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PubMed1990

[Effects of metoclopramide on Vmax of action potentials in guinea pig papillary muscles].

The effects of metoclopramide (MCP) on Vmax of action potentials of guinea pig papillary muscles were studied with intracellular microelectrodes. MCP 10-550 mumol/L abbreviated the action potential duration at 90% repolarization (APD90) and decreased the maximal rate of rise of action potential (Vmax) dose-dependently. MCP caused rate-dependent and voltage-dependent reductions of Vmax and retardation of the recovery of Vmax. The results present the possible causes of depressant effect of MCP on Na channel.

Action Potentials↗

PubMed1982

Voltage-clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle.

1. We studied the effects of a toxic concentration of ouabain on transmembrane electrical activity and on mechanical behaviour of right ventricular papillary muscles from ferrets in a single sucrose-gap using current clamp and voltage clamp.2. Ouabain (1.4-1.8 muM) induced oscillatory after-potentials and after-concentrations in current-clamp experiments. Voltage clamp showed that the oscillatory after-potential was caused by a transient inward current, similar to that in Purkinje fibres.3. The transient current had a sigmoidal dependence on the preceding (activating) voltage step V1, with a treshold around -13 mV and a plateau between +10 and 20 mV. There was a decline in current amplitude for more positive clamps. When activated by a fixed V1 voltage step, and measured at different repolarization levels V2, the transient current manifested an inverse dependence on V2 between -50 and -10 mV. No outward transient current could be detected. Total replacement of Na in the bathing medium by Tris or by sucrose abolished the transient current.4. Ouabain caused an increase of phasic (twitch) tension responses to voltage steps at all potentials without shifting the curve relating these variables on the voltage axis. The drug evoked an even greater increase in the tonic tension responses.5. After prolonged exposure, oscillatory mechanical responses were frequently recorded during positive voltage steps. Unlike the after-contraction, these mechanical fluctuations were not consistently damped and were not accompanied by detectable synchronous current fluctuations. Catecholamines and dibutyryl cyclic AMP markedly reduced the amplitude of the tonic contraction and the mechanical oscillations but increased their frequency. Caffeine had no effect on the tonic contraction amplitude but abolished the fluctuations.6. These results support the proposal that Ca is transiently released from the overloaded sarcoplasmic reticulum in ouabain-intoxicated muscle and may evoke oscillatory responses in nearby contractile fibrils. When these transient increases of sarcoplasmic free Ca are large enough, they may induce the transient transmembrane current described above.

Animals↗

PubMed1992

Effects of beta-adrenergic blockade on papillary muscle function and the beta-adrenergic receptor system in noninfarcted myocardium in compensated ischemic left ventricular dysfunction.

