Isoproterenol increases defibrillation energy requirements in dogs.

The effect of intravenous isoproterenol on the energy requirements for successful defibrillation (DF) was examined in anesthetized dogs following cholinergic blockade with atropine (n = 5) and following treatment with d- and d,l-sotalol (n = 16). Defibrillation shocks were administered through left and right ventricular epicardial patch electrodes and the energy requirements for DF were studied using two different methods. Multiple shocks of varying energies were delivered and the energies required for 50% success (E50) and 80% success (E80) in DF were estimated using logistic regression. Atropine (0.04 mg/kg) increased E50 by 32 +/- 30% (p = 0.046) and E80 by 39 +/- 38% (p = ns). Subsequent administration of isoproterenol (10 micrograms/ml), increasing the heart rate by 52 +/- 35% (p = 0.025), resulted in a further 108 +/- 21% (p = 0.015) and 88 +/- 55% (p = 0.02) rise in E50 and E80 values, respectively. In a second set of experiments, d- (n = 9) and d,l-sotalol (n = 7) (4 mg/kg bolus followed by 0.025 mg/kg/min maintenance infusion) were administered and baseline curves relating delivered energy to % success in DF were calculated. Isoproterenol (10 +/- 4 micrograms/min) was given to increase the heart rate by 54 +/- 32% (p less than 0.025), and resulted in decreases in % success at each of two energy levels, falling in the midrange of the dose-response curve. Following d,l-sotalol, % successful shocks fell from 60 +/- 15 to 42 +/- 28% (p less than 0.05); following d-sotalol, the % success fell from 66 +/- 13 to 38 +/- 36% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Bay K 8644 and nifedipine on femoral arteries of spontaneously hypertensive rats.

Vasoconstrictor effects of Bay K 8644 (an agonist known to increase Ca2+ influx through the voltage-dependent Ca2+ channels) on femoral arteries of 6 week old spontaneously hypertensive rats (SHR) were investigated, and data compared with findings in age-matched normotensive Wistar-Kyoto rats (WKY). The addition of Bay K 8644 (1 X 10(-10)-3 X 10(-7) M) elicited a dose-dependent contraction in SHR femoral artery in the absence of any contractile agent. Maximum contraction induced by this agonist was the same as the maximum induced by either K+-depolarization or alpha-adrenoceptor stimulation. Bay K 8644 was less effective in eliciting a contraction in the WKY femoral artery. Increased sensitivity to K+ was also observed in the SHR femoral artery. In contrast, contractions in response to alpha-adrenoceptor stimulation were the same in the SHR as those in the WKY. The addition of nifedipine, a Ca2+ channel antagonist, to an unstimulated preparation produced a dose-dependent relaxation in femoral arteries from SHR, but not from WKY. When the arteries were contracted with 60 mM K+, nifedipine produced similar relaxations in the SHR as those in the WKY, suggesting that the Ca2+ channels in the SHR femoral arteries are more activated than those in the WKY femoral arteries. Contractile responses to SHR femoral arteries to Bay K 8644 were antagonized competitively by nifedipine. Contractile responses to Ca2+ determined in K+-depolarized strips were also antagonized competitively by nifedipine. However, Schild plot analysis demonstrated a different pA2 value for nifedipine, suggesting that there may be a difference in the state of voltage-dependent Ca2+ channels in SHR femoral artery between the stimulation with Bay K 8644 and K+-depolarization.     

Effects of the calcium channel activator Bay K 8644 on general anaesthetic potency in mice.

1. The effects of the calcium channel activator, Bay K 8644, on the anaesthetic potencies of ethanol, argon and pentobarbitone were examined in mice. 2. Bay K 8644, at 1 mg kg-1 i.p., significantly antagonized the general anaesthetic potencies of ethanol and argon, but at 5 and 10 mg kg-1 this compound increased the general anaesthetic potency of these drugs. 3. At doses of 1, 5 and 10 mg kg-1 Bay K 8644 antagonized the anaesthetic effects of pentobarbitone. Bay K 8644, at the highest dose used, did not alter the brain concentrations of pentobarbitone or the blood concentrations of ethanol. 5. The effects of the different doses of Bay K 8644 on the actions of ethanol and of argon are compatible with the known partial agonist properties of this compound on calcium channels in vitro. 6. The actions of Bay K 8644 on the anaesthetic effects of pentobarbitone suggests that specific interactions may be involved in the anaesthetic actions of this compound.     

