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P Danilo

Publications and source records attributed to P Danilo.

At least 37 records · Page 2Linked to original sources
PubMed1997

Responses to norepinephrine of normal and "ischemic" canine Purkinje fibers are consistent with activation of different alpha 1-receptor subtypes.

INTRODUCTION: Previously we found that WB4101 (WB) 10(-7) M competitively blocks three alpha 1-adrenergic receptor-effector responses: the increase in normal automaticity occurring in Purkinje fibers (PF) at high membrane potentials; the increase in abnormal automaticity occurring in PF at depolarized membrane potentials; and the prolongation of PF action potential duration. These observations are consistent with two different hypotheses: (1) WB blocks a single alpha 1-receptor subtype, which subserves different effector pathways; and (2) WB blocks different receptor subtypes, each of which subserves an independent pathway. The aim of this study was to test both hypotheses. METHODS AND RESULTS: We used standard microelectrode techniques to study the concentration-dependent actions of three alpha 1-adrenoreceptor blockers (WB [alpha 1A > or = alpha 1D], 5-methylurapidil [5-MU] [alpha 1A > > alpha 1D], and UK52,046 [nonselective]) or norepinephrine (NE) effects in normal PF and in PF depolarized with a simulated ischemic solution ([K+]o = 10 mM; pO2 < 20 mmHg; pH 6.8; maximum diastolic potential -60 +/- 1 mV). In normally polarized PF, concentration-dependent actions of all blockers on both the positive chronotropic response and the prolongation of action potential duration completely coincide. In contrast, the response to NE of abnormal automaticity in "ischemic" PF differs from normals: there is a high sensitivity to WB and 5-MU and no response to UK52,046. CONCLUSIONS: (1) A single receptor subtype appears responsible for both the alpha 1-induced prolongation of repolarization and the positive chronotropic effect in normal PF. (2) Two different receptor subtypes may be responsible for the alpha 1-induced effects on automaticity in normal and ischemic fibers. It is likely that the latter one is alpha 1A, and that consideration of antiarrhythmic therapy with alpha 1-adrenergic blockers should focus on this subtype as a potential target.

Action Potentials↗
PubMed1995

Chloroethylclonidine increases the incidence of lethal arrhythmias during coronary occlusion in anesthetized dogs.

We studied the role of alpha1-adrenoceptors in the modulation of ventricular tachycardia and fibrillation in chloralose-anesthetized dogs subjected to 30 min left anterior descending coronary artery occlusion. Study groups were control, and those treated with the alpha1-adrenoceptor-subtype blockers WB4101 (0.5 mg/kg i.v.) or chloroethylclonidine (1.9 mg/kg i.v.). For the first set of experiments all animals were in sinus rhythm and heart rate was slower in the chloroethylclonidine-pretreated animals than the WB4101-treated group (P < 0.05). During occlusion, ventricular tachycardia and ventricular fibrillation incidence did not differ among control, WB4101 or chloroethylclonidine (3 dogs with ventricular fibrillation in each group and 0, 2 and 3 dogs respectively with ventricular tachycardia), but ventricular premature depolarizations were significantly reduced by both interventions, and nonsustained ventricular tachycardia was suppressed by WB4101. In a second set of experiments, animals were atrially paced at a cycle length of 300 ms, and divided into control, WB4101-treated or chloroethylclonidine-treated, as above. Here, 9/10 chloroethylclonidine-treated animals developed ventricular tachycardia and fibrillation during occlusion, whereas only 4/10 controls and 4/10 WB4101-treated animals did so (P < 0.05). In conclusion, during sinus rhythm, both types of alpha1-adrenoceptor subtype blockade significantly suppressed ventricular premature depolarizations and neither affected ventricular tachycardia and fibrillation. In contrast, when heart rate was held constant, chloroethylclonidine clearly enhanced the occurrence of ventricular fibrillation during occlusion. These results suggest the alpha1-adrenoceptor subtype blocked by chloroethylclonidine, but not that blocked by WB4101, is capable of increasing the incidence of lethal arrhythmias that occur at rapid atrial rates during ischemia.

Adrenergic alpha-Antagonists↗
PubMed1994

Vagal release of vasoactive intestinal peptide can promote vagotonic tachycardia in the isolated innervated rat heart.