BACKGROUND: beta-Adrenergic receptor blockade has been reported to improve hemodynamics and beta-adrenergic receptor-adenylate cyclase function in idiopathic dilated cardiomyopathy. The purpose of this study was to determine the effects of beta-adrenergic receptor blockade on the beta-adrenergic receptor system and myocardial function in a model of compensated ischemic heart failure. METHODS AND RESULTS: We examined the effects of propranolol treatment on the beta-adrenergic receptor-adenylate cyclase system and isolated papillary muscle isometric function in noninfarcted left ventricular myocardium in rats after coronary artery ligation. In untreated rats with large myocardial infarction (MI), developed tension (DT) (3.0 +/- 0.7 versus 5.1 +/- 1.1 g/mm2), peak rate of tension rise (+dT/dt) (40.3 +/- 9.5 versus 71.2 +/- 12.0 g/mm2/sec), and peak rate of tension fall (-dT/dt) (24.4 +/- 5.0 versus 38.2 +/- 6.0 g/mm2/sec) were decreased (p < 0.05). In addition, DT, +dT/dt, and -dT/dt of untreated MI rats demonstrated an impaired response to isoproterenol stimulation compared with controls. beta-Adrenergic receptor density (Bmax) measured by [125I]iodocyanopindolol (ICYP) binding was decreased 23% after infarction (9.3 +/- 0.6 versus 12.0 +/- 1.8 fmol/mg protein [prot]) (p < 0.05); however, the dissociation constant (Kd) for ICYP was not changed (24.1 +/- 5.7 versus 33.2 +/- 12.1 pM). Adenylate cyclase activity in the presence of 10(-2) M MgCl2 was reduced (p < 0.05) in MI rats (30.3 +/- 10.8 versus 45.9 +/- 12.5 pmol cAMP/min/mg prot). Maximal isoproterenol (52.5 +/- 7.3 versus 79.9 +/- 10.0 pmol cAMP/min/mg prot), guanyl-5'-imidodiphosphate (GppNHp) (95 +/- 8 versus 141 +/- 25 pmol cAMP/min/mg prot) and forskolin (503 +/- 76 versus 753 +/- 157 pmol cAMP/min/mg prot) stimulation of adenylate cyclase was also decreased (p < 0.05). In addition, manganese-stimulated adenylate cyclase activity was depressed (p < 0.05) in MI rats compared with controls (23.5 +/- 2.8 versus 52.1 +/- 9.0 pmol cAMP/min/mg prot). Chronic propranolol treatment in MI rats improved DT (4.1 +/- 0.9 versus 3.0 +/- 0.7 g/mm2) and +dT/dt (54.4 +/- 11.3 versus 40.5 +/- 9.5 g/mm2/sec) (p < 0.05); however, isoproterenol-stimulated isometric function remained impaired. Propranolol treatment normalized Bmax (11.9 +/- 1.7 versus 9.3 +/- 0.6 fmol/mg prot) (p < 0.05), whereas adenylate cyclase activity remained depressed. CONCLUSIONS: After large MI in rats, there is impaired papillary muscle function with decreased beta-adrenergic receptors and adenylate cyclase activity in the noninfarcted myocardium. Propranolol treatment improved basal isometric muscle function and beta-adrenergic receptor density in rats after myocardial infarction but did not improve adenylate cyclase activity or isoproterenol-stimulated muscle function. These data suggest that there is a primary defect in adenylate cyclase function that persists despite upregulation of receptors with propranolol treatment.

Adenylyl Cyclases↗

PubMed1986

Characterization of human pathological papillary muscles by 1H-NMR spectroscopic and histologic analysis.

Two groups of human pathological papillary muscle samples were analyzed by 1H-NMR spectroscopy and histology. The first group, mainly characterized by hypertrophy of the myocardial cells, interstitial edema and intracellular lipoperoxide accumulation showed similar T1 as well as T2 values. The second group, mainly characterized by hypertrophy of the myocardial cells, fibrosis and areas of necrosis showed T1 values longer than those of the first group while no appreciable differences were evident in the T2 values. These results suggest that a certain degree of correlation exists between the histologic features of the cardiac tissue examined and the relaxation behavior as defined by nuclear magnetic resonance spectroscopy even if a definite association between them is still not possible.

Cardiomyopathies↗

PubMed1991

[The effect of adaptation to stress exposures and to periodic hypoxia on the cardiomyocyte trigger activity of the papillary muscles in the rat].

Action potential of cardiomyocytes was recorded in experiments on isolated papillary muscle of the rat left ventricle. The effect was estimated of preliminary adaptation to intermittent hypobaric hypoxia or to short-term stress exposure on the incidence and the pronouncement of delayed after depolarization and of trigger activity induced by a high frequency stimulation against the background of isoproterenol (10(-8) M). It was shown that adaptation to hypoxia or to stress reduced the incidence of delayed after depolarization and of trigger activity, adaptation to stress exerting a more pronounced effect. Immobilization stress (6 hours) potentiated the trigger activity, adaptation to stress exerting a more pronounced effect. Immobilization stress (6 hours) potentiated the trigger activity and this potentiation was effectively prevented by either type of adaptation.

Action Potentials↗

PubMed1988

Interaction between diltiazem and halothane or enflurane in the canine blood-perfused papillary muscle and sinoatrial node preparations cross-circulated by chronically instrumented conscious donor dog.

