Biomedical subjects

H Nawrath

Publications and source records attributed to H Nawrath.

At least 19 recordsLinked to original sources

PubMed1992

Electrophysiologic and inotropic effects of alpha-adrenoceptor stimulation in human isolated atrial heart muscle.

The effects of alpha-adrenoceptor stimulation on force of contraction were investigated in human atrial heart muscle and compared with those of beta-adrenoceptor stimulation. The maximal positive inotropic effect produced by stimulation of alpha-adrenoceptors with phenylephrine (in the presence of atenolol 10 mumol/l) was significantly smaller than that seen in response to beta-adrenoceptor stimulation with isoprenaline. The maximal effect of phenylephrine (25% of the maximal effect of isoprenaline) required far higher concentrations (1 mmol/l) than isoprenaline (100 nmol/l); the EC50 values amounted to 33.1 mumol/l and 3.3 nmol/l, respectively. In the presence of the alpha-adrenoceptor blocking agent phentolamine (1 mumol/l), the concentration-response curve of phenylephrine was displaced to higher concentrations of the agonist; under these conditions, the EC50 value amounted to 52.5 mumol/l. The effects of the catecholamines noradrenaline and adrenaline on force of contraction remained unchanged in the presence of phentolamine (1 mumol/l) or prazosin (1 mumol/l). The positive inotropic effect of phenylephrine (1 mmol/l) was associated with a slight decrease in action potential duration; the effects on action potential were completely blocked in the presence of phentolamine (1 mumol/l). These findings support the view that selective stimulation of alpha-adrenoceptors may mediate a small but detectable positive inotropic effect in human atrial tissue under in vitro conditions. The requirement of high concentrations of alpha-adrenoceptor agonists and the lack of effects of the endogenous catecholamines adrenaline and noradrenaline on alpha-adrenoceptors (in concentrations which fully elicit the beta-adrenoceptors-mediated response) do not provide a basis for a functional role of alpha-adrenoceptor-mediated effects under in vivo conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1992

Modulation of cytosolic free calcium concentration by alpha 1-adrenoceptors in rat atrial cells.

The effects of alpha 1-adrenoceptor stimulation by phenylephrine (PE) and beta-adrenoceptor stimulation by isoprenaline (ISO) on Ca2+ current (ICa) and free intracellular Ca2+ concentration ([Ca2+]i) were studied in isolated atrial myocytes from rat hearts. PE did not significantly affect the magnitude of ICa, whereas large increases of peak ICa were observed in response to ISO. In electrically driven cells, PE evoked a concentration-dependent, gradual increase in diastolic [Ca2+]i and, initially, an increase in the height of peak [Ca2+]i transients. When the diastolic [Ca2+]i was increased to a greater extent, the amplitude of [Ca2+]i transients was decreased. Simultaneous measurements of [Ca2+]i and membrane potential showed that the increase in diastolic [Ca2+]i was associated with a depolarization of the membrane, and the greater amplitude of [Ca2+]i transients with a prolongation of the action potential (AP). The PE-induced increase in diastolic [Ca2+]i was eliminated when the cells were voltage-clamped at the original resting membrane potential (RP); under these conditions, an increase in [Ca2+]i transients was observed in response to PE. ISO usually caused larger increases in the amplitude of [Ca2+]i transients with only minor changes in diastolic [Ca2+]i. These results suggest that PE and ISO increase the amplitude of [Ca2+]i transients in rat atrium in different ways. The increase in [Ca2+]i transients in response to beta-adrenoceptor stimulation is commonly thought to be mediated by a greater conductance of voltage-dependent Ca2+ channels causing a greater Ca2+ influx and a release of more Ca2+ from the sarcoplasmic reticulum during the AP. The increase in diastolic [Ca2+]i in response to PE is probably a consequence of the depolarization of the membrane, possibly involving the voltage-dependent Na(+)-Ca2+ exchange mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Contribution of both alpha- and beta-adrenoceptors to the inotropic effects of catecholamines in the rabbit heart.