Effects of Bay K 8644 on contraction of the human isolated bronchus and guinea-pig isolated trachea.

The effects of Bay K 8644, a dihydropyridine which increases calcium flux through the potential-operated channels were studied on the contractions induced by histamine, acetylcholine, KCl and Ca2+ on human isolated bronchial strips and the results were compared to those obtained on guinea-pig isolated tracheal spirals. Subsequently the contractant effects of Bay K 8644 in K+-enriched medium and in the presence of Ca2+ 0.03 mM were investigated. In Krebs normal calcium medium, Bay K 8644 did not significantly modify the EC50 of acetylcholine or histamine on the human bronchus, but in concentrations of 10(-7)-10(-6)M it potentiated the effects of KCl on that preparation. It did not modify the EC50 of acetylcholine, histamine or KCl on the guinea-pig trachea. In Ca2+-free Krebs medium with additional K+ (30 mM), Ca2+ concentration-response curves were displaced to the left by Bay K 8644 in the two preparations. Shifts were 0.52 +/- 0.11 and 0.72 +/- 0.16 log units respectively with Bay K 8644 10(-8) and 10(-7) M on human bronchus (n = 4) and 0.67 +/- 0.16 and 1.06 +/- 0.19 log units respectively with Bay K 8644 10(-7) and 10(-6) M on the guinea-pig trachea (n = 5). In Krebs medium with Ca2+ 0.03 mM and K+ 30 mM, Bay K 8644 (10(-8) to 10(-6) M) contracted both the human bronchus and the guinea-pig isolated trachea. This effect was competitively antagonized by nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Bay K 8644 on 45Ca uptake and efflux and on contraction in the rabbit aorta.

Contractions induced by K+, noradrenaline and 11,9-epoxymethano prostaglandin H2 (11,9-epoxymethano PGH2) were accompanied by a large, moderate and negligible stimulation of 45Ca uptake in rabbit aortic rings, respectively. Bay K 8644, 14 and 56 nM, enhanced both the contraction and the 45Ca uptake stimulated by all 3 agonists. In the absence of agonists, Bay K 8644 (14 and 56 nM) caused a small contraction and increase in 45Ca uptake. 45Ca efflux was increased by noradrenaline, and Bay K 8644 augmented this. In Ca-free solution, contractions induced by noradrenaline or 11,9-epoxymethano PGH2 were not augmented by Bay K 8644. Nifedipine (0.1 microM) antagonized 45Ca uptake stimulated by K+ or noradrenaline. Nifedipine also reduced the stimulant effect of Bay K 8644 on 45Ca uptake in the presence of all three agonists. It is concluded that, in the rabbit aorta, Bay K 8644 enhances the opening of Ca channels both during depolarization and in the presence of receptor-specific agonists and is also able to open Ca channels under basal conditions. Bay K 8644 appears not to reduce Ca efflux or enhance Ca release from intracellular stores.     

Effects of azimilide, acidemia, and the combination on defibrillation energy requirements

We investigated the effects of azimilide, acidemia, and the combination on the defibrillation energy requirement (DER). An anesthetized canine model of internal transvenous defibrillation with biphasic shocks was used. Dogs were assigned to receive a 0.25N HCl infusion (target pH, 7.15), azimilide, azimilide with HCl infusion, or placebo (n = 7 per treatment). DERs were determined in triplicate using an increment-decrement protocol at baseline and during each treatment. Monophasic action potentials and ECG intervals were measured at baseline and during each treatment. Analysis of variance (ANOVA) with post hoc Tukey's test was used for statistical analysis. The DER was reduced by azimilide and increased above control values by both acidemia and the combination of acidemia and azimilide. All treatment groups resulted in a significant change compared with placebo (p < 0.05). The correlation between DER and various repolarization measurements was determined. The treatment-related changes in both QT intervals and monophasic action potential (MAP) durations were inversely correlated with DER. Azimilide reduces the DER, whereas acidemia increases the DER in our model. The combination of azimilide and acidemia still resulted in an increase in the DER. This finding may have clinical implications for the use of azimilide in settings such as myocardial ischemia, in which myocardial pH is reduced.     

