Effect of calcium channel blockers on histamine liberation from isolated basophils and bronchial reactivity in patients with bronchial asthma]

An effect of verapamil and nifedipine on the cellular histamine release and non-specific reactivity of the bronchi measured with methacholine test was studied. In vitro tests were carried out in basophils isolated from 19 asthmatic patients. Reactivity of the bronchi was investigated in 5 patients. Both verapamil and nifedipine significantly inhibited histamine release from the cells in vitro in all examined concentrations (10(-7)-10(-4) M) while a single dose of these drugs administered to the asthmatic patients did not exert a significant effect on the airway constriction in vivo.     

The effect of calcium antagonists on cholesterol metabolism in human aortal intima cells and macrophage lines]

Effects of two Ca-antagonists, verapamil and nifedipine, on the total cellular cholesterol content and accumulation, as well as on the synthesis and hydrolysis of cholesteryl esters in human aortic intimal smooth muscle cells and P388D1 cell line have been studied. Verapamil and nifedipine used at 10(-6) M and higher concentrations decreased the total cellular cholesterol content (by 25-40%) in intimal cells isolated from atherosclerotic lesions without any effect on the cholesterol content in normal intimal cells or P388D1 cells. At 2 x 10(-5) M verapamil and nifedipine prevented the accumulation of cholesterol induced by atherogenic blood serum or atherogenic low density lipoproteins in both types of cells. At 10(-5) M and higher concentrations verapamil and nifedipine inhibited (2-3-fold) cholesteryl ester synthesis in intimal cells and, used at 10(-6) M and higher doses, in P388D1 cells as well. Verapamil and nifedipine (2 x 10(-5) M) enhanced the hydrolysis of cholesteryl esters in both types of cells. The Ca-channel agonist Bay K8644 had no effect on cholesteryl ester synthesis, nor did it suppress its inhibition by Ca-antagonist. The beta-receptor blocker propranolol induced the accumulation of cholesterol in intimal cells and inhibited the synthesis and hydrolysis of cholesterol esters in these cells. The data obtained suggest that the antiatherosclerotic action of Ca-blockers is determined by their ability to reduce the cellular cholesterol content which is suggested to be the result of enhanced hydrolysis of cellular cholesteryl esters.     

Metabolism of cholesterol esters in cultured macrophages under the action of the calcium antagonists verapamil and nifedipine]

Using mouse macrophage cultures, the effects of verapamil and nifedipine on cholesterol ester metabolism were studied with special reference to the following parameters: i) incorporation of 14C-oleate into cholesterol esters (ChE), ii) contents of common and free cholesterol (FCh), iii) removal of 14C-oleate from ChE and incorporation of 3H-FCh into ChE and, iiii) excretion of 3H-Ch from the cells. Verapamil and nifedipine (10-100 microM) decreased the incorporation of 14C-oleate into ChE, increased the concentration of FCh but had no appreciable effect on the concentration of common Ch in macrophages cultured in the presence of acetylated low density lipoproteins. The drugs stimulated the removal of 14C-oleate from cellular ChE. The pharmacological concentrations (25-75 microM) of verapamil and nifedipine increased the excretion of 3H-Ch from ChE of macrophages in the presence of serum and high density lipoproteins. The results obtained suggest that verapamil and nifedipine mediate the antiatherosclerotic effect via reduction of intracellular synthesis of ChE, stimulation of ChE hydrolysis and cholesterol excretion from the cells.     

Comparison of verapamil and nifedipine in thrombosis models

Calcium blockers and calmodulin antagonists have been reported to inhibit the aggregation of blood platelets in vitro. In the present study, the effects of two calcium blockers, verapamil and nifedipine, were compared in several rodent thrombosis models. In rat and mouse platelet-rich plasma, preincubation with either verapamil or nifedipine had a dose-dependent inhibitory effect on collagen-induced aggregation (P less than 0.01). The concentration required for 50% inhibition of rat platelet aggregation was 0.91 X 10(-4) M for verapamil and 1.77 X 10(-4) M for nifedipine. In in vivo thrombosis models in mice, acute pretreatment with nifedipine had a significant, dose-dependent protective effect (P less than 0.05). At a dose of 500 micrograms/kg, nifedipine inhibited thrombotic sudden death provoked by arachidonic acid, a thromboxane agonist (U46619), or a combination of collagen and epinephrine. In vivo platelet depletion induced by U46619 was also inhibited by this calcium blocker. Thus, nifedipine is protective against a variety of thrombotic stimuli, and its antiplatelet aggregatory effect apparently extends to the in vivo situation. In contrast, no in vivo antithrombotic activity was observed for verapamil. Two additional calcium blockers, perhexilene and diltiazem, and three calmodulin antagonists, W-7, chlorpromazine, and trifluoperazine, were also tested in the U46619-induced thrombotic sudden death model. Of these, only diltiazem (5 and 10 mg/kg) had an acute protective effect.     