The functional role of alpha-adrenoceptors was investigated in different parts of the rabbit heart. Phenylephrine (PE) caused a marked increase in force of contraction (Fc) and a prolongation of the action potential (AP) in preparations from the left atrium and the right ventricle. The response was less pronounced in the right atrium and in the left ventricle, whereas APs of spontaneously beating sinoatrial preparations remained completely unchanged. Phentolamine as well as the diesters phorbol 12,13 dibutyrate (PDBu) or 12-O-tetradecanoyl-phorbol-13-acetate (TPA) eliminated the effects of PE. The contribution of alpha-adrenoceptors to the effects of adrenaline (Adr) and noradrenaline (NA) on Fc was determined in preparations from the right ventricle. Phentolamine and the phorbol diesters reduced the effects of Adr and NA by about 30 to 60%; the remaining response was abolished by propranolol. It can be derived from our experiments that, in some parts of the rabbit heart, a considerable amount of the effects of Adr and NA is due to the stimulation of alpha-adrenoceptors. The present findings therefore support the view that, in the rabbit heart, the maximally effective drive of the heart requires the stimulation of both alpha- and beta-adrenoceptors. The inhibitory effects of phorbol diesters on the alpha-adrenoceptor-mediated response indicate that the activation of protein kinase C (PKC) specifically uncouples alpha-adrenoceptors from the effector system, whereas the response to beta-adrenoceptor stimulation remains unchanged.

Action Potentials↗

PubMed1992

Adrenoceptor-mediated effects on calcium channel currents are antagonized by 5'-(N-ethyl)-carboxamido-adenosine in guinea-pig atrial cells.

In guinea-pig atrial myocytes, the effects of the adenosine analogue 5'-(N-ethyl)-carboxamido-adenosine (NECA) in the presence of isoprenaline (ISO) on Ca2+ channel activity were analyzed. Single Ca2+ channel currents were recorded from cell-attached patches by application of several hundred 100 ms depolarizing steps. Under control conditions, burstlike activity of channel openings during some depolarizing steps were followed by variably long periods of quiescence (blank sweeps). During superfusion with ISO (100 nmol/l), ensemble-averaged (mean) current was increased by about 150%. The underlying mechanism was found to be a significant increase in the channel availability, defined as the ratio of current-containing sweeps to the total number of sweeps. In addition, the ISO-induced reduction of blank sweeps was combined with slightly but not significantly higher values of the open probability in the current-containing sweeps. Open time and shut time histograms could be fitted by single and double exponential curves, respectively, which remained rather unaffected in the presence of ISO; accordingly, mean open time and mean shut time of the channel were not significantly changed by ISO. After the addition of NECA (1 mumol/l) in the presence of ISO, the ISO-induced increase in mean current was abolished. This effect of NECA on mean current was due to a reduction of the channel availability and a slight decrease in the open probability. The purinoceptor blocking agent 8-phenyltheophylline (10 mumol/l) antagonized the inhibitory action of NECA on the ISO-induced increase in Ca2+ channel activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1992

Positive inotropic response to 5-HT in human atrial but not in ventricular heart muscle.

The effects of 5-hydroxytryptamine (5-HT) on force of contraction (FC), action potential (AP) and calcium current (ICa) were studied in human right atrial and left ventricular heart muscle. 5-HT exerted a concentration-dependent increase in FC in multicellular atrial preparations; the EC50 was approximately 3 x 10(-7) mol/l. Maximal increases in FC (252 +/- 58% of control values; mean +/- SEM, n = 6) were obtained at 5-HT 10(-5) mol/l. At this concentration, ICa was increased four- to sevenfold in enzymatically isolated atrial myocytes. In contrast, ventricular preparations did not respond to 5-HT; FC, AP and ICa remained unaffected. In the same preparations, FC was increased by isoprenaline three- to fourfold. These results confirm the observation that 5-HT induces a positive inotropic effect in the human atrium, possibly mediated by activation of the adenylyl cyclase - cyclic AMP system. Our study demonstrates, however, the complete lack of functional 5-HT receptors, with respect to changes in FC, in the human ventricle. Since the positive inotropic effect of 5-HT in the human heart is obviously restricted to the atrium, our findings question the concept of developing 5-HT receptor agonists for the treatment of heart failure.