OBJECTIVE: The aim was to determine the extent to which endogenous release of vasoactive intestinal polypeptide (VIP) might be implicated in the modulation of sinoatrial rate in the presence and absence of muscarinic blockade or beta blockade. METHODS: Langendorff perfused rat hearts were studied with the right vagus intact. The hearts were maintained in sinus rhythm and subjected to right vagal stimuli of 5, 10, 20, and 30 Hz. RESULTS: Administration of exogenous VIP, 10(-8) M, increased sinus rate by 20% (p < 0.05). This increase in heart rate was reduced significantly to 8% by the VIP antagonist [D-p-Cl-Phe6, Leu17]VIP, 10(-7) M, which alone had no effect on sinus rate. Vagal stimulation reduced sinus rate from a control of 254(SEM 2) to 164(17) beats.min-1 (p < 0.05) at 20 Hz. VIP, 10(-8) M, increased these rates to 284(6) and 220(21) beats.min-1 (p < 0.05). In another eight vagally stimulated hearts, frequencies of 5-20 Hz reduced sinus rate. At 30 Hz heart rate increased in five, and the resultant rate was significantly faster in these [154(10) beats.min-1] than in the remainder [98(12) beats.min-1, p < 0.05]. Vagal stimulation also increased sinus rate (p < 0.05) in four of seven additional hearts perfused with atropine, 2 x 10(-6) M. This increase was completely abolished by [D-p-Cl-Phe6, Leu17]VIP. That the effect was not beta adrenergic was demonstrated in eight experiments using atropine plus propranolol, 1 x 10(-7) M. A vagally induced increment in rate still occurred (p < 0.05) and was abolished by [D-p-CL-Phe6, Leu17]VIP. The ability to ascribe a rate change to VIP release was maximal in the presence of propranolol and atropine, intermediate in the presence of atropine alone, and minimal in the absence of muscarinic or beta blockade. CONCLUSIONS: Vagally released VIP is capable of limiting the decrement in sinus rate that occurs at high frequencies of vagal stimulation, and in some circumstances can actually increment sinus rate. Its role as an endogenous modulator of vagal effects on heart rate and as a possible cause of vagal and postvagal tachycardias should be further explored.

Animals↗
PubMed1994

Mechanisms for vagal modulation of ventricular repolarization and of coronary occlusion-induced lethal arrhythmias in cats.

Our goal was to better understand the mechanisms underlying muscarinic receptor actions on the ventricle in vivo. Therefore, we studied the effects of vagal stimulation on ventricular repolarization and of vagal tone on lethal arrhythmias induced by 30 minutes of left anterior descending coronary artery ligation in anesthetized cats. Experimental groups included normal control cats subjected only to coronary ligation and cats pretreated with atropine, pertussis toxin (PTX), or propranolol. All cats received bilateral cervical vagal stimulation (Vstim) at 1, 3, and 5 Hz for 1 minute at 10-minute intervals. Before coronary ligation, Vstim slowed sinus rate, prolonged the PR interval, and lowered blood pressure. Most important from the point of view of electrophysiological function was a vagally induced acceleration of ventricular repolarization in paced and unpaced hearts, which could be explained by the effects of acetylcholine (ie, shortening the subepicardial muscle action potentials). The effect on repolarization was blocked by atropine or PTX but not by propranolol. The extent of sinus slowing and acceleration of repolarization was directly related to the level of functional PTX-sensitive G protein (P < .05). Coronary occlusion was performed during atrial pacing such that the heart rate in all groups was equal. The incidence of ventricular fibrillation (VF) was 10% in the control group and 50% and 54% in atropine and PTX groups, respectively (P < .05). During atrial pacing before coronary occlusion, a vagal index was calculated as percent QTc shortening during Vstim. When the vagal index was 13% to 26%, the incidence of VF during occlusion was zero. When the vagal index was 0% to 12%, VF was 52% (P < .01). Conclusions are as follows: (1) Vstim accelerates ventricular repolarization in cats via a pathway that incorporates a PTX-sensitive G protein and involves an altered gradient between epicardium and endocardium. (2) Removal of vagal tone during ischemia favors VF, as predicted by a vagal index.

Acetylcholine↗
PubMed1993

Chronotropic and dromotropic actions of acetylcholine on the developing fetal heart.

We studied the effect of acetylcholine (ACh), 1 x 10(-8) to 5 x 10(-7) M, on electrophysiologic characteristics of the isolated (Langendorf), perfused fetal canine heart. ACh induced concentration-dependent decreases in sinoatrial (SA) rate and recovery from overdrive pacing and in atrioventricular (A-V) conduction. These effects of ACh were greater in mid-gestation than late-gestation hearts. The effects of ACh were potentiated by inhibition of acetylcholinesterase by neostigmine, 1 x 10(-7) M, in the late- but not the mid-gestation fetal heart. Decreasing the pH of the perfusion solution from 7.3 to 6.8 potentiated the response to ACh of SA rate and A-V conduction more in mid- than in late-gestation hearts. The response to ACh of the late-gestation fetal canine heart is more sensitive to cholinesterase inhibition whereas the response of the mid-gestation heart is more sensitive to the action of ACh in the presence of acidosis.