Interaction of cardiovascular effects of diltiazem with those of halothane or enflurane was estimated in the canine isolated papillary muscle and sinoatrial node preparations perfused by arterial blood of the chronically instrumented conscious and halothane- or enflurane-anesthetized donor dog, into which diltiazem was infused i.v. at a rate of 20 micro g/kg/min for 60 min. One hour after diltiazem infusion, in the conscious donor dog, mean arterial pressure (MAP) and heart rate (DHR) were decreased to 84 +/- 3 and 84 +/- 2% and PQ interval (PQ) was prolonged to 148 +/- 5%, while in the isolated preparations, developed tension (DT) of the papillary muscle and sinoatrial rate (SAR) were decreased to 68 +/- 3 and 74 +/- 3% and blood flow (BF) was increased to 155 +/- 5% (n = 10). On the other hand, halothane (0.8%) anesthesia per se decreased MAP, DHR, DT and SAR to 89 +/- 8, 84 +/- 3, 79 +/- 3 and 89 +/- 5% (n = 7) of each basal value in conscious state 20 min after the inhalation. During halothane anesthesia, the same dose of diltiazem infused decreased MAP to 74 +/- 4 (n = 7), DHR to 66 +/- 4 (n = 6), DT to 62 +/- 7 (n = 7) and SAR to 69 +/- 1% (n = 3) of each value suppressed by halothane itself. Meanwhile, enflurane (1.7%) anesthesia itself decreased MAP, DHR, DT and SAR to 81 +/- 3, 85 +/- 2, 81 +/- 2 and 88 +/- 2% (n = 10) of each basal value in conscious state 30 min after enflurane inhalation. During enflurane anesthesia diltiazem decreased MAP to 74 +/- 3 (n = 10), DHR to 67 +/- 3 (n = 8), DT to 45 +/- 5 (n = 10) and SAR to 74 +/- 6% (n = 3) of each value under enflurane anesthesia alone. PQ interval of the donor dog heart was prolonged by halothane alone to 111 +/- 5% (n = 7) and by enflurane alone to 110 +/- 2% (n = 10) of the value before each anesthesia, and then diltiazem prolonged PQ interval to 160 +/- 8% (n = 6) and 174 +/- 10% (n = 8) of each value suppressed by the anesthetic itself during halothane- or enflurane-anesthesia, respectively. The second degree AV conduction block was induced in 1 of 7 halothane- and in 2 of 10 enflurane-anesthetized donor dogs, respectively. The sinus arrest was induced by diltiazem in 4 of 7 sinoatrial node preparations under halothane and in 7 of 10 ones during enflurane anesthesia. Moreover, plasma concentration of diltiazem 60 min after the start of infusion was 556 +/- 121 ng/ml in conscious dogs and tended to increase to 752 +/- 101 ng/ml in enflurane anesthetized donor dogs (n = 4), but there was no significant difference between two values (0.05 < P < 0.1). These results indicate that effects of diltiazem could be potentiated during halothane or enflurane anesthesia by elimination of compensatory reflex noted in conscious state, and that the negative inotropic effect of diltiazem was enhanced by enflurane anesthesia due to unknown mechanisms which probably include a slight but insignificant increase in plasma concentration.

Journal Article↗

PubMed1988

Alpha 1-adrenoceptor-mediated phosphoinositide breakdown and inotropic response in rat left ventricular papillary muscles.

alpha 1-Adrenoceptor stimulation of rat left ventricular papillary muscles by phenylephrine in the presence of propranolol resulted in rapid breakdown of phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) and a triphasic inotropic response in a concentration-dependent manner. The release of inositol trisphosphate (IP3) was maximum within 30 seconds and remained high for at least 30 minutes. The IP3 formation was associated with a rapid, but small, increase in contractile force followed by a transient decline in the contractility prior to the development of a sustained and more pronounced positive inotropic response. Inhibition of PI-4,5-P2 hydrolysis by the alpha 1-adrenergic antagonist prazosin or the PI-4,5-P2 phosphodiesterase inhibitor neomycin blocked all components of the inotropic responses. Combined addition of 2,3-diphosphoglyceric acid, a competitive inhibitor of IP3 phosphatase, with phenylephrine doubled the IP3 formation and potentiated the initial phases of inotropic responses but had no effect on the sustained positive inotropic response. Nifedipine and Mn2+ did not block the transient inotropic responses but inhibited the sustained positive inotropic response. alpha 1-Adrenoceptor stimulation resulted in restoration of slow responses in the high K+-depolarized muscles in the time course similar to that of the development in the sustained positive inotropic response. Addition of phorbol-12,13-dibutyrate alone or in combination with caffeine or A23187 failed to produce a sustained positive inotropic effect, but pretreatment with this phorbol ester (1-100 nM) for 30 minutes resulted in dose-dependent potentiation of alpha 1-adrenoceptor-mediated sustained positive inotropic effect associated with enhanced slow responses. These results suggest that the inotropic effects mediated by cardiac alpha 1-adrenoceptor stimulation occur through the phosphodiesteratic cleavage of PI-4,5-P2, such that IP3 may produce transient inotropic effects by mobilizing intracellular Ca2+, while diacylglycerol, along with cofactors that are also generated on alpha 1-adrenoceptor stimulation, may provoke a sustained positive inotropic effect by potentiating slow Ca2+ channels through activation of protein kinase C.

