Effects of nicardipine on the spontaneous beat of isolated atria of guinea pigs

Nicardipine was found to produce a concentration-dependent depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of nicardipine on the heart rate was negligibly weaker than its effect on the isometric contraction. A time-dependent depression of the isometric contraction and the atrial rate after the addition of a single dose of nicardipine was also found up to the 10th min. Calcium almost completely, isoprenaline completely and aminophylline partially antagonized the depressive action of nicardipine on the isometric contractility of the atria. Only isoprenaline antagonized the negative chronotropic action of higher doses of nicardipine. It is possible that these substances restore the contractility by compensating the calcium balance, previously changed by nicardipine, or by producing an increase in the intracellular cAMP content (isoprenaline and aminophylline).     

Comparative effects of adenosine and L-N-phenylisopropyladenosine (L-PIA) on the spontaneous contraction of the isolated atrium in the guinea-pig

It has been found that adenosine produces a concentration-dependent decrease in both the isometric contraction and the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. In the present experiments, it was of interest to study the effect of adenosine on the isometric contraction and the atrial rate in the presence of aminophylline, calcium chloride and verapamil in the organ bath. It was also of interest to compare the effects of adenosine and adenosine derivative. L-PIA on the isolated guinea-pig heart atria. The dose-response curves for both adenosine and L-PIA were shifted to the right in the presence of aminophylline (13 and 32 mumol l-1). The presence of verapamil (73 nmol l-1) in the organ bath potentiated the depressive actions of the both adenosine and L-PIA. Calcium chloride (1.8 mmol l-1) completely antagonized the negative inotropic action of both substances. Our results indicate a possible antagonism between adenosine, L-PIA and calcium, on the other hand, on the isolated, spontaneously beating guinea-pig atria. Also, our results strongly suggest competitive antagonism between adenosine, L-PIA and aminophylline at adenosine receptor sites.     

Does guanabenz have a non-specific effect on spontaneous contractions of isolated guinea pig atria?

Guanabenz was found to produce a concentration-dependent depression of the isometric contractility of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of guanabenz on the heart rate was weaker than its effect on the isometric contraction. A time-dependent depression of both the isometric contraction and of the atrial rate after the addition of a single dose of guanabenz was also found up to 10th min. Guanabenz did not change the maximal driving (following) frequency of the atria. Aminophylline partially, isoprenaline almost completely and calcium completely antagonized the negative inotropic action of guanabenz. They, however, did not antagonize the negative chronotropic action of guanabenz. It seems, regardless of what the precise mechanism(s) of action of guanabenz may be (probably nonspecific on the isolated guinea-pig atria), that all these substances (aminophylline, isoprenaline and calcium) restore the contractility of the isolated atria by compensating the calcium balance which has been previously changed by guanabenz.     

Effect of forskolin, isoprenaline and propranolol on spontaneous contractions of the isolated atrium of guinea pigs

Forskolin (0.375 mumol 1(-1)) produced positive inotropic and chronotropic effects on the isolated, spontaneously beating atria of the guinea pig. The same effects were also observed or even increased in the presence of various concentrations of isoprenaline (0.024 and 0.12 mumol 1(-1)) in the organ bath. The effects of forskolin on the isometric contraction and the atrial rate of the isolated, spontaneously beating atria of the guinea-pig were significantly inhibited by propranolol (9 mumol 1(-1)). These results indicate that the action of forskolin on the spontaneously beating atria of the guinea-pig is mediated by stimulation of the adenylate cyclase system, but in some steps of this action, a direct stimulation of beta-adrenoceptors might also be implicated.     

Characterization of the effects of AHN 086, an irreversible ligand of "peripheral" benzodiazepine receptors, on contraction in guinea-pig atrial and ileal longitudinal smooth muscle