Acetylcholine↗
PubMed1991

Anatomic distribution of autonomic neural tissue in the developing dog heart: II. Nonadrenergic noncholinergic innervation by calcitonin gene-related peptide-immunoreactive tissue.

We used immunocytochemical localization of calcitonin gene-related peptide (CGRP) to trace the ontogenesis and anatomic distribution of this component of nonadrenergic noncholinergic (NANC) innervation in fetal, neonatal, and mature canine hearts and autonomic ganglia which control cardiac function. Rare varicose CGRP-immunoreactive nerve processes were present in the heart during late gestation. Abundant CGRP-immunoreactive neural tissue in the neonate suggested a burst of NANC innervation around birth. Neonatal, 1-, and 2-month-old animals all had many varicose individual nerve processes in addition to processes within bundles; however, the density of all CGRP-immunoreactive tissue appeared to decrease during this stage of development. Similarly, there were relatively more varicose stained nerve processes in the epicardial ganglia and numerous CGRP-immunoreactive cells and smooth nerve processes in the stellate ganglia of the neonate, as compared with older animals. In the mature animal CGRP-immunoreactive neural tissue in the heart was more sparse and largely confined to heterogeneous nerve bundles in the epicardium. The extramural coronary arteries were virtually the only site of innervation by individual nerve processes; CGRP-immunoreactive neural tissue was not found adjacent to working cardiac muscle fibers. At all developmental stages, the area of the sinoatrial node was the primary focus of CGRP innervation, although the atrioventricular nodal region was also preferentially innervated. In general, the atria contained more CGRP-immunoreactive tissue than the ventricles, which were only sparsely innervated. The perinatal peak in density of CGRP-immunoreactive neural tissue with subsequent decline to reach the adult pattern suggests a developmental role for NANC innervation in the dog heart.

Aging↗
PubMed1991

Mechanical and electrophysiologic changes in rat cardiac allografts during immunologic rejection.

We studied the relationship between immunologic rejection and changes in contractility of isolated perfused papillary muscle, using heterotopically transplanted rat hearts. Rejection assessed by mononuclear cell infiltration was associated with depressed twitch amplitude and lower rates of tension development and relaxation. The relationship between maximum developed tension and [Ca2+]o was attenuated in muscle from the rejecting allografted heart, as compared with muscle of normal or isografted hearts. To determine the effects of rejection on ventricular electrophysiologic properties, we recorded transmembrane action potentials in isolated ventricular myocardium. We found that in rejecting allografted hearts the resting potential, action potential amplitude, and maximum upstroke velocity of phase zero were significantly reduced compared with normal and isografted hearts. The attenuation in the mechanical and electrophysiologic properties was largely prevented by treating the transplanted rat with anti-lymphocyte-globulin on days 0, 1, and 2 after transplantation. In summary, the present study demonstrates that immunologic rejection of the heterotopically allotransplanted rat heart is associated with marked attenuation of both mechanical and electrophysiologic properties of the ventricular myocardium.

Action Potentials↗
PubMed1991

Beta-adrenergic receptor sensitivity and guanine nucleotide regulatory proteins in transplanted human hearts and autotransplanted baboons.