2,3-Diphosphoglycerate↗

PubMed2005

Effects of diazoxide treatments on electrophysiologyic properties in guinea pig papillary muscles undergoing ischemia/reperfusion.

The effects of diazoxide treatments on electrophysiologyic properties in guinea pig papillary muscles undergoing ischemia/reperfusion was studied using intracellular microelectrode technique. Twenty-four guinea pigs were randomly divided into three groups (n=8 in each group). In control group, St. Thomas solution was given. In experimental group, St. Thomas solution with diazoxide (100 mol/L) was given. In pretreatment group, the muscle was treated with diazoxide 20 min before arrested with St. Thomas cardioplegia. The results showed that the APD50 and APD90 in experimental and pretreatment groups were significantly shorter after 5 and 10 min reperfusion (P <0.01, P<0.05), but longer after 30 min reperfusion (P<0.01, P<0.05) than in control group. In experimental and pretreatment groups, APA, OS, Vmax recovered more quickly than those in control group. The time to re-systole after reperfusion in control group was longer than that in experimental and pretreatment groups. There was no significant difference in RP among three groups. The time of arrest in pretreatment group was longer than that in experimental and pretreatment group (P<0.05). This study indicates that protective effects of St. Thomas solution with diazoxide is better than that of pretreatment with diazoxide or St. Thomas solution alone.

Adenosine Triphosphate↗

PubMed1981

Effects of low pH on the action potential and contraction of normal and hypoxic papillary muscles.

The effects of low pH (6.5) on action potentials and contractions of rabbit papillary muscles were examined under aerobic and hypoxic conditions (pO2 = 65- 75 mmHg, 8.6-10.0 kPa). An acid medium reduced overshoot, Vmax of phase O and action potential duration, without changing the resting potential, under aerobic aerobic conditions. Maximum twitch tension was reduced and resting tension was increased by 40% and 6% respectively of control values. Upon returning to normal Tyrode, all parameters returned to control values. The effects of acidosis under hypoxic conditions were essentially the same as those described above; acidosis potentiated the effects of hypoxia. It is concluded that in the given experimental conditions, low pH potentiates the effects of hypoxia on electrical and contractile activity, although probably by different mechanisms. The effects of acid medium on the action potential could be well accounted for the a reduction in slow inward current and by an increase in outward background potassium current, probably in relation to an increase in internal free calcium concentration.

Action Potentials↗

PubMed1986

Daunomycin-induced cardiomyopathy in rabbits: isolated heart and papillary muscle energetics.

Daunomycin was administered to one of each pair of litter mate rabbits at a weekly dosage rate of 40 mg/m2. Treated animals were killed when their pre-ejection period: left ventricular ejection time ratio (PEP:LVET) reached 0.4 and there was other evidence of cardiac abnormalities or when they had received 12 doses of daunomycin. Langendorff-perfused hearts from the treated animals had lower intrinsic heart rates (16%) and decreased coronary resistance (31%) in the arrested state. There was no significant difference between the basal metabolism of the arrested control and treated hearts but the magnitude of the activation component, measured under beating non-working conditions, was depressed by daunomycin. After the whole heart perfusion studies were complete, approximately 2 h after cardiectomy, papillary muscles were dissected out from the right ventricles and mechanical, myothermic and polarographic studies were undertaken. The resting heat production, in support of the whole heart metabolic data, was practically unchanged by the treatment regime. Peak stress development and work output were similar in both the control and treated groups. In energetic terms the slope of the relationship between total stress development and active heat production per beat was unchanged but there was a 21% depression of the activation heat component in the treated animals. Daunomycin treatment had not altered the work output per contraction or significantly changed energy output and hence mechanical efficiency was unaltered. It is clear that 2 h of Langendorff perfusion does not produce any depression of contractile or energetic properties in papillary muscles.