The effects of AHN 086 and its reversibly acting structural analogue Ro 5-4864 were studied in the spontaneously beating guinea-pig atria and field-stimulated guinea-pig ileal longitudinal smooth muscle in the presence and absence of dihydropyridine calcium channel modulators. The treatment of guinea-pig atria with AHN 086 followed by extensive washing did not alter contraction. However, AHN 086 (0.5 microM) potentiated (88%) the positive inotropic responses by BAY K 8644, an effect that was not reversed by extensive washing of the tissue. Higher concentrations of AHN 086 (greater than 2 microM) irreversibly inhibited the intropic, but not the chronotropic responses to BAY K 8644, nifedipine, and isoproterenol. Ro 5-4864 (10 microM) produced a reversible enhancement of the inotropic responses and block of the chronotropic responses to BAY K 8644. In guinea-pig ileal longitudinal smooth muscle, both AHN 086 and Ro 5-4864 reversibly inhibited field-stimulated contractions. Neither Ro 5-4864 nor AHN 086 affected the ability of nifedipine to inhibit field-stimulated contractions of ileal longitudinal smooth muscle. Treatment of intact atrial with 5 microM AHN 086 followed by extensive washing resulted in a significant inhibition (30-50%) of [3H]Ro 5-4864 binding to peripheral benzodiazepine receptors and of [3H]nitrendipine binding to voltage-operated calcium channels, but did not affect [3H]dihydroalprenolol binding to beta-adrenergic receptors on atrial membranes. The same treatment applied to intact ileal longitudinal smooth muscle affected neither [3H] (-)-quinuclidinyl benzilate binding to muscarine receptors nor [3H]nitrendipine binding, but did result in a significant inhibition (30-50%) of [3H]Ro 5-4864 binding to ileal longitudinal smooth muscle membranes.(ABSTRACT TRUNCATED AT 250 WORDS)     

The cardiac effects of amitraz in the guinea-pig in vivo and in vitro

Intravenous amitraz caused significant hypotension and bradycardia in pentobarbitone anaesthetized guinea-pigs. Depression of blood pressure reached a plateau with a dose of 10 mg/kg but heart rate continued to fall in a dose-dependent manner, up to a fall of 90 beats per minute after a total of 160 mg/kg/min. Amitraz was then tested on spontaneously beating guinea-pig isolated atria. The maximum bath concentration approximated a blood concentration produced by 5 mg/kg amitraz in the guinea-pig (2.3 X 10(-4) M). Amitraz did not significantly shift the dose-response curve to isoprenaline or acetylcholine but antagonized histamine rate responses competitively in the presence of propranolol (2 X 10(-6) M). Propranolol unmasked a dose-dependent depressant effect of amitraz on atrial rate, an effect abolished with atropine (1 X 10(-5) M). Amitraz increased atrial force of contraction, an effect which was not seen when propranolol was present in the bath solution. Amitraz also depressed atrial rate directly, but this effect was minor in comparison to bradycardia seen in the guinea-pig. It is likely that the cardiovascular depression seen in the guinea-pig following amitraz i.v. is caused by an alteration in autonomic drive rather than a significant direct cardiac effect.     

Analysis of the direct and indirect effects of adenosine on atrial and ventricular cardiac muscle

The effects of adenosine were examined upon the tension developed by isolated paced left atria, left ventricular papillary muscles, and right ventricular strips, and upon the spontaneous rate of contraction of right atria of guinea pigs. Three aspects of the direct and indirect actions were examined: the direct effects upon resting developed tension and rate, the indirect activity when added to tissues prestimulated by isoprenaline, and the indirect activity upon isoprenaline concentration--response curves when added prior to exposure to isoprenaline. The direct effects on the atria were decreases in left atrial tension and right atrial rate. These responses were antagonized by 8-phenyltheophylline (8-PT) and therefore were due to stimulation of cell surface P1 purinoceptors. This antagonism was greater in the left atria than the right. The direct ventricular effects were, in contrast, increases in force of contraction, which were not antagonized by 8-PT. This positive inotropy was also unaffected by reserpine pretreatment of the guinea pigs and therefore not due to release of endogenous catecholamines. A possible intracellular effect of adenosine is discussed. Adenosine reduced the isoprenaline-prestimulated tension or rate in both atrial and ventricular tissues, and this indirect effect was susceptible to antagonism by 8-PT. In the presence of adenosine, concentration-response curves of the left and right atria for isoprenaline were displaced to the right, and the maxima were reduced. In contrast, there was no antagonism of the papillary muscle curves to isoprenaline, but the maximum developed tension was elevated. The minimal inhibitory effects of adenosine in ventricular muscles and the high concentrations required are discussed in the context of a physiological role for endogenous adenosine in attenuating cardiac overstimulation by the sympathetic nervous system or endogenously released catecholamines.     