Adult↗

PubMed1992

Pharmacology of bipyridine phosphodiesterase III inhibitors.

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity.

Amrinone↗

PubMed1991

Differential electrophysiologic and inotropic effects of phenylephrine in atrial and ventricular heart muscle preparations from rats.

Stimulation of alpha 1-adrenoceptors evokes a different pattern of inotropic responses in atrial and ventricular heart muscle preparations from rats. The inotropic effects are accompanied by different changes in membrane potential. In an attempt to clarify the question whether or to which extent these events are causally related, the effects of phenylephrine on force of contraction, transmembrane potential, Ca2+ current (ICa) and K+ currents were comparatively studied in either tissue. In atrial preparations, phenylephrine 10 mumol/l caused an increase in force of contraction, a marked prolongation of the action potential duration and a depolarization of the membrane at rest. In the ventricle, however, the addition of phenylephrine 10 mumol/l produced first a decline in force of contraction associated with a hyperpolarization of the membrane and a reduction in the action potential duration. These changes were followed by an increase in force of contraction and a slight prolongation of the action potential, whereas the resting membrane potential remained increased. The hyperpolarization was eliminated in the presence of ouabain 100 mumol/l. In enzymatically isolated atrial and ventricular myocytes, the whole-cell voltage clamp technique was used to study membrane currents on exposure to phenylephrine. Phenylephrine 30 mumol/l did not affect the magnitude of ICa in either cell type. Transient and steady state K+ outward currents, however, were significantly diminished to a similar extent in atrial and in ventricular myocytes. It is concluded that the positive inotropic effect of alpha 1-adrenoceptor stimulation in the rat atrium is related to an increase in action potential duration and a decrease in resting membrane potential due to a decrease in K+ currents.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1991

Depolarization-induced influx of sodium in response to phenylephrine in rat atrial heart muscle.

1. The effects of alpha 1-adrenoceptor stimulation on transmembrane potential, currents and ion fluxes were investigated in multicellular preparations and/or single cells obtained from the left atrium of rat hearts. 2. In multicellular preparations, phenylephrine caused a concentration-dependent positive inotropic effect, an increase in action potential duration, and a decrease in resting potential; the effects were antagonized by phentolamine. 3. In the presence of phenylephrine (100 mumol/1), two levels of resting potential were observed when the preparations were, alternately, electrically stimulated or kept at rest (-74 +/- 1 mV during activity and -62 +/- 4 mV at rest; mean +/- S.E.M.; n = 9). 4. In resting preparations, the depolarization in response to phenylephrine was eliminated in low-Na+ solution (12 mmol/l) and antagonized by tetrodotoxin (10 mumol/l). 5. The phenylephrine-induced depolarization was also seen in nominally Ca(2+)-free solution and in the presence of (-)-devapamil (1 mumol/l). 6. The alkylating agent N-ethyl-maleimide (30 mumol/l) abolished the depolarizing effect of phenylephrine. 7. Phorbol 12,13-dibutyrate (10 mumol/l) also abolished the depolarizing effect of phenylephrine. 8. Phenylephrine caused a significant increase of 22Na+ uptake in resting preparations and of 45Ca2+ uptake in beating preparations. 9. The depolarizing effect of phenylephrine was also observed in single atrial myocytes. Steady-state membrane currents in response to 500 ms depolarizing and hyperpolarizing voltage clamp steps were decreased. The cross-over of I-V curves under control and test conditions was at about -70 mV. The effects of phenylephrine were antagonized in the presence of phentolamine. 10. After suppression of potassium currents by substitution of CsCl for internal and external KCl ([KCl]o), phenylephrine had no effect on membrane currents. 11. In conclusion, we presume the following sequence of events in response to phenylephrine in rat atrial heart muscle. First, the stimulation of alpha 1-adrenoceptors decreases the K+ conductance thereby producing a depolarization in the presence of an inward current. Second, the change of the membrane potential in the depolarizing direction induces a TTX-sensitive Na+ window current which further propels the depolarization. Third, the increase in Na+ influx may increase Ca2+ influx by activating the Na(+)-Ca2+ exchange in mechanism. The greater influx of Ca2+ may contribute to the positive inotropic effect in response to phenylephrine.

