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MODULATION OF CALCIUM CHANNELS IN ARTERIAL SMOOTH-MUSCLE CELLS BY DIHYDROPYRIDINE ENANTIOMERS
Full text linkThe actions of the optical enantiomers of BAY K 8644 and Sandoz 202,791 were studied on barium inward currents recorded using the whole-cell configuration of the patch clamp technique from enzymatically isolated smooth muscle cells from the rabbit ear artery. The enantiomers were applied by bath perfusion or rapidly by a concentration jump technique, which enabled the study of drug action under equilibrium and nonequilibrium conditions. A larger effect of agonists was seen on peak inward current in 110 mM Ba when small rather than large depolarizations were applied. The midpoint voltage of the steady-state inactivation curve of IBa was -12.8 +/- 1.9 mV (n = 4) in the absence of drug, -16.4 +/- 2.5 mV (n = 4) in 1 microM (+)202,791, and -31.4 +/- 0.4 mV (n = 4) in 1 microM (-)202,791. The rate of onset of action of the agonist and antagonist enantiomers of BAY K 8644 and Sandoz 202,791 was studied by rapid application during 20-ms depolarizing steps from different holding potentials to +30 mV at 1 or 0.2 Hz. The drugs were applied as concentration jumps between two single pulses of a pulse train. The rates of onset of drug action on peak IBa during a 1-Hz pulse train were concentration dependent over the range of 100 nM-3 microM for both (+) and (-)202,791. The rate of onset of inhibition of peak current by antagonist enantiomers was not significantly influenced by the test pulse frequency. At a holding potential of -60 mV, the onset rate of the increase in peak IBa on application of 1 microM of agonist enantiomers (+)202,791 or (-)BAY K 8644 during a train of pulses occurred with mean time constants of 2.1 +/- 0.7 s (n = 7) and 2.3 +/- 0.2 s (n = 4), respectively. The onset of current increase on application of 1 microM (+)202,791 during a single voltage clamp step to 20 mV was faster, with a mean time constant of 380 +/- 80 ms (n = 3)
Disparate effects of calcium channel blockers on pressure dependence of renin secretion and flow in the isolated perfused rat kidney
No full textUsing the model of isolated perfused rat kidneys this study was performed to investigate whether or not voltage-operated calcium channels are essentially involved in the pressure control of renin secretion from the kidneys. At a perfusion pressure of 100 mm Hg (13.3 kPa) renin secretory rates were 4.2 +/- 0.7 (ng angiotensin I h-1) min-1 g-1. Stepwise reduction of renal perfusion pressure to 80, 60, and 40 mm Hg (10.6, 8.0, 5.3 kPa) resulted in an increase of renin release yielding a 30-fold stimulation at 40 mm Hg vs 100 mm Hg. Increasing the perfusion pressure above 100 mm Hg did not further significantly decrease renin secretion. The perfusate flow rate was also pressure-dependent. Flow rates increased linearly with pressure and reached a plateau at 100 mm Hg, which was maintained up to 160 mm Hg (21.3 kPa). The averaged flow rate at the plateau was 15.5 ml min-1 g-1. In the presence of the three different calcium antagonists nifedipine (5 microM), nitrendipine (3 microM) and verapamil (5 microM), myogenic autoregulation of flow was abolished as indicated by the rise of the pressure/flow curve between 40 and 160 mm Hg. At the same time, however, these calcium channel blockers did not alter the relationship between perfusion pressure and renin secretion. Moreover, the calcium channel agonist Bay K 8644 (5 microM) caused a strong and long-lasting vasoconstriction, without changing renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS
BAY-K-8644-stimulated amylase secretion from pancreatic acinar cells
No full text Pancreatic acinar cells do not contain depolarization-sensitive calcium channels. Nonetheless, in the current study, the calcium channel activator, BAY-K-8644, was found to stimulate a time- and concentration-dependent increase in the spontaneous release of amylase. Secretion was dependent on the presence of extracellular calcium in the incubation medium. Racemic BAY-K-8644 and (or) its S(−)optical isomer did not enhance the secretory response to either carbachol or cholecystokinin octapeptide; however, when co-applied with either phorbol ester, vasoactive intestinal peptide, or forskolin, they potentiated amylase secretion. Nifedipine and the R(+)isomer of BAY-K-8644, which are both calcium channel antagonists, did not alter basal or forskolin-stimulated amylase secretion, and [3H]nitrendipine did not bind to acinar cell membranes. Neither atropine nor dibutyryl cGMP, inhibitors of cholinergic and cholecystokininergic receptors, respectively, affected BAY-K-8644-induced amylase secretion. While BAY-K-8644 stimulated concentration-dependent cGMP synthesis in acinar cells, it had no effect on basal or forskolin-stimulated cAMP formation. The data suggest that BAY-K-8644 may bind to acinar cell sites that are not functional calcium channel proteins but are coupled nevertheless to the secretory response, and that calcium channel antagonists do not bind to these sites. The mechanism of the secretagogue action of BAY-K-8644 remains to be elucidated. </jats:p