Animals↗

PubMed1981

Effects of disopyramide on transmembrane action potentials in guinea-pig papillary muscles.

The effects of disopyramide on the transmembrane action potential in guinea-pig papillary muscles were studied with special reference to the dependence of the effects on the external concentrations of K+ ([K+]0), stimulation rates, and diastolic intervals. Disopyramide, 2 micrometer, prolonged the 90% action potential duration (ADP90) without changing the maximum rate of phase 0 depolarization (Vmax) (class 3 action), whereas disopyramide, 20 micrometer, reduced Vmax, (class 1 action). The class 3 action was prominent in 2.7 and 5.4 mM [K+]0, at 0.25--1 Hz, and so was the class 1 action in 8.1 mM [K+]0, at 2--5 Hz. Disopyramide, 20 micrometer, enhanced the rate-dependent reduction in Vmax only in 8.1 mM [K+]0. Neither concentration of disopyramide altered the recovery kinetics of APD90 in the premature responses in three [K+]0, but slowed that of Vmax only in 8.1 mM [K+]0. These results indicate that the manifestation of class 3 action of disopyramide is favored with low concentrations of the drug, low [K+]0, and low stimulation rates, whereas the reverse is true in the class of the class 1 action.

Action Potentials↗

PubMed1987

Time course of aerobic recovery after contraction of rabbit papillary muscle.

The time course of oxygen uptake after isometric twitch contractions of isolated rabbit papillary muscles was determined at 20 degrees C by continuous polarographic measurement of the partial pressure of oxygen in a 219-microliters glass chamber in which the fluid circulated rapidly. The response time of the oxygen-measuring system was characterized by a delay of 1.1 s and a time constant of 2.1 s after that delay. Depending on the stimulation frequency (0.125-1.0 Hz) the total amount of oxygen uptake for 120 twitches varied from 5.3 to 32.7 nmol/mg dry wt, and the steady-state oxygen consumption rate varied from 0.4 to 8.5 nmol X min-1 X mg dry wt-1. On the basis of a diffusion model we eliminated the effect of oxygen storage on the measured time course of oxygen consumption to determine the mitochondrial kinetics. We found a time constant of an average 19-22 s of mitochondrial off kinetics. By use of this time constant for the change in oxygen consumption rate after contraction, it can be estimated that 9-10% of the oxygen required to restore ATP levels is already taken up by the mitochondria during the twitch.

Animals↗

PubMed1989

[Acute pulmonary edema due to dysfunction and/or rupture of the papillary muscles in patients with coronary insufficiency. Surgical results].

Acute mitral regurgitation due to severe papillary muscle dysfunction or rupture has a poor clinical outcome and often requires an emergency surgical procedure. Pulmonary venous congestion generally occurs as an end-stage event and in these patients surgery is often postponed or even not considered. We studied 14 consecutive patients with coronary artery disease that suffered acute pulmonary edema soon after mitral regurgitation was diagnosed; they were 8 (57%) male and 6 (43%) female with mean age 60-8 years (49 to 69 years). Five patients had an acute myocardial infarction and 9 had an old infarction or stable angina. Surgical treatment was indicated to all patients: mitral valve replacement or reconstructive procedure (annuloplasty) was the only procedure in 2 patients and was associated to coronary artery revascularization in the other 12. Two patients (14.3%) with acute myocardial infarction died in hospital; the remaining 12 (85.7%) had hospital discharge and did well in the late follow-up period. We concluded that this high-risk group of patients is particularly suitable for surgical management since medical treatment carries a very poor prognosis.

Acute Disease↗

PubMed1987

Analysis of the inotropic effect of prenalterol in papillary muscles from guinea-pig hearts.

