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PubMed1987

Pharmacological modulation of bradykinin-, acetylcholine- and calcium ionophore A23187-induced relaxation of rabbit pulmonary arterial segments.

Bradykinin (BK; 10(-10)-10(-7) M) relaxes phenylephrine-contracted rabbit isolated pulmonary arterial rings. The mechanical destruction of the endothelial layer obliterates acetylcholine (ACh) and A23187-induced relaxation without influencing BK-, isoproterenol-, sodium nitroprusside- and papaverine-induced relaxations. Atropine and propranolol selectively antagonized ACh- and isoproterenol-induced relaxation, respectively, without influencing BK-induced relaxation. Indomethacin (1.4 X 10(-5) M, a potent cyclooxygenase inhibitor, 30-60 min) and p-bromophenacylbromide (5 X 10(-6) M, p-BPB, a potent phospholipase A2 inhibitor, 30-60 min) selectively inhibited BK-induced relaxation without influencing relaxation to isoproterenol, sodium nitroprusside and papaverine. These data suggest that BK stimulates PLA2 and releases arachidonic acid (AA), which is further metabolized via cyclooxygenase and prostaglandin synthetase to prostacyclin (PGI2), causing relaxation of rabbit pulmonary arterial segments. The inhibition of ACh- and A23187-induced relaxation by p-BPB, but not by indomethacin, suggest that initial activation of PLA2 causes the release of AA, which is subsequently metabolized to endothelial-derived relaxant factor (EDRF; lipid peroxides, ROOH, ROO-?).

Acetylcholine↗
PubMed1990

Effects of CGS-15943A on the relaxations produced by adenosine analogs in human blood vessels.

The antagonistic effects of CGS-15943A on the relaxations produced by adenosine and its analogs in human blood vessels were investigated in vitro. Donor hearts were the source of coronary arteries, whereas the internal mammary arteries and saphenous veins were obtained from patients undergoing coronary bypass surgery. Adenosine and its analogs, 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine (CAD), produced concentration-dependent relaxations in KCl-contracted coronary rings. CGS-15943A antagonized, significantly, the relaxations produced by adenosine, NECA and CAD in coronary arteries. Similarly, the adenosine receptor antagonist, 8-phenyltheophylline (8PT, 10-mumol/l), caused a significant attenuation of the relaxing responses to adenosine, NECA and CAD in coronary arteries. In rings obtained from internal mammary arteries and saphenous veins, adenosine, NECA and CAD all produced concentration-dependent relaxations. These relaxations were smaller in magnitude than those obtained in coronary arteries, and were slightly greater in rings contracted with 10 mumol/l prostaglandin F2 alpha (PGF2 alpha) as compared to 35 mmol/l KCl. However, the mammary arteries and saphenous veins relaxed completely in response to 100 mumol/l papaverine. CGS-15943A (10 mumol/l) did not antagonize the relaxing effects of adenosine and its analogs in these vessels. The results show that coronary arteries are more responsive than mammary arteries or saphenous veins to the relaxing effects of adenosine analogs and that these relaxing responses are dependent on the contracting agent. Furthermore, CGS-15943A demonstrated antagonism of the adenosine response in coronary arteries.

Adenosine↗
PubMed1992

Effect of 3-isobutyl-1-methylxanthine and zaprinast on non-adrenergic non-cholinergic relaxation in the rat gastric fundus.

Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) have been proposed as inhibitory non-adrenergic non-cholinergic (NANC) neurotransmitters in the rat gastric fundus. The smooth muscle relaxant actions of VIP and NO are medaited by cAMP and cGMP, respectively; therefore the effect of inhibitors of phosphodiesterases responsible for cyclic nucleotide breakdown on relaxation induced by VIP, NO and electrical field stimulation was investigated. The non-specific phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), the cGMP-specific phosphodiesterase inhibitor, zaprinast, the adenylate cyclase activator, forskolin, and the cyclic nucleotide analog, 8-bromo cGMP, produced concentration-dependent relaxation of rat gastric fundus strips precontracted by PGF2 alpha. IBMX potentiated isoprenaline-induced relaxation but not relaxation induced by sodium nitroprusside, VIP, NO or electrical field stimulation. Zaprinast potentiated the relaxation induced by sodium nitroprusside, while having no influence on relaxation due to any other stimulus. The combination of both phosphodiesterase inhibitors did not significantly affect the electrically induced relaxation. It is concluded that both cAMP and cGMP mediate relaxation in the rat gastric fundus. Further research is needed to investigate the role of the cyclic nucleotides during NANC relaxation of this tissue.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Investigation of nicotine-induced relaxation of circular smooth muscle of the guinea-pig gastric fundus.

A possible mechanism for the nicotine-induced relaxation of circular muscle strips of the guinea-pig gastric fundus was investigated. In the presence of atropine (0.2 microM), nicotine produced concentration-dependent relaxation with a maximum effect at 100 microM (mean pEC50 value, 4.60). The maximum relaxation due to nicotine was greatly reduced by pretreatment with tetrodotoxin (0.3 microM) or hexamethonium (10 microM), but not with metitepine (0.3 microM). Combined pretreatment with timolol (0.3 microM) and phentolamine (0.3 microM) or chemical sympathectomy by 6-hydroxydopamine pretreatment partially inhibited the nicotine-induced relaxation. alpha-Chymotrypsin (2 u/ml) which abolished the equivalent relaxation induced by vasoactive intestinal polypeptide (VIP) had no effect on nicotine-induced relaxation. NG-Nitro-L-arginine (L-NNA) and NG-Nitro-L-arginine methyl ester (L-NAME) caused a concentration-dependent inhibition of the nicotine-induced relaxation (98% inhibition at 10 microM of L-NNA), but had no effect on sodium nitroprusside- or noradrenaline-induced relaxation. The inhibitory effect of L-NNA or L-NAME was reversed completely by L-arginine (3 mM), but not by D-arginine (3 mM). From these results, we concluded that nicotine-induced relaxation of the guinea-pig gastric fundus is mediated largely by the release of nitric oxide or a related substance and partially by the release of noradrenaline. Possible contributions of 5-hydroxytryptamine or VIP to the nicotine-induced relaxation appear to be negligible.

Amino Acid Oxidoreductases↗
PubMed1993

Nitric oxide-dependent and -independent neurogenic relaxation of isolated dog urethra.

In the presence of adrenergic and cholinergic blocking agents, transmural electrical stimulation evoked a relaxation in isolated dog urethra precontracted with histamine. The response was abolished by tetrodotoxin, indicating its neurogenic origin. The non-adrenergic and non-cholinergic relaxation developed rapidly and was transient at low stimulation frequencies (< or = 1 Hz). However, at higher frequencies (> or = 5 Hz) the recovery phase of the relaxation became slow and often showed a notch, suggesting the presence of transient and slow components. NG-Monomethyl-L-arginine, a nitric oxide synthase inhibitor, inhibited the transient relaxation but did not affect the relaxation evoked at high stimulation frequencies. NG-Nitro-L-arginine, a more potent nitric oxide synthase inhibitor, abolished the transient relaxation produced at low stimulation frequencies and markedly attenuated the transient component at high frequencies. However, NG-nitro-L-arginine did not affect the slow component. The inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine was reversed by the addition of L- but not D-arginine. Exogenously applied vasoactive intestinal polypeptide (VIP) produced a slowly developing relaxation. The slow relaxation induced by transmural electrical stimulation and VIP was not affected by [4-Cl-D-Phe6,Leu17]VIP, a reportedly competitive VIP antagonist. NG-Nitro-L-arginine did not affect the relaxation induced by VIP and sodium nitroprusside. These results suggest that the non-adrenergic and non-cholinergic relaxation induced by transmural electrical stimulation is composed of nitric oxide-dependent and -independent components in the isolated dog urethra.