This study was conducted in human subjects and in baboons to assess elements of the beta-adrenergic receptor complex in vivo and in vitro following cardiac transplantation. In human subjects, the concentration at which administered isoproterenol increased heart rate by 25 beats per min was within the normal range (mean, 3.2 +/- 0.4 micrograms). Myocardial biopsies and lymphocytes were obtained from 14 transplant recipients undergoing routine right heart catheterization. The stimulatory guanine nucleotide regulatory protein, Gs, was significantly greater in the lymphocyte than in right ventricular myocardium (5.8 +/- 1.7 vs. 2.0 +/- 0.5 relative to standard rat heart membrane preparation, P less than 0.05). In contrast, Gi was significantly greater in the myocardium than in the lymphocyte (4.2 +/- 1.3 vs. 1.1 +/- 0.3, P less than 0.025). There was no correlation between lymphocyte and cardiac G protein determinations. In the autotransplanted baboon heart, beta-receptors were increased (73 +/- 4 vs. 36 +/- 10 fmol/mg, P less than 0.05). Gs was not significantly different in denervated myocardial tissue vs. control cardiac tissue (1.1 +/- 0.2 vs. 0.8 +/- 0.2, P greater than 0.05). However, the inhibitory G protein, Gi, was significantly greater in transplanted animals (0.4 +/- 0.1 vs. 0.2 +/- 0.04, P less than 0.05). Relative enrichment of a Gi-like protein in the autotransplanted baboon heart was associated with a non-statistically significant trend towards a uniform reduction in basal and Gs-mediated adrenergic effects on adenylate cyclase activity. Despite the lack of biochemical evidence of enhanced beta-adrenergic receptor-mediated adenylate cyclase coupling, denervation in the autotransplanted baboon was associated with in vitro evidence of chronotropic and inotropic supersensitivity to isoproterenol. The results call into question the notion of adrenergic hypersensitivity in human subjects following cardiac transplantation, indicate the potential role for guanine nucleotide regulatory proteins in mediating responses of the denervated heart, and distinguish between several characteristics of the chronically denervated, transplanted human heart compared with the acutely auto-denervated of the baboon heart.

Adenylyl Cyclases↗
PubMed1991

Nonadrenergic noncholinergic innervation. Anatomic distribution of calcitonin gene-related peptide-immunoreactive tissue in the dog heart.

Calcitonin gene-related peptide (CGRP) has inotropic and chronotropic effects in rat and guinea pig hearts. It also may mediate nonadrenergic noncholinergic regulation of canine cardiac electrophysiology. In this study, immunohistochemistry was used to determine the anatomic distribution of CGRP in mature dog heart and autonomic ganglia controlling cardiac function. The stellate ganglia had scattered CGRP-immunoreactive cells and nerve processes; intracardiac ganglia contained stained nerve processes but no CGRP-immunoreactive cells. Although the extramural coronary arteries were modestly innervated by varicose individual nerve processes, the great majority of CGRP-immunoreactive neural tissue in the heart existed adjacent to the sinoatrial node where varicose nerve processes coursed in numerous large nerve bundles. Each bundle contained only a few stained processes, however, indicating that CGRP-immunoreactive nerve processes were accompanying another type of autonomic tissue. Double staining and immunoultrastructure confirmed that the nerve bundles were heterogeneous. Similar nerve bundles were fewer in the left atrium, the region of the atrioventricular node, atrioventricular bundle, and the ventricles. In contrast to the distribution of sympathetic neural tissue, CGRP-immunoreactive nerve processes virtually were nonexistent among muscle fibers. We conclude that 1) CGRP-immunoreactive neural tissue likely affects sympathetic and parasympathetic ganglia that control cardiac function, 2) the preponderance of this nonadrenergic noncholinergic tissue near regions of specialized muscle (especially the sinoatrial node) suggests an efferent function in the canine heart, and 3) the presence of varicosities along CGRP-immunoreactive nerve processes within heterogeneous nerve bundles may indicate that direct axo-axonal contact is the mechanism by which these nonadrenergic noncholinergic nerve processes modulated other autonomic neural tissue.

Animals↗
PubMed1990

Anatomic distribution of autonomic neural tissue in the developing dog heart: I. Sympathetic innervation.

We used immunocytochemical localization of tyrosine hydroxylase to trace the ontogenesis and anatomic distribution of sympathetic innervation in fetal, neonatal, and mature canine hearts. Sparse tyrosine hydroxylase-positive neural tissue first appeared in the atrium, including sinoatrial and atrioventricular nodes, and the ventricular epicardium at midgestation and progressively increased in extent to reach the adult pattern by 2 months following birth. Sympathetic innervation of the atrioventricular bundle occurred relatively later, with no nerve processes in the neonate but a mature pattern by 2 months. At each developmental stage the atria contained more tyrosine hydroxylase-positive neural tissue than the ventricles. Thus, sympathetic nerve processes appear in the developing canine heart earlier than was previously recognized. The time course of sympathetic innervation as defined by this anatomic study is in accord with electrophysiologic studies indicating progressive neonatal development of sympathetic effect which achieves maturity by 2 months of age.

Animals↗
PubMed1990

Sympathetic neural modulation of cardiac impulse initiation and repolarization in the newborn rat.