The inotropic effects of prenalterol were studied in papillary muscles isolated from the right ventricle of guinea-pig hearts. Force production and action potential were recorded. The preparations were paced at 0.4 Hz (at 31-32 degrees C) under isometric conditions. Prenalterol, in concentration 0.1 microM did not change the action potential duration whereas the peak force and the maximum rate of force development increased by 40.3 and 36.3%, respectively. Time to peak force was slightly shortened (-3.0%) and so was the time from peak force to half relaxation (-5.2%). A predetermined stimulus protocol was used for assessment of the recirculation fraction of activator calcium. At selected times an extra contraction was introduced in order to obtain contractile potentiation. Force of the subsequent two test contractions (after fixed intervals) was analysed. Prenalterol slightly reduced the decay of the postextrasystolic potentiation measured in the two test contractions. It is suggested that the inotropic effect of prenalterol is due to an intensified calcium influx during the action potential, and to some extent to more efficient re-utilization of released calcium. There seems to be a more rapid release of calcium from troponin C giving rise to a shortened time to peak force and an enhanced relaxation.

Action Potentials↗

PubMed1990

Inotropic mechanisms of amrinone in papillary muscles from guinea-pig hearts.

Isometric force and action potentials were recorded in papillary muscles from guinea-pigs (temperature 33 degrees C, stimulation frequency 0.5 Hz). Amrinone (1 mM) increased peak twitch force (to 220% of control, n = 12) and rate of rise of force (to 221% of control, n = 12), while time from peak to half-relaxation was markedly reduced (to 70% of control). The time to peak force was not significantly changed. Action potential at 50% repolarization was shortened (93.3% of control, n = 8), whereas plateau voltage became more positive. Peak twitch force in response to a test stimulus after a varied interval, i.e. mechanical restitution, was increased at all intervals by the drug. However, the time to full mechanical restitution (1.5 s) was not affected. Forces in response to the test interval preceding the previous contraction (post-extrasystolic potentiation) were analysed. Maximum potentiation was 16.0 mN mm-2 (2.7 +/- 0.4%) before and 22.6 mN mm-2 (1.7 +/- 0.1%) after addition of the drug, i.e., the relative potentiation was diminished in the presence of the drug. The test interval for optimum potentiation was shortened from 370 to 320 ms (P less than 0.05, n = 12) in 1 mM amrinone. During decay of post-extrasystolic potentiation peak force of the post-potentiated contraction was linearly related to force of the potentiated contraction. The slope of this line (which is believed to monitor recirculation of activator calcium) was increased by amrinone from 0.37 to 0.50 (P less than 0.01, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed2001

Effects of ageing on the activation metabolism of rat papillary muscles.

1. A myothermic technique has been used to investigate the mechanics and energetics of left ventricular papillary muscles from 6-, 15-, 22- and 27-32-month-old Sprague-Dawley rats. 2. There was a significant increase in the left ventricular mass to body mass (LVM:BM) ratio in the senescent. 27-32-month-old group of animals compared with the younger animals (P<0.05). 3. The maximum stress developed in the senescent groups was reduced by almost 40% in comparison with the stress developed by the 6-, 15- and 22-month-old groups (P<0.001). The mean rise time, half relaxation time and half width were increased significantly (P<0.05) in the 22-month-old group but, unexpectedly, this effect was not seen in the senescent group. 4. Heat production per beat versus total stress relationships were obtained in two different ways to determine the magnitude of the activation heat and the isometric economy (given by the slope of the relationship). The activation heat was not significantly different between groups with either method, but there was a significant increase (P<0.001) in the economy with which stress was developed in the senescent group in comparison with the 6- and 15-month-old groups. 5. A combination of forskolin (2.5-6.5 micromol/L) and high Ca2+ (7.5 mmol/L) was used to increase the energy usage per beat. In the 6- and 15-month-old groups, these agents caused a four-fold increase in the activation heat magnitude compared with a less than two-fold increase in the 22-month-old and senescent groups (P<0.001). There was no effect of forskolin/high calcium on the slope of the heat:total stress relationship. 6. The data suggest that, under conditions known to increase cardiac contractility, there is a reduced ability to cycle calcium in the 22-month-old and senescent groups relative to the young adult 6-month-old and adult 15-month-old groups.

Aging↗

PubMed1976

Relationship between the level of cAMP and the contractile force under stimulation of alpha- and beta-adrenoceptors by phenylephrine in the isolated rabbit papillary muscle.