Calcium Antagonists Prevent Monocyte and Endothelial Cell-Induced Modification of Low Density Lipoproteins

Low density lipoprotein (LDL) incubated in the presence of the calcium antagonists verapamil, nifedipine and flunarizine were more resistant than control LDL to human monocyte- or endothelial cell-induced modification, as assessed by electrophoretic mobility in agarose gel, thiobarbituric acid reactive substance content, and degradation by J774 macrophages. The efficiency of the drugs was: flunarizine > nifedipine > veraparml. Moreover, a 24 h preculture with calcium antagonists significantly impaired the ability of cells to modify LDL in the absence of the drugs. All the studied drugs also inhibited copper-induced autooxidation of LDL. None of the studied calcium antagonists, at concentrations up to 10^-4 M, significantly reacted with free radicals as assessed by the l,1-diphenyl-2-picrylhydrazyl test. It is suggested that such a protective effect of calcium antagonists against LDL peroxidation could play a role in the previously reported antiatherogenic effect of these drugs.     

Effect of calcium entry blockers and adenosine on the relaxation of large and small coronary arteries

The mechanism(s) by which adenosine causes dilation of the vascular smooth muscle is not properly understood. Several mechanisms including the inhibition of calcium influx and intracellular translocation have been suggested for its action. This study is an attempt to further elucidate the site of action of adenosine in relation to calcium by making use of calcium entry blockers. Large (1 +/- 0.2 mm, o.d.) and small (0.5 +/- 0.2 mm, o.d.) branches of bovine left anterior descending coronary artery (LADCA) contracted with 50 mM K+ were used as a model for these studies. Concentration-response curves for various calcium entry blockers were obtained and the order of potency was found to be: D-600 greater than nifedipine greater than verapamil greater than diltiazem greater than lidoflazine for large branches and nifedipine greater than D-600 greater than verapamil greater than lidoflazine greater than diltiazem for small branches of LADCA. The concentration-response relationship for adenosine (10(-6)-10(-4) M) in the presence and absence of these drugs (10(-9)-10(-7) M) was unchanged. 8-phenyltheophylline (2 X 10(-5) M), an adenosine receptor antagonist was without an effect on the relaxations induced by various calcium entry blockers, however, it antagonized the relaxing response to adenosine. Lidoflazine at concentrations of 7 X 10(-7) M and 2 X 10(-7) M potentiated the effect of adenosine in relaxing the large and small LADCA, respectively. In summary, the data show an increased sensitivity of small coronary vessels to nifedipine, D-600 and lidoflazine. The data further suggest a different site of action for adenosine and calcium entry blockers.     

Evidence for a tonic inhibitory role of nifedipine-sensitive calcium channels in aldosterone biosynthesis.

This study investigated the effects of the calcium channel blockers nifedipine (a dihydropyridine) and verapamil (a papaverine derivative), on aldosterone production utilizing isolation of the early and late phases of aldosterone biosynthesis. Pregnenolone production (the early phase of aldosterone biosynthesis) was assessed in trilostane-treated bovine glomerulosa cells, used to inhibit the conversion of pregnenolone onwards to aldosterone. Conversion of exogenous corticosterone to aldosterone, an index of late phase activity, was assessed using aminoglutethimide to inhibit endogenous aldosterone production. Low concentrations of nifedipine, 10(-11)-10(-9) M, stimulated basal total aldosterone biosynthesis by enhancing the late phase although the early phase was inhibited. In the presence of 12 mM potassium (K+), which is less effective in stimulating aldosterone production than lower K+ concentrations, aldosterone production was enhanced by nifedipine, 10(-8) M, by an effect on the late phase. At K+ 6 and 8 mM, nifedipine, 10(-4) M, inhibited the early phase. Nifedipine 10(-5) inhibited angiotensin II (AII)-stimulated total aldosterone biosynthesis by independent effects on the early and late phases. Verapamil, 10(-4) M, inhibited total and early phase aldosterone production at K+, 4 mM and inhibited both phases at K+, 8 mM, stimulation was not observed using verapamil. Verapamil, 10(-4) M, also inhibited AII-stimulated aldosterone production. Basal and AII-stimulated pregnenolone production were inhibited by verapamil, 10(-4) M (basal) and 10(-6) M (AII-stimulated). These studies using nifedipine have revealed subtle calcium-dependent mechanisms involved in the tonic inhibition of activity in the late phase of aldosterone biosynthesis and the reversal of the inhibitory effect of high K+ concentrations also on the late phase. In addition, the data reported indicate that both AII and K+ independently enhance activity in the early and late phases of aldosterone production by calcium-dependent mechanisms.     