Bay K 8644 potentiates the anxiolytic effect of ethanol.

The possible role of voltage-sensitive calcium channels (VSCCs) in the anxiolytic effect of ethanol was investigated using three different doses of ethanol (0.5, 1.0 and 2.0 g/kg) with calcium agonist Bay K 8644 (0.5 mg/kg) and calcium antagonist nifedipine (5 mg/kg) in rats. Ethanol produced an anxiolytic effect in a dose-dependent manner. The Bay K 8644-potentiated anxiolytic effect of ethanol, however, Bay K 8644 did not alter anxiety when used alone. Nifedipine itself showed an anxiolytic effect but did not change the ethanol-induced anxiolytic effect. This finding may lead to the consideration of the neurochemical mechanisms of the anxiolytic effects of ethanol and nifedipine as they vary from each other.     

Increased vascular reactivity to Bay K 8644 in genetic hypertension.

These experiments compared potential-operated calcium channel function in smooth muscle from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Carotid artery strips from adult male SHRSP and WKY rats were suspended in tissue baths for isometric force recording. Contractile force was expressed as percent of response to 100 mmol/l KCl. Vascular strips from SHRSP were more sensitive to KCl (ED50 = 25 mmol/l) compared to strips from WKY rats (ED50 = 37 mmol/l). The calcium channel agonist Bay K 8644 (2.8 x 10(-10) to 2.8 x 10(-7) mol/l) produced tonic contractions in carotid artery strips from SHRSP (34% of the contractile response to 100 mmol/l KCl) but not in those from WKY rats. Incubation of vascular strips in 1.8 or 6 x 10(-10) mmols/l norepinephrine did not alter the maximal contractile response to Bay K 8644 in either strain of rats. In 12 mmol/l KCl, the maximal contractile response to Bay K 8644 was increased in both SHRSP (71%) and WKY rats (25%). In 18 mmol/l KCl, maximal contractile responses to Bay K 8644 in the two strains were similar (SHRSP = 73%, WKY = 76%). Removal of the endothelium did not significantly affect contractile responses to Bay K 8644 in either strain of rats. There were no differences in contractile responses to the calcium ionophore A23187 or in nifedipine-induced relaxation of potassium-activated vessels between carotid arteries from SHRSP and WKY rats. In summary, these results suggest that a difference in voltage-operated calcium channel function may underlie the increased sensitivity of SHRSP vascular smooth muscle to depolarizing stimuli.     

Effects of intracoronary administration of endothelin in anesthetized dogs: comparison with Bay k 8644 and U 46619.

The effects of synthetic endothelin on the coronary circulation were studied in pentobarbital-anesthetized dogs and compared with those of Bay k 8644, a dihydropyridine calcium channel agonist, and U 46619, a thromboxane analogue. Intracoronary bolus administration of endothelin reduced coronary blood flow and increased coronary arterial resistance. Similarly, intracoronary bolus administration of equipotent doses of Bay k 8644 or U 46619 significantly reduced coronary blood flow and increased coronary arterial resistance. The coronary vasoconstrictor effects of endothelin were long-lasting as compared with the transient actions of Bay k 8644 and U 46619. Intracoronary bolus injection of endothelin also reduced left ventricular (LV) dP/dt arterial pressure (MAP), and cardiac output (CO). In contrast, Bay k 8644 increased LVdP/dt but did not alter CO or MAP. Intracoronary bolus injection of U 46619 did not affect MAP, CO, or LVdP/dt. In a separate group of animals, intracoronary infusion of nitrendipine significantly increased coronary blood flow and reduced coronary arterial resistance. Other cardiovascular parameters measured were not significantly altered. In the presence of nitrendipine, the effects of intracoronary administration of endothelin and U 46619 on coronary blood flow, coronary arterial resistance, and LVdP/dt were only partially antagonized. On the other hand, the effects of Bay k 8644 were completely prevented in the presence of nitrendipine. These studies show that at doses which reduce coronary blood flow to the same extent, only endothelin produces myocardial depression in anesthetized dogs. The cardiovascular actions of endothelin were only partially antagonized by nitrendipine, suggesting that mechanisms other than calcium influx through voltage-operated channels are involved.     