We injected neonatal rats with nerve growth factor, the antiserum to nerve growth factor, or placebo for the first 10 days of life. Our goal was to determine the relation between sympathetic innervation of the developing heart, the electrocardiographic expression of cardiac rhythm, and the response of the heart to alpha-adrenergic stimulation with phenylephrine. We were especially interested in the latter area because of the prior demonstration in isolated cell systems of sympathetic neural modulation of a 41-kDa GTP regulatory protein and alpha-adrenergic responsiveness. Ten- to 11-day-old rats treated with nerve growth factor had more complete sympathetic innervation, faster heart rates, and higher levels of the 41-kDa protein than the placebo group. Electrophysiological studies were performed on isolated ventricular septa superfused with Tyrode's solution at 37.0 degrees-37.5 degrees C. The electrophysiological response of septa to 10(-9) and 10(-8) M phenylephrine from the 10-11-day-old nerve growth factor group was comparable with that of 3-week-old control animals. In contrast, 10-11-day-old antiserum-treated rats had an abnormal innervation pattern, lower levels of the 41-kDa protein, and a more immature electrophysiological response to alpha-adrenergic stimulation than the placebo group. In addition, antiserum-treated rats had an abnormally prolonged electrocardiographic QT interval. Our results demonstrate for the first time in intact animals a direct link between sympathetic innervation and alpha-adrenergic receptor-effector coupling as well as the dependence on innervation of the modulation of impulse initiation by alpha-agonists. This sequence of developmental events may be important not only in the regulation of normal cardiac rhythm but also in the expression of certain pathological entities such as the congenital long QT syndrome and the sudden infant death syndrome.

Animals↗
PubMed1990

Developmental changes in the muscarinic stimulation of canine Purkinje fibers.

Acetylcholine (ACh) hyperpolarizes adult canine Purkinje fibers and induces a decrease in their automaticity. In Purkinje fibers from young dogs, there is a biphasic effect on automaticity, which increases at low and decreases at high ACh concentrations. We used standard microelectrode techniques to study these actions of ACh. In fibers from young dogs, 10(-10) to 10(-9) M ACh increased automaticity and 10(-5) M ACh decreased automaticity. The decrease was blocked by the M2 muscarinic blocker AFDX-116, whereas the increase was blocked by the predominant M1 blocker pirenzepine. The M2 agonist oxotremorine never increased automaticity. Rather, it decreased automaticity and hyperpolarized adult and young fibers, the former more than the latter. The hyperpolarization and biphasic effect on automaticity of ACh in fibers from young dogs failed to occur after treatment with pertussis toxin, suggesting that these effects are dependent on a pertussis toxin-sensitive G protein. These electrophysiologic studies suggest that postsynaptic M1 and M2 muscarinic processes modulate the automatic response of Purkinje fibers from young dogs and that the postsynaptic M1 pathway is no longer seen in the adult.

Acetylcholine↗
PubMed1988

A canine model of torsades de pointes.

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.

Aconitine↗
PubMed1988

Sympathetic neural and alpha-adrenergic modulation of arrhythmias.

alpha 1-Adrenergic stimulation of the neonatal heart may induce either an increase or a decrease in ventricular automaticity, with the latter response predominating as age increases. We used isolated tissues from the hearts of neonatal and adult dogs and rats, as well as rat myocytes in tissue culture alone or in coculture with sympathetic nerves, to study the role of sympathetic innervation in modulating the alpha-adrenergic response. In the absence of sympathetic innervation, alpha-adrenergic stimulation uniformly increases automaticity. As the myocyte is innervated, an increased quantity of a GTP regulatory protein is detectable. That this protein is an essential transducer of alpha-adrenergic inhibition of automaticity is evidenced by the conversion of the alpha response from excitatory to inhibitory as the protein develops. ADP-ribosylation of the protein with pertussis toxin causes the alpha response to revert to excitation in both adult canine hearts and innervated myocytes in tissue culture. Hence, we have evidence for sympathetic modulation of cardiac rhythm via a regulatory protein whose function depends on normal neuronal development. Abnormal development of innervation may predispose to arrhythmogenesis via persistence of a primitive response to alpha stimulation.

Animals↗
PubMed1988

Developmental changes in the effects of nadolol on adult and neonatal canine Purkinje fibers.