Action Potentials↗

PubMed1990

Effects of papaverine on human isolated bladder muscle.

Papaverine is a non-specific smooth muscle relaxant and is thought to act at a site beyond the receptor sites on the cell membrane. In this study the relaxing properties of papaverine were tested in isolated muscle strips from the human bladder dome. In carbachol-induced contractions papaverine, even in high concentrations of 10(-4) mol/l had virtually no effects on peak tension generation, whereas the fading was accelerated and the steady state tension at 30 min. was reduced by about 54%. In contrast, high potassium-induced contractions were relaxed by papaverine in a concentration-dependent way; a concentration of papaverine of 10(-4) mol/l produced full relaxation. These findings might possibly be explained if it is assumed that papaverine blocks calcium ion channels in the cell membrane. However, the observation that rather high concentrations of papaverine were necessary to fully relax high potassium contractions and the fact, that papaverine affects cellular cAMP levels separate this drug from more selective calcium channel blockers. The calcium movements responsible for the peak tension generation in carbachol-induced contractions are obviously not affected by papaverine. Although papaverine had little effect on carbachol-induced contractions in vitro it cannot be excluded that the drug is effective in diseases were non-cholinergic mechanisms are involved.

Calcium Channel Blockers↗

PubMed1989

Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle.

The opioid agonists morphine (selective for mu-receptors) and ethylketocyclazocine (selective for kappa-receptors), at concentrations evoking strong effects in neuronal structures, did not significantly affect the configuration of the intracellularly recorded action potential and the force of contraction in ventricular heart muscle isolated from guinea pigs, rabbits and man. These results suggest that any changes of heart functions in vivo in response to opioid-like drugs are probably not mediated postsynaptically at the myocardial cell membrane but rather presynaptically, influencing the release of noradrenaline and/or acetylcholine from the nerve terminals.

Acetylcholine↗

PubMed1989

Stimulation of calcium uptake by norepinephrine or high external potassium in human calyces and renal pelvis.

The effects of stimulation with either 10 mumol/l norepinephrine or 85 mmol/l extracellular potassium concentration on calcium uptake were studied in muscle strips from human renal calyces and from the renal pelvis. The apparent uptake of calcium under control conditions was essentially complete after 30 min. Stimulation of the muscle strips with norepinephrine or high external potassium significantly (P less than 0.05) increased the calcium uptake over the control values at 30 and 100 min, whereas 45Ca efflux was virtually not affected. It is concluded that the mechanical responses of the muscle strips to norepinephrine or high external potassium correspond with an increased uptake of calcium suggesting that both types of activation are mediated by an increase of intracellular calcium concentration similar to that described in other smooth muscles.

Calcium↗

PubMed1989

Stimulation of voltage-dependent contractions by calcium channel activator Bay K 8644 in the human upper urinary tract in vitro.

The effects of calcium agonist Bay K 8644 on mechanical activity were studied in isolated preparations of the human upper urinary tract. Bay K 8644 increased the amplitude of phasic-rhythmic contractions in calyceal segments in a concentration-dependent way. In inactive and unstimulated ureteral muscle strips, Bay K 8644 did not induce contractions. After depolarization of ureteral segments with an extracellular potassium concentration of 48 mmol./l., Bay K 8644 produced a concentration-dependent increase of contractile force and enhanced phasic-rhythmic activity. The EC50 of the drug was 7.23 X 10(8) mol./l. The potassium and calcium concentration-response-curves were shifted to the left and the maximum force development was increased. Tonic contractions induced by norepinephrine in calyceal and pelvic segments were not affected by Bay K 8644, but the tendency for phasic-rhythmic activity was increased. In contrast to calcium-antagonistic dihydropyridines like nifedipine, the dihydropyridine derivative Bay K 8644 displayed completely opposite effects, which are obviously limited to voltage-induced activation. These observations can be explained by assuming that these agents act at sites that are components or are associated with voltage-controlled calcium channels. Occupation of these sites may either increase (Bay K 8644) or decrease (nifedipine) the transmembrane calcium flux into the cell.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1989

Adrenoceptor-mediated changes of excitation and contraction in isolated heart muscle preparations.