Suppressive Effects of Bay K 8644 on Toxicity of Calcium Channel Blockers in Cultured Rat Embryos

Previous study revealed that calcium channel blockers (CCBs)reduced embryonic heart rates (HRs) and produced morphologicalabnormalities when Gestational Day (GD) 11.5 rat embryos werecultured for 20 hr. The present study was to investigate whethera calcium channel agonist, Bay K 8644 (BAY), prevented CCB-inducedembryotoxicity in vitro. GD 11.5 embryos were exposed to nifedipine(NIF), diltiazem (DIL), and verapamil (VER) either alone orin combination with BAY at 0.1, 1.0, and 10 µg/ml. Thesedoses of BAY alone had no effect on gross morphology. EmbryonicHRs were increased at 10 µg/ml of BAY, but were withincontrol levels at 0.1 and 1.0 µg/ml. The doses of NIF,DIL, and VER were 40, 6.0, and 2.0 µg/ml, respectively,and were the minimum concentrations to produce a 100% effecton morphological abnormalities. Embryonic HRs were reduced to22, 31, and 34% below control levels in the NIF, DIL, and VERgroups, respectively. The negative chronotropic effects of CCBswere inhibited by coadministration with BAY, depending on itsconcentration. When embryos exposed to each CCB were supplementedwith BAY at 1.0 or 10 µg/ml, embryonic HRs were comparableto those of controls. Combined exposures of each CCB and 10µg/mlBAY did not cause any morphological abnormalities. These resultssuggested that mechanisms of CCB embryotoxicity were directlyrelated to pharmacological consequences of calcium channel blockagein developing rats.     

Effects of the Ca agonists Bay K 8644 and CGP 28392 on vascular smooth muscle tone

1. Nifedipine (5 x 10(-9) M) reduced and the Ca agonists CGP 28392 (10(-6) M) and Bay K 8644 (10(-7) M) increased the contractions elicited by K+ in segments of rat aorta, whereas those caused by noradrenaline (NA) were unaffected. 2. CGP 28392 and Bay K 8644 evoked concentration-dependent contractions in segments moderately depolarized with 15 mM K+; these responses were reduced by nifedipine. 3. 45Ca uptake induced by 50 mM K+ or NA (10(-7) M) was reduced by nifedipine (10(-6) M). Bay K 8644 (10(-6) M) only increased the 45Ca uptake induced by K+, which was inhibited by nifedipine (10(-6) M). 4. These results indicate that in this vascular preparation: (a) Ca agonists only activate voltage-dependent Ca channels (VDCs), the potency of Bay K 8644 being higher than of CGP 28392, and (b) VDCs and receptor-operated Ca channels have different pharmacological properties.     

Effects of intracoronary Bay k 8644, a calcium channel agonist, in anesthetized dogs

Bay k 8644, a new dihydropyridine calcium channel activator has been shown to have positive inotropic and vasoconstrictor properties following intravenous (i.v.) administration. In the present study, intracoronary administration of Bay k 8644 was used to isolate drug effects on regional myocardial blood flow and contractility independent of systemic hemodynamic actions in beta-adrenoceptor-blocked anesthetized dogs. Intracoronary infusion of Bay k 8644 (1.5, 3.7, 7.4, 14.8 micrograms/min) produced significant increases in contractility (percentage of segment shortening) in the drug-perfused region. Peak positive dP/dt, an index of global contractility, was increased in parallel with increases of regional contractility. No other changes in systemic hemodynamics occurred. Transmural tissue blood flow distribution as measured by radioactive microspheres was also unchanged by Bay k 8644. Intracoronary infusion of KB-944, a nondihydropyridine calcium channel blocking agent, increased coronary blood flow and decreased regional segment shortening and peak positive dP/dt. KB-944 inhibited increases in contractility produced by Bay k 8644. Thus, Bay k 8644 was shown to have a direct positive inotropic effect in vivo which was inhibited by calcium channel blockade.     

Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs.

The effect of the dihydropyridine calcium agonist Bay K 8644 on the coronary, femoral, mesenteric and renal circulations was investigated and compared with that of noradrenaline in pentobarbitone-anaesthetized dogs. The left anterior descending coronary, femoral, cranial mesenteric and renal arteries were cannulated and their arterial beds perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 (0.1-300 nmol) and noradrenaline (0.1-300 nmol) were injected intra-arterially. Bay K 8644 decreased blood flow (vasoconstriction) in all 4 arterial beds. A maximum decrease was attained at 100 nmol and a further increase in dose did not appear to result in a further decrease in blood flow. At maximum effects blood flow decreased to about 35% of the basal value in coronary, 30% in femoral, 20% in renal and 15% in mesenteric circulation. Normalized ED50 values (ED50 divided by basal flow) of Bay K 8644 were 0.07 +/- 0.02 nmol in the femoral, 0.08 +/- 0.01 nmol in the coronary, 0.16 +/- 0.06 nmol in the mesenteric and 0.55 +/- 0.19 nmol in the renal circulation. At 100 nmol, the values for the half-duration of Bay K 8644 vasoconstrictor effects were about 196 s in the renal, 78 s in the mesenteric, 84 s in the femoral and 21 s in the coronary circulation. Noradrenaline produced a dose-dependent decrease in blood flow in femoral, mesenteric and renal circulations, and was about 2 times in femoral, 4 times in mesenteric and 9 times in renal circulation more potent than Bay K 8644.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of endothelins, Bay K 8644 and other oxytocics in non-pregnant and late pregnant rat isolated uterus.

Endothelins 1, 2 and 3 (ET-1, ET-2 and ET-3; 1-30 nM) caused long-lasting concentration-dependent tonic contractions of uterine strips from non-pregnant rats. The potency of ET-1 (EC50 7 nM) was similar to that of angiotensin II (AII) and greater than that of ET-2 or ET-3 (EC50S greater than or equal to 10 nM), bradykinin, Bay K 8644, oxytocin (OT), 5-hydroxytryptamine, prostaglandin F2 alpha (PGF2 alpha) or acetylcholine. Strips from 21-day pregnant rats were 2- to 3-fold more sensitive to ET-1, AII, OT and PGF2 alpha and 200-fold more sensitive to Bay K 8644 than non-pregnant preparations. The development of tonic responses to ET-1 (30 nM) and of phasic-rhythmic ones to Bay K 8644 (300 nM) was fully prevented in strips from non-pregnant rats bathed in Ca2(+)-free medium, but stepwise reintroduction of Ca2+ (0.03-3 mM) to the solution allowed the manifestation of contractions in response to both agonists. Responses to ET-1 required less Ca2+ than those to Bay K 8644. Strips challenged with ET-1 while in Ca2(+)-free medium developed greater contractions upon reintroduction of Ca2+ than preparations stimulated with the peptide in normal medium. The reverse occurred with Bay K 8644-induced contractions. Nicardipine (10 nM) abolished the responses of strips from non-pregnant rats to Bay K 8644 (300 nM), but only attenuated ET-1-induced (30 nM) contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of the dihydropyridine Bay K 8644 in guinea-pig isolated trachealis.