Animals↗
PubMed1993

Involvement of vasoactive intestinal polypeptide in gastric reflex relaxation.

We have previously presented evidence for a non-adrenergic, vagally mediated colono-gastric inhibitory reflex induced by distension of the colon. We also found that pain stimulation by putting pressure on a testicle induced a pronounced gastric relaxation mediated by both adrenergic and vagal non-adrenergic fibres in anesthetized rats. Previous in vitro studies by other workers have strongly indicated that vasoactive intestinal polypeptide (VIP) is a neural mediator of gastric relaxation. The aim of the present in vivo study was to investigate, in anesthetized rats, whether VIP is involved in the gastric reflex relaxation induced by colonic distension and pain stimulation. A volumetric method was used to monitor changes in gastric volume. Gastric reflex relaxation following colonic distension was significantly and markedly inhibited by VIP antiserum as compared to the control relaxation before administration of the antiserum. Non-immunized control serum did not significantly influence gastric relaxation caused by colonic distension. Pain-induced gastric relaxation was moderately but significantly reduced after the administration of VIP antiserum but not after control serum. The selective beta 2-adrenoceptor agonist, salbutamol, induced a pronounced gastric relaxation of the same magnitude before and after the administration of VIP antiserum. VIP antiserum changed the pattern of gastric motility by inducing a specific type of gastric contraction appearing spontaneously or in response to colonic distension. A close intra-arterial injection of VIP induced gastric relaxation and inhibition of phasic gastric contractions. The present results in the rat suggest that VIP or a VIP-like peptide is involved in gastric reflex relaxation induced by colonic distension and pain stimulation.

Animals↗
PubMed1994

Influence of endothelium on Mg(2+)-induced relaxation in noradrenaline-contracted aorta from DOCA-salt hypertensive rat.

The aim of this study was to examine the influence of vascular endothelium on the relaxation induced by increased extracellular Mg2+ concentrations on isolated and noradrenaline-precontracted aorta from deoxycorticosterone acetate-salt (DOCA-salt) hypertensive and normotensive rats. In Mg(2+)-free physiologic salt solution (PSS), addition of Mg2+ (0.1-6.0 nM) caused concentration-dependent relaxation of noradrenaline-precontracted aorta with intact or disrupted endothelium. Mg(2+)-induced relaxation in intact aorta, however, was less in DOCA-salt hypertensive rats than in normotensive rats. When endothelium was disrupted, Mg(2+)-induced relaxation was depressed in aorta from both DOCA-salt hypertensive and normotensive rats. The same observations were made in presence of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor nitric oxide (EDRF/NO) biosynthesis. Mg(2+)-induced relaxation following contraction with noradrenaline was significantly less in intact aorta treated with L-NAME from DOCA-salt hypertensive rats than in intact aorta from normotensive rats. Indomethacin did not affect Mg(2+)-induced relaxation in intact aorta from normotensive rats whereas indomethacin significantly increased it in DOCA-salt hypertensive rats. It is concluded that (1) Mg(2+)-induced relaxation can be mediated by endothelium-dependent mechanisms implicating EDRF/NO; (2) the influence of EDRF/NO is more pronounced on the impaired Mg(2+)-induced relaxation of aorta from DOCA-salt hypertensive rats; (3) Mg(2+)-induced relaxation seems masked by vasoconstrictor prostaglandin release in DOCA-salt hypertensive rats; (4) these differences between normotensive and hypertensive rats could be related to the impaired endothelial function in aorta from DOCA-salt hypertensive rats.

Animals↗
PubMed1989

Role of peptide histidine isoleucine in relaxation of cat lower esophageal sphincter.