The time course of changes of the level of 3',5'-cyclic AMP (cAMP) and of the tension developed under stimulation of alpha- and beta-adrenoceptors by phenylephrine was investigated in the isolated rabbit papillary muscle. Furthermore the dose-response relationships for increases of cAMP and of developed tension elicited by phenylephrine were determined. 1. A submaximally effective concentration of phenylephrine (10(-5) M) increased significantly the level of cAMP of the papillary muscle at 15 and 30 s by 45 and 36% respectively; the level of cAMP returned to the control value at 60 s after the administration. The developed tension increased significantly not before 45 s and reached its maximal level at 180 s. 2. When alpha-adrenoceptors were blocked by phentolamine (10(-6) M), the positive inotropic effect of phenylephrine was decreased significantly but the increase of cAMP induced by phenylephrine was not reduced. In the presence of phentolamine the increase of cAMP induced by phenylephrine lasted longer than in the control experiments. 3. The effects of phenylephrine (10(-5) M) both on the level of cAMP and the developed tension mediated via stimulation of beta-adrenoceptors in the presence of phentolamine were enhanced by the phosphodiesterase inhibitor papaverine throughout the course of responses. 4. Phenylephrine produced an increase in developed tension as well as in cAMP. The corresponding dose-response curves run parallel to each other but differed by about 1.5 log units whereby the developed tension was evoked by lower concentrations. Phentolamine (10(-6) M) shifted the curve for the positive inotropic action by about 1.5 log units but did not affect that for increase in cAMP. Therefore, in the presence of the alpha-adrenolytic drug phentolamine the difference between both curves became smaller so that both curves were superimposed. Papaverine (10(-5) M) shifted the whole curve for cAMP upwards and enhanced the maximal contractile response to phenylephrine mediated by stimulation of beta-adrenoceptors. 5. The present results indicate that the positive inotropic action of phenylephrine in lower concentrations (less than 10(-5) M) induced by stimulation of alpha-adrenoceptors is independent of the level of cAMP. The positive inotropic action of the higher concentrations of phenylephrine induced via stimulation of beta-adrenoceptors was preceded by an accumulation of cAMP; the inhibition of the cAMP phosphodiesterase activity by papaverine enhanced the actions of phenylephrine both on the level of cAMP and on the contractile force.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Effects of isoflurane on intracellular calcium and myocardial crossbridge kinetics in tetanized papillary muscles.

BACKGROUND: Isoflurane depresses the intracellular Ca2+ transient and force development during a twitch, but its effects on crossbridge cycling rates are difficult to predict because of the transient nature of the twitch. Measurements of the effects of isoflurane on crossbridge cycling kinetics during tetanic contractions, which provide a steady state level of activation in intact cardiac muscle, have not been previously reported. METHODS: Ferret right ventricular papillary muscles were isolated, and superficial cells were microinjected with the bioluminescent photoprotein aequorin to monitor the intracellular Ca2+ concentration. The rate of tension redevelopment (kTR) was measured during steady state isometric activation (tetanic stimulation, frequency 20 Hz, 1 microM ryanodine, temperature = 30 degrees C) in the absence of isoflurane (2, 6, and 12 mM extracellular [Ca2+]) and in the presence of 0.5, 1.0, and 1.5 minimum alveolar concentration isoflurane (12 mM extracellular [Ca2+]). RESULTS: Intracellular [Ca2+], isometric force, and kTR all increased when the extracellular [Ca2+] increased. Isoflurane (0.5, 1.0, and 1.5 minimum alveolar concentration) caused intracellular [Ca2+], isometric force, and kTR to decrease in a dose-dependent manner in the presence of 12 mM extracellular [Ca2+]. In the presence of increasing concentrations of isoflurane, the relation between intracellular [Ca2+] and force remained unchanged, whereas the relation between intracellular [Ca2+] and kTR was shifted toward higher [Ca2+]. CONCLUSIONS: These results indicate that isoflurane depresses myocardial crossbridge cycling rates. It appears that this effect is partially mediated by a decrease in the intracellular [Ca2+]. However, additional mechanisms must be considered to explain the shift of the relation between intracellular [Ca2+] and kTR toward higher [Ca2+].

Anesthetics, Inhalation↗