In trachea bathed by Krebs solution containing indomethacin 0.8 mumol l-1, Bay K 8644 (0.01-1 mumol l-1) evoked mild spasm. Peak tension was achieved after 10 min and was generally less than 20% of an acetylcholine (ACh) maximum. The effect of Bay K 8644 was not potentiated by addition of 2.5 mmol l-1 potassium chloride (KCl) to the Krebs solution. Bay K 8644 (1 mumol l-1) caused a small potentiation of KCl and tetraethylammonium (TEA). In contrast it did not modify the actions of ACh or histamine. Bay K 8644 (1 mumol l-1) caused a small potentiation of the effect of calcium chloride (CaCl2) tested in trachea bathed by a K+-rich, Ca2+-free, MOPS-buffered physiological salt solution. Organic inhibitors of calcium influx such as nifedipine (0.1 mumol l-1), verapamil (1 mumol l-1) or diltiazem (10 mumol l-1) each caused marked depression of concentration-effect curves to KCl. Bay K 8644 (0.01-1 mumol l-1) provided concentration-dependent protection against this effect in all three cases. Estimation of calcium influx by the lanthanum technique revealed that Bay K 8644 (1 mumol l-1) was able to promote the cellular influx of Ca2+. Intracellular electrophysiological recording showed that Bay K 8644 (1 mumol l-1) caused no change in the resting membrane potential of trachealis cells and no change in the properties of the spontaneous electrical slow waves. However, Bay K 8644 was able to delay the slow wave suppression evoked by 1 mumol l-1 nifedipine. The ability of Bay K 8644 to promote Ca2+ influx and its ability to protect against the effects of several structurally-unrelated inhibitors of Ca2+ influx are consistent with Bay K 8644 acting as an agonist at the dihydropyridine receptor associated with the voltage-operated Ca2+ channel (VOC) of trachealis muscle. By this action it potentiates those spasmogens (KCl, TEA) which act by permitting Ca2+ influx through VOCs. In contrast it has no effect on those spasmogens (ACh, histamine) which principally act to liberate Ca2+ from intracellular sites of sequestration.     

Effects of calcium channel antagonists and Bay K 8644 on the analgesic response to pentazocine and U 50488H.

1. The effects of diltiazem, nifedipine and verapamil and the calcium channel agonist Bay K 8644 on the analgesic responses to the subcutaneous (s.c.) or intracerebroventricular (i.c.v.) administration of pentazocine and U 50488H were investigated in mice. 2. The three calcium channel antagonists and Bay K 8644 reduced the number of writhes induced by the intraperitoneal administration of acetic acid. 3. The analgesic responses to the low doses of pentazocine (s.c.) were additive with the effects of diltiazem, nifedipine or Bay K 8644; while, in contrast, the higher doses produced underadditive responses. Only verapamil increased the effects of the i.c.v. administration of the opioid. 4. The effects of U 50488H (s.c.) were additive with those of diltiazem and Bay K 8644; verapamil only increased the response to the lower dose of the opioid. Nifedipine plus pentazocine always induced underadditive responses. The i.c.v. effects of U 50488H were only increased by verapamil. 5. These findings are discussed in relation with a possible interaction of kappa agonists with calcium channels in the central nervous system.     

Effects of Bay K 8644 on the spontaneous electrical and mechanical activities of the rat portal vein

Summary Effects of Bay K 8644 on the spontaneous electrical and mechanical activities of the rat portal vein were studied. Bay K 8644 enhanced contractions in amplitude and duration. Bay K 8644 prolonged the duration of the spontaneous spike potential bursts and increased the number of spike potentials in a burst. These results indicate that the increase in the amplitude and duration of spontaneous contractions of the rat portal vein induced by Bay K 8644 are mediated mainly by the facilitation of the membrane electrical activity.Send offprint requests to: K. Shimamura at the above address     

Bay K 8644 induces a reversible spasticity-like syndrome in rats

The dihydropyridine Bay K 8644 exerts a positive modulation of Ca²⁺ channels. Administration of Bay K 8644 3–5 mg/kg i.p. to rats induces within 15 min a severe spasticity syndrome consisting of stiff tail, arched back, stretching and twisting of forelimbs and hindlegs and backwards motility and rolling over. The syndrome was effectively antagonized by nifedipine 3–30 mg/kg but not by the other Ca²⁺ channel blockers flunarizine, diltiazem and verapamil. Diltiazem even enhanced the spasticity. Diazepam 10–30 mg/kg i.p. completely blocked the spasticity whereas the other muscle relaxants (−)-baclofen and the β-carboline ZK 93423 were completely inactive. These findings with Bay K 8644 suggest that spasticity may be caused by changed Ca²⁺ homeostasis.     

Effects of caffeine and ryanodine on depression of post-rest tension development produced by Bay K 8644 in canine ventricular muscle.