Effect of calcium, bay K 8644, and reduced perfusion on basic indices of myocardial function in isolated hearts from rats after prolonged exposure to ethanol
No full textWe previously reported findings consistent with a marked upregulation in functional L-type voltage-operated calcium channels (L-VOCCs) in hearts obtained from rats exposed over the long term to ethanol. These experiments were undertaken to establish whether detrimental effects on cardiac function were associated with excess calcium entry into the myocardium in these hearts. Isolated hearts from adult male Sprague-Dawley rats received intoxicating concentrations of ethanol for 6-10 days by inhalation, were perfused with Krebs-Henseleit buffer by a modified Langendorff technique, and several functional parameters were assessed continuously. In some experiments, the calcium concentration in the perfusate was first reduced from the physiologic range (1.2 mM) to 0.15 mM and then increased in a step-wise fashion to 4 mM. In other experiments, hearts were exposed to buffer containing concentrations of the L-VOCC activator, (±)Bay K 8644, increasing from 10−9 to 10−6M. These perfusion protocols were repeated in hearts from treated animals subject to reduced coronary flow because of induction of partial left ventricular ischemia. There were some close similarities in the effects of these different stimuli. When the calcium concentration in the perfusate exceeded a physiologic level, there were signs of decreased function relative to controls in the hearts from ethanol-exposed rats. Thus R-wave amplitude and systolic pressure were lower, diastolic pressure also was reduced, but heart rate was elevated above that of controls. Similarly the presence of (±)Bay K 8644 in the perfusate caused a decrease in systolic and diastolic pressure and an increase in heart rate in hearts from ethanol-exposed rats. When cardiac perfusion was reduced in vitro by inflation of a balloon in the left ventricle, some of the effects of excess calcium and (±)Bay K 8644 were reproduced in control hearts. However, imposition of this "ischemic" stress did not appear to exacerbate the effects of prior exposure to ethanol. In general, in control hearts, indices of contractility were increased across the range of calcium concentration or by perfusing with (±)Bay K 8644. Hearts from ethanol-exposed rats, however, showed no further increase in these parameters once physiologic levels of calcium were exceeded, or showed inhibition of contractility in the presence of (±)Bay K 8644. The results are consistent with calcium entry through L-VOCCs in hearts from ethanol-exposed animals having detrimental effects on cardiac function once physiologic levels are exceeded. However, it is possible that these channels also may be involved in maintenance of cardiac function at hypocalcemic levels.Peer reviewedfinal article publishedEthanolCardiomyopathyPartial ischemiaVoltage-operated calcium channels(±)Bay K 8644Isolated heart
Possible inhibition of canine ventricular sarcoplasmic reticulum by BAY K 8644
No full text The calcium-channel agonist-antagonist racemic mixture of BAY K 8644 as well as the pure calcium-channel agonist enantiomer, converted rest potentiation in canine ventricular muscle to rest depression. The depressed postrest beats had increased action potential plateau heights and durations, suggesting that extracellular calcium entry was enhanced. BAY K 8644 did not alter the time to peak tension of either steady-state or postrest beats. Although BAY K 8644 slightly increased the amplitude of rapid-cooling contractures (RCC) immediately after an electrically evoked steady-state contraction (RCCss), the RCC amplitude rapidly decreased with increasing durations of rest. These results suggest that increased calcium influx because of BAY K 8644 increases the pool of releasable calcium during steady-state stimulation. However, they also indicate that BAY K 8644 causes acceleration of diastolic loss of calcium from the sarcoplasmic reticulum (SR). Scattered light intensity fluctuation measurements showed that the negative inotropic effect of BAY K 8644 on postrest contraction was not caused by calcium overloading of the SR, since BAY K 8644 reduced asynchronous myofilament motion. A negative relationship found between extracellular calcium and BAY K 8644-induced postrest depression also rules out the possibility that the latter effect is caused by intracellular calcium overload. BAY K 8644 seems to accelerate the loss of calcium from the SR during diastole by a pathway that does not appear to pass through the myofilaments. </jats:p
TRH and BAY K 8644 synergistically stimulate prolactin release but not 45Ca2+ uptake