Influence of 2.45-GHz CW microwave radiation on spontaneously beating rat atria

The chronotropic and inotropic effects of 2.45-GHz continuous wave (CW) microwave radiation were investigated in the isolated spontaneously beating rat atria. Isolated atria were placed in specially designed tubes inserted into a waveguide exposure system. The atria were then irradiated for a period of 30 min, followed by a 30-min recovery period. The control atria were prepared simultaneously and sham exposed. Experiments were conducted at two temperatures, 22 and 37 °C, and two specific absorption rates, 2 mW/g and 10 mW/g. At both temperatures the rate of atrial contraction was not altered by a 30-min exposure at either 2 or 10 mW/g. The average rate (beats per min) was approximately 100 for both the control and exposed atria at 22 °C and 215 beats per min for both the control and exposed atria at 37 °C. In addition, no inotropic effects on the spontaneously beating atria were noted at any exposure level. These data suggest that 2.45-GHz CW microwave radiation at these intensities has no overt effect on these variables in isolated rat atria.     

Chronotropic response to hyperosmotic solutions of isolated rat atria

The changes in spontaneous rate of isolated rat atria in response to increased extracellular osmotic pressure were examined using sucrose, urea and several polyhydroxyalcohols (mannitol, glycerol and ethylene glycol) as test solutes. Sucrose, mannitol and urea induced a fall in atrial rate, which was transient with the last compound. On the other hand, media made hyperosomotic by addition of glycerol or ethylene glycol increased the beating frequency. Sucrose effect was not affected by low extracellular calcium, nifedipine or atropine. Glycerol-induced increase in atrial rate was a calcium-dependent mechanism sensitive to nifedipine. Thus, positive chronotropic effect occurs in the rat atria only with certain diffusible solutes which probably promote calcium entry. The response to pure osmotic change, resulting from changes in concentration of ions within the cell as water moves out, is a negative chronotropic effect.     

Dihydropyridine Binding Sites Regulate Calcium Influx Through Specific Voltage-Sensitive Calcium Channels in Cerebellar Granule Cells

In primary cultures of cerebellar granule cells, [3H]nitrendipine binds with high affinity to a single site (KD 1 nM and Bmax 20 fmol/mg protein). The 1,4-dihydropyridine (DHP) class of compounds such as nitrendipine, nifedipine, and BAY K 8644 displace [3H]nitrendipine binding at nanomolar concentrations. Verapamil partially inhibits whereas diltiazem slightly increases the [3H]nitrendipine binding. In these cells, the calcium influx that is induced by depolarization is very rapid and is blocked by micromolar concentrations of inorganic calcium blockers such as cadmium, cobalt, and manganese. The calcium influx resulting from cell depolarization is potentiated by BAY K 8644 and partially inhibited (approximately 40%) by nitrendipine and nifedipine. Other non-DHP voltage-sensitive calcium channel (VSCC) antagonists, such as verapamil and diltiazem, completely blocked the depolarization-induced calcium influx. This suggested that nitrendipine and nifedipine block only a certain population of VSCCs. In contrast, verapamil and diltiazem do not appear to be selective and block all of VSCCs. Perhaps some VSCCs can be allosterically modulated by the binding site for the DHPs, whereas verapamil and diltiazem may block completely the function of all VSCCs by occupying a site that differs from the DHP binding site.     

Naloxone's effect on the inotropic and chronotropic responses of isolated, electrically stimulated or spontaneously beating rat atria