The inotropic effects of sympathetic stimulation on the heart are mainly ascribed to the activation of beta-adrenoceptors. However, several findings suggest that alpha-adrenoceptors also may help mediate the inotropic response to catecholamines under certain conditions. The onset of the positive inotropic effect mediated by beta-adrenoceptors occurs within seconds and is associated with a faster rate of relaxation. Both beta 1- and beta 2-adrenoceptors are stimulatorily coupled to the enzyme adenylate cyclase, thereby leading to the generation of cyclic AMP. Cyclic AMP increases the slow inward calcium current and enhances the uptake of calcium into the sarcoplasmic reticulum. GTP-binding protein Gs is important for the transmembrane signal transduction. Muscarine and adenosine receptors are inhibitorily coupled to adenylate cyclase, thereby decreasing the inotropic response to catecholamines. Another GTP-binding protein, Gi, is involved in this pathway. The stimulation of the myocardium through the activation of alpha-adrenoceptors seems to differ both qualitatively and quantitatively. Myocardial alpha-adrenoceptors of most species are, if existent, predominantly of the alpha 1-subtype; the functional role of these receptors obviously considerably varies among species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Characterization of adenosine receptors in guinea-pig isolated left atria.

1. The effects of purinergic stimulation on action potential, force of contraction, 86Rb efflux and 45Ca uptake were investigated in guinea-pig left atria. 2. Adenosine exerted a negative inotropic effect which was antagonized by adenosine deaminase but enhanced by dipyridamole. 3. The negative inotropic effect of adenosine was mimicked by 5'-(N-ethyl)-carboxamido-adenosine (NECA) and the isomers of N6-(phenyl-isopropyl)-adenosine, R-PIA and S-PIA. NECA and R-PIA were about 100 times more potent than adenosine, whereas R-PIA was about 100 times more potent than S-PIA. 4. The inotropic effects of adenosine (in the presence of dipyridamole), NECA, R-PIA and S-PIA were competitively antagonized either by theophylline (pA2 about 4.5) or 8-phenyltheophylline (pA2 about 6.3). 5. NECA and R-PIA shortened the action potential duration and increased the rate constant of the efflux of 86Rb in a concentration-dependent manner with no differences in potency; the effects were competitively antagonized by 8-phenyltheophylline. 6. Barium ions reduced the efflux of 86Rb under control conditions and antagonized the increase induced by NECA and R-PIA. 7. NECA and R-PIA significantly reduced 45Ca uptake in beating preparations. 8. It is concluded that adenosine, NECA and R-PIA activate a common receptor population (P1 or A3) on the outside of the cell membrane of atrial heart muscle to increase the potassium conductance and to reduce the action potential and, thereby, calcium influx and force of contraction.

Action Potentials↗

PubMed1989

Pronounced cholinergic but only moderate purinergic effects in isolated atrial and ventricular heart muscle from cats.