Suppression of mediator secretion in murine neogenic motor synapses with the participation of L-type Ca<Superscript>2+</Superscript>-channels and ryanodine receptors

L-type Ca²⁺-channel blockers, verapamil (5 μM) and nifedipine (10 μM), have increased the quantum composition of endplate potentials (EPP) and the level of induced rhythmic activity of neogenic synapses. L-type Ca²⁺-channel activator BAY K 8644 (1 μM) has a decreased mediator secretion level. Nifedipine (10 μM) has not changed the frequency and amplitude of diminutive EPPs in the dormant state or during potassium depolarization. Blocking of the prejunctional ryanodine receptor with ryanodine (10 μM) led to an increase in the single EPP quantum composition that was qualitatively similar to nifedipine and verapamil, but more marked, and also caused the reinforcement of mediator release during the rhythmic EPP salvo. Ryanodine receptor activation with ryanodine (1 μM) resulted in reduction of the quantum composition of single and rhythmic EPPs. This effect was partially prevented with nifedipine (10 μM).     

Arachidonic acid metabolism in isolated aorta and lung of the rat: Effects of dipyridamole,nifedipine, propranolol,hydralazine and verapamil

Effects of some vasodilating (dipyridamole, nifedipine and verapamil) and antihypertensive (propranolol, hydralazine) drugs on arachidonic acid metabolism in isolated rat aorta and lung have been studied. Dipyridamole significantly increased the formation of PGI₂ in aorta and lung. Nifedipine and verapamil decreased the formation of PGI₂ in aorta, these drugs though significantly increased the formation of PGI₂ in lung. Nifedipine showed no appreciable effect on the generation of TxA₂ in rat aorta but in lung both nifedipine and verapamil reduced TxA₂ formation though significantly only in the latter case. Dipyridamole showed no effect. The beneficial effect of dipyridamole, seems, at least in part, to be due to its ability to enhance the production of PGI₂ both in the aorta and lung, and probably in other tissues as well. Nifedipine and verapamil may show their antianginal effect by a combined effect of enhanced PGI₂ and reduced TxA₂ formation in lung. In lung, whereas hydralazine reduced the formation of both PGI₂ and TxA₂, propranolol increased the formation of PGI₂. Hydralazine reduced the formation of TxA₂ and increased PGI₂ formation in aorta. The effect of the drugs on the ability of rat aorta to inhibit collagen induced platelet aggregation of human blood platelets was also examined.     

Nitric oxide stimulates growth hormone secretion in vitro through a calcium- and cyclic guanosine monophosphate-independent mechanism