Experiments were conducted to determine (i) how naloxone administration alone could modify the inotropic (in electrically stimulated (ES) rat atria) and both the inotropic and chronotropic responses (in spontaneously beating (SB) rat atria) isolated from normotensive and hypotensive (hemorrhaged) rats, and (ii) how naloxone administration would modify the inotropic and chronotropic responses of isolated rat atria previously administered an opiate agonist (morphine), a muscarinic agonist (carbachol), or an alpha- and beta-adrenergic agonist (noradrenaline). Naloxone (51-340 microM) added to ES atria caused a delayed but dose-related decrease in atrial tension (AT), whereas in SB atria, naloxone caused atrial heart rate (AHR) to fall and atrial tension (AT) to increase. Naloxone (68-340 microM), given to SB atria from acutely hypotensive rats, caused a similar increase in atrial tension as seen in the "normotensive" isolated (SB) atria and a similar decrease in atrial heart rate. Morphine sulphate (MS), 37-375 microM, administered to ES atria caused a delayed fall in AT; which was further decreased when naloxone (340 microM) was also added. In the SB atria, morphine caused a dose-related decrease in atrial heart rate whereas atrial tension increased. In SB preparations, atrial heart rate fell even further when naloxone was added to morphine compared with when morphine sulphate was given alone, whereas atrial tension was increased. Noradrenaline (3 or 12 microM) caused a positive, dose-related inotropic response in the ES atria, effects not influenced by the addition of naloxone. In the SB atria, naloxone caused no change in the dose-related increases in atrial tension and heart rate when combined with the lower dose of noradrenaline but decreased AT when combined with 12 microM noradrenaline, compared with when this dose of noradrenaline was given alone. Carbachol (683 nM-1.37 microM) caused a dose-related decrease in atrial tension in ES atria, which was reversed completely by the addition of naloxone. In SB atria, carbachol decreased both atrial tension and heart rate, and with the addition of naloxone (340 microM), a further slight drop in atrial heart rate occurred, but concurrently, a marked rise in atrial tension was observed. The results indicate that naloxone can act with receptors directly within atrial tissue to cause changes in atrial tension and heart rate. The comparable delayed responses of morphine and naloxone suggest their effects are mediated by nonopiate receptors which, in time, cause decreases in calcium influx into the atria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a specific bradycardic agent (AQ-A39) and verapamil on beta-adrenergic responses in isolated guinea pig atria

AQ-A39 (5,6-dimethoxy-2-[3-[(3,4-dimethoxy)phenylethyl)methylamino]propyl)- phthalimidine), a specific bradycardic agent, and verapamil, a calcium channel blocker, were studied for their ability to alter rate and force of contraction in the presence and absence of isoproterenol, a beta-adrenergic stimulant, using isolated guinea pig atria. Both compounds (10(-7)-10(-4) M) produced dose-related decreases in frequency of spontaneously beating right atria. Verapamil decreased, while AQ-A39 increased, the force of contraction of electrically stimulated (1.0 Hz) left atria. At equal negative chronotropic concentrations, AQ-A39 was more effective than verapamil in reducing the maximum isoproterenol-induced tachycardia. Verapamil, but not AQ-A39, antagonized positive inotropic responses to isoproterenol. Therefore, AQ-A39 differed from verapamil in that (i) AQ-A39 was a more selective bradycardic agent in both beta-adrenergically stimulated and nonstimulated preparations and (ii) AQ-A39 was more effective in reducing isoproterenol-elevated heart rate compared with basal heart rate. This profile of activities suggests that AQ-A39 will be beneficial in cardiac pathologies where sympathetic nervous system activity is elevated and a lowering of heart rate without a reduction in cardiac contractility is desired.     

The influence of calcium on ANF release in the isolated rat atrium.

We developed an in vitro model of the isolated, perfused rat atrium with which to examine the mechanisms linking muscular stretch to atrial natriuretic factor (ANF) secretion. It was shown that an increase in atrial pressure causing distension of the atria is associated with a rise in ANF secretion correlating with the degree of pressure load. Pressure-induced ANF secretion is enhanced by the calcium blocker nifedipine or omission of calcium from the perfusion buffer. The changes in atrial volume in response to a given pressure load are also more pronounced in the absence of calcium or following the addition of the calcium blocker. These data suggest that in nonbeating atria, stretch-induced ANF secretion does not rely on calcium influx.     

Dihydropiridines Mechanism of Action in Striatal Isolated Nerve Endings: Comparison with ω-Agatoxin IVA

The relative contribution of Ca2+ and Na+ channels to the mechanism underlying the action of the dihydropiridines (DHPs), nimodipine, nitrendipine and nifedipine was investigated in rat striatum synaptosomes. The rise in internal Ca2+ (Ca(i), as determined with fura-2) induced by high K+ was unchanged by the DHPs, which like tetrodotoxin (TTX) inhibited both the rise in internal Na+ (Na(i), as determined with the Na+ selective indicator dye, SBFI) and the rise in Ca(i) induced by veratridine. Nimodipine and nitrendipine were much more potent than nifedipine. Oppositely to TTX and to the DHPs, the P/Q type Ca2+ channel blocker, omega-agatoxin IVA did not inhibit the rise in Ca(i) induced by veratridine, but inhibited the rise in Ca(i) induced by high K+. Veratridine-evoked release of dopamine, GABA, Glu, and Asp (detected by HPLC) was inhibited by nimodipine, nitrendipine, and TTX, while high K+-evoked release was unchanged by the DHPs or TTX. It is concluded that the reduction in presynaptic Na+ channel permeability might contribute to the cerebral effects of DHPs.     

