV), retrograde (VA), intraventricular conduction and is slightly depressive on the intrinsic pacemaker properties.

Animals↗

PubMed1987

Post-translational processing of the porcine gastrin precursor by phosphorylation of the COOH-terminal fragment.

The gene sequence encoding porcine preprogastrin is known; in order to clarify pathways of post-translational processing of the predicted precursor peptide we have characterized material reacting with antibodies to a synthetic peptide corresponding to the expected extreme COOH-terminal portion of the precursor. Radioimmunoassay was used to identify and monitor the purification of peptides in porcine antral mucosa. Two peptides (I and II) were isolated to homogeneity by steps involving gel filtration, ion exchange, and reversed-phase high performance liquid chromatography. The two co-eluted on gel filtration but were separated on anion-exchange chromatography. The more acidic peptide (II) was less hydrophobic on high performance liquid chromatography. Automated gas-phase microsequencing revealed the less acidic peptide (I) to have the sequence of porcine preprogastrin 96-104 (SAEEGDQRP); it would be produced by tryptic-like cleavage of Arg95-Ser96. The second peptide did not yield a phenylthiohydantoin-derivative on the first cycle but thereafter it sequenced as the first peptide (i.e. -AEEGDQRP). Incubation in alkali liberated almost equimolar amounts of phosphate from peptide II but not from I. In addition, alkaline phosphatase liberated phosphate and converted the acidic peptide to the less acidic one. The results suggest that serine in the first position is phosphorylated in peptide II but not I. The tripeptide -Ser(P)-Ala-Glu- also occurs in adrenocorticotropic hormone; this tripeptide is a substrate for physiological casein kinase. Potential phosphorylation sites occur at comparable positions in the precursors of a number of regulatory peptides.

Alkaline Phosphatase↗

PubMed1987

Isolation and characterization of the intact gastrin precursor from a gastrinoma.

Antibodies to the extreme C-terminal region of human progastrin have been used to monitor the isolation of high-Mr immunoreactive material in a gastrinoma extract. Microsequence analysis of the product revealed amino acid residues in the first 18 positions corresponding to those predicted from the cDNA sequence for preprogastrin starting at position 22; the sequence and immunochemical data together allow the identification of this material as intact progastrin. Implications for gastrin biosynthesis are discussed.

Amino Acid Sequence↗

PubMed1987

Effects of antiarrhythmic drugs on premature action potential duration in canine ventricular muscle fibers.

The range of premature action potential duration (APDs) during the first 100 ms of electrical restitution was determined in canine ventricular muscle fibers (VM) in the presence of lidocaine (4 and 8 micrograms/ml), mexiletine (8 micrograms/ml), flecainide (2 and 4 micrograms/ml), procainamide (50 micrograms/ml), quinidine (10 micrograms/ml), and disopyramide (10 micrograms/ml). The drug effects on the characteristics of action potential at the basic cycle lengths (BCLs) of 500 and 1,000 ms were similar to those reported previously. At control, the range of premature APDs was approximately 40 ms at BCL of 1,000 ms and approximately 30 ms at BCL of 500 ms. It was decreased 26-52% by lidocaine, mexiletine, and flecainide, not changed significantly by procainamide, and increased 17-53% by quinidine and disopyramide. The range of premature APDs at control and in the presence of drugs in ventricular muscle was smaller than in Purkinje fibers at the same or lower drug concentrations (Varro et al., J Pharmacol Exp Ther 1985;233:304). The four factors influencing the premature APD range in the Purkinje fibers operated in the VM as follows: The difference between the duration of effective refractory period (ERP) and the APD at BCL (APDb) (i.e., the ERP-APDb interval) was increased by lidocaine, mexiletine, and flecainide; normalized restitution curve was shifted toward longer premature APD values only by flecainide; the kinetics of restitution were slowed only by procainamide; and APD at BCL of 1,000 ms was shortened by lidocaine and mexiletine, and prolonged at BCLs of 1,000 and 500 ms by the other four drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