In the last years, nitric oxide (NO) has emerged as an important intra- and intercellular transmitter involved in the control of the hypothalamic-pituitary axis, and NO synthase (NOS) has been identified in pituitary cells. To determine the role of NO in the control of GH secretion acting directly at the pituitary level, we have studied GH release by hemipituitaries incubated in the presence of different concentrations (10(-7)-10(-3) M) of sodium nitroprusside (SNP), a potent NO donor. We found that SNP (10(-4)-10(-3) M) stimulated GH release. This effect was mediated by the release of NO since it was abolished in the presence of hemoglobin, a scavenger of NO, but preserved in the presence of rhodanese + sodium thiosulfate (inactivators of cyanides generated from SNP). To analyze the participation of cyclic guanosine monophosphate (cGMP), the second messenger for a wide range of NO actions, in SNP-stimulated GH secretion, hemipituitaries were incubated in the presence of 8-bromo-cGMP (8-Br-cGMP; 10(-7)-10(-3) M). In addition, hemipituitaries were stimulated with SNP plus oxadiazoloquinoxaline (OQD) or LY 83,583 (inhibitors of guanylyl cyclases). We found that 8-Br-cGMP was ineffective in eliciting GH release, and that the stimulatory effect of SNP was maintained in presence of OQD and LY 83,583. Finally, to analyze calcium dependence, the SNP effect was studied in hemipituitaries incubated in free medium calcium, in the presence of nifedipine and verapamil (blockers of calcium channels) and after depletion of intracellular Ca(2+) stores with caffeine. We found that the SNP-induced GH secretion is also detected after incubation of hemipituitaries in free calcium medium, in the presence of nifedipine and verapamil, and after caffeine preincubation. We conclude that NO stimulates GH secretion in vitro through a specific calcium-cGMP-independent mechanism. Copyrightz1999S.KargerAG,Basel     

Multiple effects of BAY K 8644 and nifedipine on isolated diaphragmatic fibers in vitro.

The dose-response effects of BAY K 8644 and nifedipine on diaphragmatic contractility were assessed in vitro. Isolated diaphragmatic fibers were obtained from rats and placed in an open-topped channel of a Plexiglas tissue chamber perfused with continuously flowing Krebs solution heated to 37 degrees C. Isometric twitch force, generated in response to 1-Hz supramaximal electrical stimulation (4 times/min), was measured with a highly sensitive photoelectric force transducer. Low doses of BAY K 8644 or nifedipine (10(-7) M) were without effect on twitch tension. For 10(-6) M, twitch tension increased by 10 +/- 1% (P less than 0.005) for both drugs. For 10(-5) M, twitch tension increased by 12 +/- 1% (P less than 0.05), and maximal contractures were observed (BAY K 8644 and nifedipine). Simultaneous drug administration did not reveal mutual antagonism as expected; instead the effects were additive, with twitch tension increasing by 30 +/- 2% (P less than 0.001) for 10(-5) M BAY K 8644 + nifedipine. Both BAY K 8644 and nifedipine altered twitch characteristics. In low-calcium media (0.5 mM) twitch potentiation produced by the two drugs was further enhanced (increasing 60% for 10(-5) M BAY K 8644 or nifedipine). Contractures, by contrast, were abolished. From these results it is difficult to reconcile a unique action of these drugs on calcium channels as is conventionally accepted.     

The heart of Daphnia magna: effects of four cardioactive drugs

We used Daphnia magna bioassays to determine the LC(50) and the effects on the heart of the cardioactive drugs ouabain, verapamil, metaproterenol and metoprolol. Distinctions were made between the pharmacological and toxicological effects of these drugs and the adequacy of physicochemical characteristics of its habitat (reconstituted water). Video microscopy and digital image processing were used to study the pharmacological effects on the heart. D. magna exhibited the expected sensitivity to the reference toxicant sodium dodecyl sulfate with a LC(50) of 15.6+/-4.5 mg/l. All drugs were toxic with 48 h-LC(50) of 2.03 mg/l ouabain, 7.04 mg/l verapamil, 32.45 mg/l metaproterenol and 76.21 mg/l metoprolol. Ouabain was the most toxic and caused a positive concentration-dependent inotropic effect. Verapamil caused positive chronotropic and inotropic effects, while metaproterenol showed positive concentration-dependent chronotropic effects at high concentrations (10(-3) and 10(-4) M). Metoprolol induced a positive chronotropic effect at low concentrations (10(-8), 10(-7), 10(-6) M) and a negative chronotropic effect at high concentration (10(-4) M). Ouabain, metaproterenol and metoprolol in D. magna caused similar effects to those produced in mammals. In contrast, verapamil caused opposite effects. The results suggest the presence of Na(+), K(+)-ATPase receptors to verapamil and of non-specific adrenergic receptors in heart of D. magna.     