Vasoactive intestinal peptide (VIP) is a candidate as an inhibitory neurotransmitter mediating relaxation of the lower esophageal sphincter (LES) because VIP antiserum reduces LES relaxation in response to neural stimulation. Vasoactive intestinal peptide antiserum, however, does not completely block LES relaxation. Thus it is possible that other neurotransmitters may be involved. Peptide histidine isoleucine has structural homologies with VIP, is synthesized with VIP from a common precursor protein, coexists in some nerve cells, and is coproduced with VIP in some tumors. In numerous organ systems VIP and peptide histidine isoleucine (PHI) produce similar effects, with PHI being less potent than VIP by approximately one log number. In the LES both VIP and PHI produce tetrodotoxin-resistant dose-dependent relaxation, with PHI being almost equipotent with VIP. We therefore tested the hypothesis that PHI may be a second neurotransmitter, partly responsible for relaxation of the cat LES, by using a highly specific rabbit PHI antiserum that exhibits minimal cross-binding with VIP, secretin, and glucagon. In 3 animals, LES and brain tissue were extracted in 0.1 N HCl and assayed with a PHI radioimmunoassay. The antiserum cross-reacted with cat brain and LES showing PHI concentrations greater than 100 ng/g, with the LES containing equal or greater concentrations of PHI than brain tissue. In other animals consecutive LES circular muscle strips were cut, mounted in 1-ml muscle chambers, and stimulated with 6-s square-wave trains of 0.1-, 0.2-, 0.4-, and 0.8-ms pulses at 1, 2, and 5 Hz. These parameters produced relaxation that was completely blocked by tetrodotoxin, and reduced by VIP antiserum, but not affected by adrenergic or cholinergic receptor antagonists. Some strips were incubated in 5% or 10% PHI antiserum, whereas others were incubated in the same concentration of preimmunization serum from the same animal. Incubation in normal serum did not significantly affect relaxation, whereas in the antiserum-treated strips, LES relaxation was reduced by a significant amount (20%-30%) at all parameters of stimulation tested. Incubation in antiserum however had no effect on relaxation induced by VIP (10(-8)-10(-6) M). These data suggest that PHI may play a role in LES relaxation induced by electrical stimulation.

Animals↗
PubMed1995

Cyclic GMP relaxes the internal anal sphincter in Hirschsprung's disease.

In Hirschsprung's disease (HD), the aganglionic colon and internal anal sphincter (IAS) fail to relax. Aganglionic colon of HD patients relaxes in response to exogenous nitric oxide (NO), whereas the IAS from HD patients does not relax. The authors hypothesized that the failure of IAS relaxation is caused by a local deficiency of cyclic guanosine monophosphate (cGMP), the final metabolite in NO-mediated smooth muscle relaxation. To test this hypothesis, the authors measured the isometric tension of smooth muscle strips taken from the IAS and aganglionic colon of patients with HD before and after exposure to cGMP and compared this with ganglionic colon and IAS from normal controls. In HD patients both the IAS and aganglionic colon relaxed in response to cGMP (P < .05). The amount of relaxation observed in both the aganglionic colon and IAS was comparable to that measured in the normal controls. The observation that exogenous cGMP relaxes the IAS, whereas exogenous NO does not, suggests that mechanisms for relaxation may be different than those in the aganglionic colon and may explain persistent IAS dysfunction after resection of aganglionic colon. The defect of the IAS in HD may be the inability of the NO/cGMP pathway to induce smooth muscle cell relaxation rather than a defect in the smooth muscle cell.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Modulation of nitric oxide-dependent relaxation of pig tracheal smooth muscle by inhibitors of guanylyl cyclase and calcium activated potassium channels.