We used standard microelectrode techniques to determine developmental differences in the direct membrane and beta-blocking effects of nadolol on the electrophysiologic properties of adult and neonatal canine Purkinje fibers (PF). To study direct membrane effects, we superfused PF with nadolol 1 X 10(-8)-1 X 10(-4) M while stimulating them at a BCL of 800 ms. Nadolol less than 1 X 10(-5) M had no effect on the transmembrane potential in either age group. Nadolol, greater than or equal to 1 X 10(-5) M, increased action potential duration at 100% repolarization (APD100) in adult fibers and nadolol, 1 X 10(-4) M, decreased Vmax and APD at 50% repolarization (APD50) in neonatal fibers (p less than 0.05). The beta-blocking effects of nadolol were studied by examining the chronotropic response in automatic PF to cumulative doses of l-isoproterenol.HCl 3 X 10(-10)-3 X 10(-6) M, alone and then in the continued presence of nadolol 5 X 10(-8)-5 X 10(-6) M. Nadolol caused a concentration-dependent shift to the right of the concentration-response curve in both age groups. pA2 determinations in adult (7.88) and neonatal (7.57) PF indicated that there was no developmental difference in the affinity of nadolol for the beta-receptor (p greater than 0.05). Our results indicate that nadolol shows developmental changes in its direct membrane effects but not its beta-blocking effects. The latter characteristic differs from that of the more highly lipid-soluble beta-blocker, propranolol. This suggests that different beta-blocking molecules have differing abilities to block the beta-receptor at different ages that are influenced importantly by their lipid solubility.

Action Potentials↗
PubMed1988

Role of a pertussis toxin-sensitive protein in the modulation of canine Purkinje fiber automaticity.

We previously have shown that alpha-adrenergic stimulation of canine Purkinje fibers and rat ventricle decreases automaticity. Experiments on rat ventricular myocytes in tissue culture have suggested that the decrease in automaticity induced by alpha-adrenergic stimulation depends on the development of sympathetic innervation and the presence of a pertussis toxin-sensitive, 41-kDa guanosine triphosphate (GTP)-regulatory protein. In the present study, microelectrode and biochemical techniques were used to test the role of the pertussis toxin-sensitive protein and sympathetic innervation in modulating automaticity of adult canine Purkinje fibers. Fibers were incubated in Tyrode's solution alone or in Tyrode's solution plus pertussis toxin (0.1-0.5 microgram/ml) for 24 hours and were then superfused with phenylephrine. Phenylephrine in the 5 x 10(-9)-5 x 10(-8) M range induced a decrease in automaticity in 63% of the 16 fibers not treated with pertussis toxin and an increase in automaticity in 37%. The former group had a higher level of pertussis toxin-sensitive substrate by the [32P]nicotinamide adenine dinucleotide adenosine diphosphate (ADP)-ribosylation assay than the latter. In contrast, all fibers treated with pertussis toxin (0.5 microgram/ml) showed increased automaticity in response to phenylephrine and had no detectable pertussis toxin-sensitive substrate. Over the range of pertussis toxin concentrations studied, there was a smooth concentration-response relation between the substrate levels measured and the automatic response to phenylephrine. As ADP-ribosylatable substrate levels decreased, the percent of fibers showing an increase in automaticity increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate Ribose↗
PubMed1988

Reduction of Vmax by QX-314 and benzocaine in neonatal and adult canine cardiac Purkinje fibers.

The authors have previously shown that the use-dependent action of lidocaine on the Vmax of canine Purkinje fibers and on intraventricular conduction in the in situ heart undergoes significant developmental changes. In this study, they use standard microelectrode techniques to test whether these age-related differences are due to the charged, more hydrophilic form or to the uncharged, more lipophilic form of a local anesthetic. QX-314, a permanently charged lidocaine derivative, depressed Vmax to a significantly greater extent in adult than in neonatal Purkinje fibers. This difference was due to its use-dependent blocking action and not to its tonic blocking action. The kinetic time constant (tau on) for the development of use dependence was shorter in adults (90 +/- 9 vs. 134 +/- 15 beats; P less than .05), whereas the time constant for recovery from use dependence (tau off) was shorter in neonates (53 +/- 4 vs. 106 +/- 10 sec; P less than .05). QX-314 (3 X 10(-5) M) shifted the curve of Vmax vs. activation voltage in a hyperpolarizing direction by 16.2 +/- 2.4 mV in adults and 5.1 +/- 1.1 mV in neonates (P less than .05). In contrast, the uncharged tertiary amine benzocaine (1 X 10(-5)-5 X 10(-4) M) showed no developmental differences in its effects on Vmax. Adult and neonatal fibers showed comparable tonic block and no use-dependent block. These results extend those of the authors' previous studies and suggest that developmental differences in the action of local anesthetics depend primarily on the use-dependent action of the charged molecular form.

Action Potentials↗