1. The effects of cholinergic and purinergic stimulation on action potential, force of contraction and 86Rb efflux were investigated in cat atrial and/or ventricular heart muscle. 2. Acetylcholine and carbachol exerted a concentration-dependent negative inotropic effect in cat atrial heart muscle. Carbachol 10 mumol l-1 completely abolished the force of contraction and increased the rate constant of 86Rb efflux 2-3 fold, whereas the action potential duration was shortened to about 1/10 of its length under control conditions. 3. The effects of acetylcholine and carbachol in cat atrial heart muscle were mimicked, qualitatively, by adenosine and its analogues 5'-(N-ethyl)-carboxamido-adenosine (NECA) and (-)-N6-(R-phenyl-isopropyl)-adenosine (R-PIA). Maximal purinergic effects, however, amounted to about 15-50% in comparison to those of cholinergic stimulation. 4. In cat ventricular heart muscle, cholinergic or purinergic stimulation had no significant effects on the force of contraction in the absence of a cyclic AMP-dependent positive inotropic effect. Carbachol antagonized the positive inotropic effect elicited by either 3-isobutyl-1-methylxanthine, isoprenaline or cyclic 8-(4-chlorphenylthio)adenosine-3':5'-monophosphate; NECA and R-PIA were less effective. The inhibition by carbachol of the effects of isoprenaline was not related to a change in the rate constant of 86Rb efflux. 5. It is concluded that the effects of cholinoceptor and purinoceptor agonists in the cat heart involve a change in the potassium conductance in the atrium, whereas the effects in the ventricle may be related to changes of intracellular cyclic AMP levels. It seems reasonable to assume that, in comparison to cholinergic stimulation, a low density of purinoceptors in the cat heart is responsible for the relatively weak effects of adenosine agonists in this species.

Acetylcholine↗

PubMed1989

Functional role of cholinoceptors and purinoceptors in human isolated atrial and ventricular heart muscle.

1. The effects of cholinergic and purinergic stimulation on action potential, force of contraction and 86Rb efflux were investigated in human atrial and ventricular heart muscle. 2. In atrial heart muscle, carbachol and (-)-N6-(R-phenyl-isopropyl)-adenosine (R-PIA) and 5'-(N-ethyl)-carboxamido-adenosine (NECA) evoked transient decreases of action potential duration and force of contraction; the steady-state effects on force of contraction were virtually identical to control values. In the presence of propranolol, steady-state values after carbachol, R-PIA or NECA amounted to about 50% of control values. 3. In ventricular heart muscle, carbachol, NECA and R-PIA did not significantly affect the action potential configuration or force of contraction. 4. Carbachol, NECA and R-PIA induced a maintained depression of the positive inotropic response to isoprenaline in both atrial and ventricular heart muscle. 5. The rate constant of 86Rb efflux was slightly increased by carbachol, NECA and R-PIA in atrial (10-20%) but not in ventricular heart muscle. 6. In the presence of isoprenaline, carbachol, NECA and R-PIA did not significantly affect the rate constant of 86Rb efflux in both atrial and ventricular heart muscle. Isoprenaline alone increased the rate constant of 86Rb by about 25% in both tissues.

Action Potentials↗

PubMed1988

Tetrodotoxin slightly shortens action potential duration in ventricular but not in atrial heart muscle.

Tetrodotoxin (TTX), at concentrations significantly decreasing maximal upstroke velocity (dV/dtmax) of the action potential, exerted variable effects on action potential duration (APD) in different myocardial preparations. APD was virtually unchanged by tetrodotoxin in the guinea pig atrium, but slightly shortened in the guinea pig ventricle at maximally effective concentrations. In the human ventricle, both dV/dtmax and APD were reduced in the same concentration range of TTX. These results suggest that a TTX-sensitive sodium current significantly contributes to the repolarization phase of the action potential in ventricular but not in atrial heart muscle.

Action Potentials↗

PubMed1988

Analysis of the hyperpolarizing effects of forskolin in guinea-pig atrial heart muscle.

The effects of forskolin on action potential configuration and on both uptake and efflux of 86Rb+ were studied in guinea-pig left atria. The action potential was prolonged by forskolin in the plateau range but shortened at the end of repolarization; maximal upstroke velocity and amplitude of slow response potentials were enhanced. In partially depolarized preparations, the resting potential was increased by forskolin; this effect was not prevented by atropine 1 mumol/l. Forskolin augmented the rate constant of 86Rb+ efflux in beating and in resting preparations. The uptake of 86Rb+ was enhanced by forskolin in resting preparations. It is concluded that forskolin stimulates the Na+,K+-pump and activates a background potassium conductance. Both effects may account for the shortening effect of the drug on the action potential and the increase in resting potential seen in partially depolarized preparations.

Animals↗