Differential sensitivity of Dahl salt-sensitive and Dahl salt-resistant rats to the hypotensive action of acute nifedipine administration

The calcium antagonist, nifedipine, was intravenously administered in a cumulative fashion, from 0.5 to 12 mg/kg, to Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats which had been maintained on a high (8.0%) or low (0.4%) salt (NaCl) diet. We observed, compared with the DR rats, dose-related and significant (P less than 0.001) falls in the systolic (SBP) (72 +/- 3 and 60 +/- 9%, respectively) and diastolic blood pressure (DBP) (67 +/- 2 and 62 +/- 6%) o the DS rats maintained either on the low (0.4%) or high (8.0%) salt diets. In contrast, nifedipine therapy comparatively produced only moderate changes in the SBP and DBP of the DR rats (36 +/- 12, 27 +/- 9, 31 +/- 10, and 30 +/- 11%, respectively). We hypothesize that this differential sensitivity of the DS and DR rats to the hypotensive action of nifedipine may reflect a significantly more important role for a high resting Ca2+ influx, through nifedipine sensitive channels, in the maintenance of the blood pressure of the DS rat.     

Verapamil enhances high-density lipoprotein processing in Hep G2 cells preloaded with cholesterol

The effects of the calcium channel blocker of the arylalkylamine series verapamil have been investigated on high-density lipoprotein (HDL3) catabolism in the human hepatoma cell line Hep G2. It was found that verapamil markedly enhanced HDL3 binding, uptake and degradation in Hep G2 cells preloaded with nonlipoprotein cholesterol. This effect was dose-dependent, and a 1.5-2-fold increase of the three studied parameters was observed in cells pretreated 24 h with 100 microM verapamil. No significant effect of the drug was found in cells not preincubated with cholesterol. Verapamil induced an increase in the cellular cholesterol content in preloaded cells. Other calcium antagonists such as diltiazem, nifedipine, nitrendipine or amphiphilic drugs such as phenothiazines and propranolol also enhanced HDL3 uptake by Hep G2 cells. These effects of verapamil on HDL3 metabolism could be related to its amphiphilic characteristics, and to its calcium antagonist properties.     

The beta-adrenergic receptor and adenylate cyclase of rat reticulocytes as a test system for screening pharmacologic preparations

The effect of cardio- and neurotropic drugs was studied on beta 2-adrenergic receptors and coupled adenylate cyclase (AC) from rat reticulocytes. Trifluperazine, chlorpromazine, levomepromazine, metaphenazine, haloperidol, (+) and (-) isomers of butaclamol, as well as imipramine, vinblastine and verapamil, at a concentration of 10(-4) M failed to influence AC stimulation by isoproterenol. Thioproperazine and trifluperidol inhibited isoproterenol-stimulated AC with Ki = 4.0.10(-5) M and Ki = 4.5.10(-5) M, respectively. This inhibitory effect was due to the direct action of thioproperazine and trifluperidol on the beta-adrenergic receptors, since this drugs displace the receptor-bound (3H) dihydroalprenolol with Ki = 5.10(-6) M and 9.10(-6) M, respectively. The results obtained suggest that adrenolytic effect of trifluperidol and thioproperazine might play a significant role in their side effects.     

Further investigation of a potential calcium channel modulator isolated from rat erythrocytes

The contractile effects of a peptide isolated from rat erythrocytes were further studied in rat aortic rings. Previous data showed that preincubation of aortic tissue with the peptide had no effect on resting tension, but significantly enhanced K+ and norepinephrine (NE) induced contraction. The calcium channel antagonist verapamil noncompetitively blocked the effect of the peptide, whereas nifedipine blockage appeared to be competitive. In the present study the peptide enhanced K+, NE, and phenylephrine (PE) induced contraction in a concentration-dependent manner, with a maximum enhancement at peptide concentrations of 10(-7)-10(-6) M. At a concentration as low as 10(-9) M, the peptide significantly enhanced K(+)-induced, but not NE- or PE-induced, contraction. The magnitude of maximal enhancement was greater for K(+)-induced contraction than that for NE- or PE-induced contraction. Preincubation of the tissues with the peptide caused a leftward shift of cumulative concentration-response curves to K+ and NE. The peptide enhancement of contraction increased with increasing K+ and NE concentration. The peptide potentiated the contractile response to Ca2+ in K(+)-depolarizing medium. It also enhanced the contractile response to NE in intracellular Ca2(+)-pool-depleted tissue following the replenishment of extracellular Ca2+, but had no apparent effect on the mobilization of intracellular calcium. Addition of nifedipine caused a rightward shift of both the peptide and Bay K 8644 concentration-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipid peroxidation of phosphatidylcholine liposomes depressed by the calcium channel blockers nifedipine and verapamil and by the antiarrhythmic-antihypoxic drug stobadine