Sodium ion stimulates the release of atrial natriuretic polypeptides (ANP) from rat atria

The release of atrial natriuretic polypeptides from spontaneously beating isolated rat atria was found to be sensitive to the increase in the concentration of sodium ion. The osmotic pressure, when produced by pharmacologically inactive choline chloride, also increased the release of ANP but substantially less than the sodium ion. Sodium ion and osmotic pressure stimulated the release of ANP in the hyperosmotic but not in the hypo-osmotic range. Neither stretch nor several neurotransmitters tested had any effects on the rate of ANP secretion.     

Interaction of the autonomic nervous system with intrinsic cardiac rate regulation in the guinea-pig, Cavia porcellus.

In the denervated mammalian heart a change in right atrial pressure will still alter heart rate (intrinsic rate response, IRR). We have examined the IRR in isolated right atria of the guinea-pig maintained in oxygenated Krebs-Henseleit solution at 37 degrees C, to compare with and extend studies in other species, and to determine whether the guinea-pig is a suitable model for electrophysiological studies of the IRR. Baseline diastolic transmural pressure was set at 2 mmHg. A 6-mmHg increase in right atrial pressure (RAP) caused an increase in atrial rate that reached a steady value of 15 min(-1) after 1-2 min. This response was enhanced by carbamylcholine and attenuated by isoprenaline. The influence of RAP on the rate response to vagal stimulation was examined. With RAP set at 8 mmHg, the reduction in atrial rate following vagal stimulation was 72+/-5% of that at 2 mmHg (n=6, mean+/-S.E., P<0.005). Continuous vagal stimulation produced a sustained bradycardia, and the effect of this bradycardia on the IRR was examined. When atrial rate was reduced 6% by vagal stimulation, the IRR was augmented to 202+/-21% of the control (n=6, P<0.005). This augmentation was larger (P<0.05) than that seen when atrial rate was reduced 8% by carbamylcholine (130+/-8% of control; n=7, P<0.05). Overall, the IRR in the guinea-pig is similar to that in the rabbit, and shows similar interactions with the autonomic nervous system.     

Nicardipine inhibits axon conduction but causes dual changes of acetylcholine release in the mouse motor nerve

The effects of nicardipine, a dihydropyridine Ca2(+)-channel antagonist, on neuromuscular transmission and impulse-evoked release of acetylcholine were compared with those of nifedipine. In the isolated mouse phrenic nerve diaphragm, nicardipine (50 microM), but not nifedipine (100 microM), induced neuromuscular block, fade of tetanic contraction, and dropout or all-or-none block of end-plate potentials. Nicardipine had no significant effect on the resting membrane potential and the amplitude of miniature end-plate potentials but increased the frequency and caused the appearance of large size miniature potentials. The quantal contents of evoked end-plate potentials were increased. In the presence of tubocurarine, however, nicardipine depressed the amplitude of end-plate potentials. The compound nerve action potential was also decreased. It is concluded that nicardipine blocks neuromuscular transmission by acting on Na+ channels and inhibits axonal conduction. Nicardipine appeared to affect the evoked release of acetylcholine by dual mechanisms, i.e., an enhancement presumably by an agonist action on Ca2+ channels, like Bay K 8644 and nifedipine, and inhibition by an effect on Na+ channels, like verapamil and diltiazem. In contrast with its inactivity on the amplitude of miniature end-plate potentials, depolarization of the end plate in response to succinylcholine was greatly depressed. The contractile response of baby chick biventer cervicis muscle to exogenous acetylcholine was noncompetitively antagonized by nicardipine (10 microM), but was unaffected by nifedipine (30 microM). These results may implicate that nicardipine blocks the postsynaptic acetylcholine receptor channel by enhancing receptor desensitization or by a use-dependent effect.     