1. Post-rest inotropy in canine ventricular myocardium has proved a useful indicator of sarcoplasmic reticular calcium release. This phenomenon is converted to rest depression by the calcium channel activator (agonist), Bay K 8644 as well as other chemically diverse agents such as caffeine and ryanodine. 2. Rapid cooling contractures and post-rest contraction amplitude were used as independent measures of sarcoplasmic reticular calcium content and release. Simultaneous recordings of transmembrane action potentials and their accompanying contractions were obtained to determine the association between electrophysiological and mechanical events. The present study was designed to elucidate the mechanism by which Bay K 8644, caffeine and ryanodine alter force production after variable periods of rest. 3. Bay K 8644 (1 microM) increased steady state contraction in response to a constant train of stimulation, caused rest-depression after 2 and 8 min rest, prolonged action potential duration and increased action potential plateau amplitude. Augmented steady state tension was not accompanied by any change in time to peak tension or rapid cooling contracture amplitude. However, the post-rest rapid cooling contracture was greatly diminished compared to that observed prior to Bay K 8644 treatment. 4. Caffeine (3 and 5 mM) caused rest-depression with an increase in steady state contraction amplitude. Along with this there was a slight decrease in action potential duration and plateau amplitude and an increase in time to peak tension. The rapid cooling contractures were virtually abolished at all conditioning intervals. The effect of caffeine on twitch tension and cooling contracture is consistent with the ability of this compound to inhibit calcium sequestration by the sarcoplasmic reticulum. 5. A combination of Bay K 8644 and caffeine caused significantly less rest-depression than that seen with Bay K 8644 alone. The augmented twitch tension was accompanied by a long time to peak tension and action potential duration. However, there was no increase in the amplitude of the rapid cooling contracture, either after a regular train of stimulation or after rest, compared to that seen after Bay K 8644. 6. Ryanodine (10 nM), produced rest-depression, reduced steady state twitch tension and augmented the rest-depression produced by Bay K 8644. The steady state rapid cooling contracture remained unchanged when both agents were present simultaneously, while the post-rest rapid cooling contracture was significantly depressed compared to that observed with Bay K 8644 alone. 7. Bay K 8644 and ryanodine appear to have similar actions with respect to promoting diastolic loss of calcium from the sarcoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of Bay K 8644 on cat adrenal catecholamine secretory responses to A23187 or ouabain

Calcium ionophore A23187 increases the rate of spontaneous catecholamine release from cat adrenal glands perfused at 37 degrees C with oxygenated Krebs bicarbonate solution, in a time- and Ca-concentration-dependent manner. The secretory profile obtained with the ionophore was not modified in the presence of the Ca channel activator Bay K 8644. Ouabain also enhanced the rate of spontaneous catecholamine outputs in a time- and concentration-dependent manner. The threshold ouabain concentration capable of producing a clear, yet delayed secretory response was 10(-6) M. Increasing ouabain concentrations up to 10(-4) M enhanced catecholamine release and shortened the time to peak release. The dihydropyridine Ca channel activator Bay K 8644 (10(-6) M) markedly potentiated the secretory effects of all ouabain concentrations used (10(-7)-10(-4) M). However, the most impressive potentiations were seen at 10(-5)M ouabain; while at this concentration ouabain alone released 2.6 +/- 0.07 micrograms catecholamines per 30 min, in the presence of Bay K 8644 the release was 73.4 +/- 5.7 micrograms per 30 min. Conversely, at a fixed ouabain concentration (10(-5) M), the potentiation was also dependent on the Bay K 8644 concentration (10(-8)-10(-5) M). Although K deprivation inhibits Na pumping as does ouabain, Bay K 8644 did not modify the rate of catecholamine release evoked by K removal from the perfusion medium. Potassium deletion, nimodipine or high Mg all reversed the fully developed secretory response evoked by ouabain plus Bay K 8644. In glands depolarized by continuous perfusion with high K solutions, once the secretory response was inactivated, the introduction of ouabain caused an enhancement of the catecholamine secretory rate.(ABSTRACT TRUNCATED AT 250 WORDS)