Nifedipine, verapamil and stobadine were tested and compared with butylated hydroxytoluene (BHT) as possible free radical scavengers inhibiting lipid peroxidation in phosphatidylcholine liposomes. Liposomes were peroxidized by incubation in air at 50 degrees C. Verapamil less than nifedipine less than BHT less than stobadine depressed the lipid peroxidation as detected spectroscopically for conjugate diene and thiobarbituric acid product formation. Verapamil and stobadine were tested as OH radical scavengers in a Fenton-type reaction against spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO), as detected by ESR spectroscopy. The tested drugs competed with DMPO in trapping OH radicals, with stobadine being more effective than verapamil. ESR spectra of nifedipine in the incubated liposomes revealed that nifedipine could be involved in free radical reactions in the liposomes leading to nifedipine-stable radical(s) which were immobilized in the membrane. The obtained results suggest that some of the beneficial effects of the studied drugs can be mediated in disease by their ability to scavenge free radicals and by their protective effect on lipid peroxidation.     

Prolongation of the effective refractory period on isolated guinea pig atria by some anti-arrhythmia agents: relevance in a comparison of their potentialities]

The effects of bepridil, nifedipine, verapamil, lignoca?ne and amiodarone on the atrial effective refractory period were investigated in the guinea-pig. The observed results permitted elucidation of a remarkable activity by both nifedipine and verapamil, and by bepridil and lignoca?ne. In contrast, in the experimental conditions, no activity was detected with amiodarone up to concentrations of 10(-4) M. The efficacity rating of the test compounds is not reflected by their anti-arrhythmic efficacity as demonstrated in vivo in the animal, nor by their therapeutic anti-arrhythmic efficacity as reported in the clinical literature. However, this efficacity rating may be related to the interaction of the compounds with the transmembrane sodium or calcium movements.     

Nitrergic relaxation in rat gastric fundus: influence of mechanism of induced tone and possible role of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase

The aim of this study was to investigate the influence of the mechanism of induced tone and the role of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) in nitrergic relaxation of rat gastric fundus. Prostaglandin F(2alpha) (PGF(2alpha)), thapsigargin (TSG) and cyclopiazonic acid (CPA) were used in concentrations that induced a similar contraction (20 g force/g tissue). Nifedipine (3 x 10(-7) M) completely relaxed PGF(2alpha)-contracted tissues and relaxed tissues contracted by TSG and CPA by 20 +/- 6% and 56 +/- 12% respectively; contraction induced by the three contractile agents was fully reversed by a general Ca2+ entry blocker 1-[2-(4-methoxyphenyl)-2-[3-(4-metoxyphenyl)propoxy]ethyl-1H-imidazole HCl (SKF 96365; 10(-5) M). In the presence of nifedipine (3 x 10(-7) M) or verapamil (10(-5) M), PGF(2alpha) and CPA-induced contractions were still approximately 50% relaxed by SKF 96365. This suggests that contractions induced by PGF(2alpha) are related to Ca2+ entry through L-type voltage-operated Ca2+ channels and that contractions by TSG are mainly related to Ca2+ entry through store-operated Ca2+ channels. Relaxant responses to exogenous nitric oxide (NO), to endogenous NO released by electrical field stimulation, and to vasoactive intestinal polypeptide (VIP) were studied in tissues contracted by TSG and CPA and compared to responses in tissues contracted by PGF(2alpha). Responses to exogenous and endogenous NO were greatly attenuated in TSG-contracted tissues, but not in CPA-contracted tissues. When contraction was induced by CPA in the presence of nifedipine or verapamil, relaxations to exogenous and endogenous NO were also significantly reduced. Relaxation induced by VIP was reduced in tissues contracted by either TSG or CPA in the presence of nifedipine or verapamil. These results suggest that the ability of the nitrergic neurotransmitter to induce relaxation of rat gastric fundus is influenced by the mechanism used to induce tone and are indicative for a role for SERCA in nitrergic relaxation. However, activation of SERCA appears to not be unique for nitrergic relaxation, but might also be used by VIP, a co-transmitter of NO in this tissue.