Role of cell contractions in cAMP-induced cardiomyocyte atrial natriuretic peptide release

Incubation of spontaneously beating ventricular cardiomyocytes from neonatal rats with prostaglandin E(2) (0.1 microM) or forskolin (0.1 microM) simultaneously increased the rate of cellular contraction and atrial natriuretic peptide (ANP) secretion. Both responses were maximal within 10-20 min of application and were accompanied by three- to fourfold increases in cAMP formation. By contrast, a higher regimen of forskolin (10 microM) promoted a 20- to 30-fold increase in basal cAMP production, which was accompanied by the abolition of contractile activity and ANP release. Low regimens of forskolin (0.1 microM) doubled the occurrence of cytosolic Ca(2+) transients associated with monolayer contraction, whereas higher regimens of forskolin (10 microM) completely suppressed Ca(2+) transients. Moreover, in quiescent cultures that were pretreated with ryanodine, tetrodotoxin, nifedipine, or butanedione monoxime, prostaglandin E(2) (0.1 microM) and forskolin (0.1 microM) failed to elicit significant ANP secretion, suggesting that cAMP-elevating agents promote ANP secretion to a great extent via an increase in cellular contraction frequency in ventricular cardiomyocytes.     

嘌呤拟似物对豚鼠胃窦环行肌自发性收缩及电活动的影响

为探讨非肾上腺素能非胆碱能神经递质对胃窦环行肌功能的调节作用,在离体胃平滑肌上观察了嘌呤拟似物对胃窦环行肌自发性收缩活动和电活动的影响。电活动用传统的细胞内微电极记录,并和收缩活动同步描记于多道生理记录仪。结果表明,嘌呤能P2Y受体激动剂,三磷酸腺苷(ATP)和2-methylthio ATP(2-MeSATP)均增强胃窦平滑肌的收缩活动,但不影响电活动,而且ATP和2-MeSATP对胃平滑肌收缩活动的增强作用可被嘌呤能P2Y受体阻断剂,reactive blue-2和苏拉明(suramin)所阻断。用100μmol／L α,β-MeATP引起的脱敏感使P2X受体被阻断,ATP增强胃窦平滑肌收缩活动的效应不受影响。嘌呤能P2X受体激动剂,α,β-MeATP明显抑制胃窦环行肌自发性收缩活动,同时使膜电位明显超极化。ATP对胃窦平滑肌的收缩作用不被L型钙通道阻断剂尼卡地平(nicardipine)阻断,但细胞外用无钙液灌流时这种效应则完全被阻断。用前列腺素合成抑制剂消炎痛预先处理20min后,ATP和2-MeSATP仍能增强胃窦平滑肌的自发性收缩活动。以上结果提示：(1)ATP和2-MeSATP通过嘌呤能P2Y受体增强胃窦平滑肌的自发性收缩活动,而α,β-MeATP或β,γ-MeATP通过嘌呤能P2X受体使膜电位超极化,引起胃窦平滑肌的舒张;(2)ATP和2-MeSATP增强胃窦平滑肌自发性收缩活动的效应依赖于细胞外钙,但钙离子进入细胞的途径并不是电压依赖性钙通道;(3)ATP和2-MeSATP增强胃窦平滑肌自发性收缩活动的效应不通过前列腺素介导。     

The endothelium-derived vasoconstrictor peptide endothelin inhibits renin release in vitro

The effect of endothelin, a newly identified endothelium-derived vasoconstrictor peptide, on renin release from rat kidney cortical slices was examined. Endothelin produced a concentration-dependent inhibition of renin release and this inhibitory effect was dependent on extracellular calcium. The dihydropyridine calcium channel blockers nifedipine and nicardipine did not antagonize the inhibitory effect induced by endothelin. On the other hand, nifedipine completely antagonized the extracellular high potassium- or Bay K 8644-induced inhibition of renin release. The endothelin-induced inhibition of the release was markedly blocked by the addition of Co2+. Similar blocking effects of Co2+ were also observed with extracellular high potassium or Bay K 8644. Thus, endothelin exerts an inhibitory action on renin release in vitro, in a calcium-dependent manner. This inhibition may be mediated by the increased calcium influx through dihydropyridine-insensitive calcium channels.