No full textThyrotropin-releasing hormone (TRH) (1 microM) and the Ca2+-channel agonist BAY K 8644 (1 microM) each induced transient increases in prolactin secretion from primary cultures of rat anterior pituitary cells in perifusion. When BAY K 8644 was added after a TRH-induced secretory peak, the additional effect of BAY K 8644 on prolactin release was approximately twofold greater over a 30-min period than the effect of BAY K 8644 on previously untreated cells. TRH and BAY K 8644 were also synergistic when added in the opposite order or simultaneously. Substitution of other agents for BAY K 8644 revealed that only high K+ (40 mM) was at least additive with TRH in stimulating prolactin secretion; treatment with TRH inhibited, rather than facilitated, subsequent stimulation of prolactin secretion by angiotensin II (100 nM) or the ionophore A23187 (20 microM). The cooperative effect was not specific for TRH because BAY K 8644 also acted synergistically with angiotensin II or 40 mM K+. In GH4C1 cells, in which TRH and BAY K 8644 were also synergistic in releasing prolactin, measurements with the fluorescent indicator indo-1 showed that TRH and BAY K 8644 could each elevate cytosolic Ca2+ above the level stimulated by the other. Unexpectedly, TRH was found to inhibit BAY K 8644-stimulated 45Ca2+ uptake in both GH4C1 and primary cultured cells. These results indicate that BAY K 8644 and TRH synergistically stimulate prolactin secretion by a mechanism other than a cooperative effect on the activity of dihydropyridine-sensitive Ca2+ channels.</jats:p
Interaction of dihydropyridine Ca2+ agonist Bay K 8644 with normal and transformed pituitary cells
No full textThe dihydropyridine (DHP) Ca2+ agonist Bay K 8644 produced a dose-dependent increase in 45Ca2+ uptake by GH4C1 rat pituitary tumor cells. For agonist concentrations between 10(-9) and 10(-5) M, the enhanced 45Ca2+ uptake was well correlated with simultaneous increases in prolactin (PRL) secretion. Bay K 8644 combined with depolarizing concentrations of KCl produced more than additive effects on net Ca2+ uptake and hormone release. Nisoldipine, a DHP Ca2+ antagonist, competitively blocked Bay K 8644-stimulated 45Ca2+ uptake. This drug also potently inhibited 45Ca2+ uptake triggered by depolarization with KCl (estimated half-maximal inhibiting concentration: 2 nM). Bay K 8644 enhanced PRL secretion from normal rat pituitaries in culture and in a perifusion system. These results indicate that Bay K 8644 is a potent modulator of voltage-sensitive Ca2+ channels of both normal and transformed pituitary cells. In this respect endocrine cell Ca2+ channels resemble those found in heart, smooth muscle, and neuronal cell bodies.</jats:p
Inhibition of rest potentiation in canine ventricular muscle by BAY K 8644: comparison with caffeine
No full text Rest potentiation, believed to be due to increased utilization of sarcoplasmic reticular calcium, was converted to rest depression by BAY K 8644 (1 microM). Plateau height and duration of the postrest beat were enhanced by BAY K 8644, suggesting an enhancement of extracellular calcium entry. Caffeine (3 mM) also produced depression at all rest intervals, although to a lesser extent than BAY K 8644. Compared with BAY K 8644, treatment with caffeine resulted in an elevation of plateau amplitude and a shortening of action potential duration. Action potential configuration changes induced by rest were unaltered by caffeine despite reduction in rest potentiation. Caffeine-induced rest depression was associated with an increase in the time to peak tension. This was not observed with BAY K 8644. Treatment with both caffeine (3 mM) and BAY K 8644 (1 microM) greatly prolonged time to peak tension. Action potential duration and plateau height were either maintained or increased. Less rest depression was observed with the combination than with either agent alone. These results suggest that 1) BAY K 8644 and caffeine inhibit rest potentiation by different mechanisms, and 2) caffeine-induced inhibition of calcium uptake by the sarcoplasmic reticulum may enhance the effect of BAY K 8644-induced increase in calcium influx on the contractile apparatus. </jats:p
New Ca2+ agonist (Bay K 8644) enhances and induces cardiac slow action potentials
No full text Bay K 8644 is an analogue of nifedipine that has positive inotropic and vasoconstricting actions and was postulated to be a Ca agonist (i.e., a Ca2+-channel activator). To test this hypothesis, we examined the electrophysiological effects of this compound in isolated guinea pig papillary muscles. Bay K 8644 (10(-6) M) had little effect on the normal fast action potentials, although it did increase contractility. Bay K 8644 did, however, induce Ca2+-dependent slow action potentials (fast Na+ channels inactivated by 25 mM K+). When slow action potentials had been previously induced by tetraethylammonium chloride (10 mM) plus Ca2+ (4.0 mM) or isoproterenol (2 X 10(-7) M), 10(-6) M Bay K 8644 potentiated the slow action potentials, i.e., increased their maximal rate of rise (Vmax), concomitant with its positive inotropic effect. All effects of Bay K 8644 could be reversed by 10(-6) M nifedipine. Thus it appears that Bay K 8644 enhances Ca2+ influx through the myocardial slow channels, consistent with the concept that Bay K 8644 is a Ca2+-channel stimulator. </jats:p
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