Nitric oxide is released from intrinsic nonadrenergic, noncholinergic (NANC) nerves of pig tracheal smooth muscle (TSM) in response to electrical field stimulation (EFS). In this study, we investigated the role of guanylyl cyclase in the NANC relaxation by using guanylyl cyclase inhibitors, LY83583 and methylene blue (MB). The role of large conductance calcium-activated potassium (KCa) channels in mediating NANC relaxation was studied by using inhibitors of this channel, charybdotoxin and iberiotoxin. In carbachol-contracted TSM strips, LY83583 (10-20 microM) and MB (10-100 microM) resulted in inhibition of EFS-induced relaxations at all frequencies studied. Relaxations induced by exogenous 8-Bromo-cyclic 3',5'-guanosine monophosphate (8-Br-cGMP) were unaffected by LY83583. The concentration-relaxation curves to isoproterenol, which acts by elevating adenosine-3',5'-cyclic monophosphate (cAMP), and the nitric oxide donors sodium nitroprusside (SNP) or S-nitroso-n-acetylpenicillamine (SNAP) were unaffected by LY83583. Both charybdotoxin (240 nM) and iberiotoxin (180 nM) attenuated relaxations induced by EFS and SNAP. The role of guanylyl cyclase activation in the relaxation to EFS of pig TSM is suggested by the sensitivity of the responses to MB. The selective inhibitory effects of LY83583 on relaxation to neurally released, but not to the nitric oxide donors, suggests that it acts by inhibiting nitric oxide release. The lack of any effect of LY83583 on isoproterenol- or guanosine, 3'5'-cyclic monophosphate (cGMP)-mediated relaxation suggests a mechanism that does not involve elevation of cAMP but lies proximal to the generation of cGMP. The susceptibility of the relaxations to EFS and SNAP to charybdotoxin and iberiotoxin suggests a mechanism that involves the selective activation of KCa channels in airway smooth muscle cells.

Aminoquinolines↗
PubMed1981

Relative contracting and relaxing potencies of a series of prostaglandins on isolated canine mesenteric artery strips.

The contracting and relaxing potencies of and interactions between a number of prostaglandins (PGs) were studied in vitro on spiral strips of small canine mesenteric arteries (outside diameter less than 1 mm). PGF2 alpha and PGE2, the most potent contracting PGs, were nearly equal in potency (EC50 4 x 10(-7) M) and did not cause relaxation under our experimental conditions. PGI2 and PGE1 were equal and the most potent relaxing PGs (EC50 3 x 10(-9) M). PGE1 also caused contraction, but this effect was not consistent. PGI2 did not cause contraction in concentrations up to 3 x 10(-6) M. In higher concentrations, however, it caused abrupt and near maximal contraction. PGD2 was weak in both respects, causing incomplete relaxation and contraction or biphasic effects. Interaction studies showed that PGE1 and PGI2 mutually excluded the relaxing effects of each other. PGE1 also reversed the relaxing effect of isoproterenol. However, pre-exposure to PGD2 did not attenuate the relaxing effect of PGE1 or PGI2 nor was the relaxing effect of PGD2 changed by pre-exposure to PGE1. Two different orders of potency of PGs suggest two PG receptors subserving contraction and relaxation, respectively. Further, it appears that several PGs can act upon both receptors which may explain unusual interactions between the PGs and some of their atypical effects. Finally, the data also suggest that there may be subtypes of the PG receptors subserving contraction and relaxation.

Animals↗
PubMed1981

Prostacyclin (PGI2) mediates hypoxic relaxation of bovine coronary arterial strips.

Bovine coronary arterial strips (BCA) exhibiting spontaneous tone, relax in response to a decrease in the pO2 of the bathing medium. Experiments were performed to determine if prostaglandins (PGs) mediate the oxygen-induced changes in tension. BCA were equilibrated in Krebs-bicarbonate solution at 37 degrees C gassed with 95% O2, 5% CO2 and tension was measured isometrically. When the pO2 of the bathing medium was decreased, BCA exhibited reversible reductions in tension. Switching from 95% O2, 5% CO2 to 95% N2, 5% CO2 (anoxia) elicited an initial relaxation followed by a contraction. In contrast, a change to 5% O2, 5% CO2, 90% N2 (hypoxia) was followed by a sustained relaxation. Re-introduction of O2 to anoxic strips produced a biphasic response: relaxation followed by contraction. Indomethacin or eicosatetraynoic acid (EYA) increased tone and inhibited the relaxation produced by anoxia or hypoxia. Indomethacin or EYA did not inhibit the relaxation of anoxic strips during re-introduction of O2, but did inhibit the contraction partially. Relaxation of arterial strips to arachidonic acid (AA) was similar to relaxation to prostacyclin (PGI2). Anoxia limited the relaxation to AA but not to PGI2. We conclude that PG synthesis contributes to the basal tone and the hypoxia-induced relaxation of BCA. In addition, hypoxia, unless severe, does not prevent the conversion of AA to PGI2.

Animals↗
PubMed1994

Tachykinin NK3 receptor mediates NANC hyperpolarization and relaxation via nitric oxide release in the circular muscle of the guinea-pig colon.

In the presence of atropine (1 microM), guanethidine (3 microM) and of the tachykinin NK1 (SR 140,333 0.1 microM) and NK2 (GR 94,800 3 microM) receptor antagonists, the application of the tachykinin NK3 receptor selective agonist senktide, or that of neurokinin B, produced concentration-dependent sustained nonadrenergic noncholinergic (NANC) relaxation of mucosa-free circular muscle strips from the guinea-pig proximal colon. The maximal relaxant responses to senktide and neurokinin B were similar, approaching about 70% of the relaxation to 1 microM isoprenaline. Senktide (EC50 0.16 nM) was about 64-fold more potent than neurokinin B (EC50 10.3 nM). When tested in the presence of peptidase inhibitors (thiorphan 1 microM, captopril 1 microM and amastatin 10 microM), neurokinin B (EC50 0.24 nM) was equipotent to senktide (EC50 0.19 nM). At 1 nM, substance P and neurokinin A were ineffective in producing a NANC relaxation of the colon. At 1 microM substance P, neurokinin A and neurokinin B produced a NANC relaxation, which averaged 23, 40 and 79% of the maximal response to isoprenaline, respectively. In the presence of peptidase inhibitors, 1 nM substance P and neurokinin A produced threshold relaxant responses and, at 1 microM, the three natural tachykinins were equieffective (66 +/- 8, 72 +/- 5 and 75 +/- 5% of the relaxation to isoprenaline for substance P, neurokinin A and neurokinin B, respectively). The relaxant response to 1 nM senktide (producing about 70-80% of its maximal effect) was totally abolished by 1 microM tetrodotoxin and largely (> 90%) inhibited by 100 microM L-nitroarginine (L-NOARG). The inhibition by L-NOARG was partially reversed by L-arginine (3 mM) but not D-arginine. Apamin (1 microM) produced a slight (about 20%) inhibition of the response to senktide. The peptide blocker of N-type calcium channels, omega-conotoxin (0.1 microM) was ineffective. In sucrose gap electrophysiological experiments, superfusion with senktide (0.1 microM for 10 s) produced a slowly developing and prolonged hyperpolarization of the membrane and relaxation. Both effects were inhibited by L-NOARG while apamin had no effect. These findings indicate that a neuronal NK3 receptor mediates NANC hyperpolarization and relaxation of the circular muscle of the guinea-pig proximal colon, principally through the release of NO. NO generation/release in response to NK3 receptor stimulation does not require calcium influx through N-type calcium channels.

Animals↗
PubMed1994

Glibenclamide inhibits hypoxic relaxation of isolated porcine coronary arteries under conditions of impaired glycolysis.

The possible involvement of ATP-sensitive K+ channels (KATP) in hypoxic relaxation of isolated porcine coronary arteries was investigated. Tubular segments taken from the left anterior descending artery were suspended in myographs for recording of isometric contractile force. Hypoxia (pO2 = 20.3 mm Hg +/- 0.5) produced a greater relaxation in preparations contracted by 30 mM K+ (49.7% +/- 7.2) compared with 124 mM K+ (19.9% +/- 2.2) which is compatible with the involvement of K+ channel activation in the mechanism of hypoxic relaxation. In a normal glucose-containing Krebs solution the KATP blocker glibenclamide (1 microM) failed to influence the hypoxic relaxation of preparations contracted by the thromboxane A2 analogue U-46619. Under conditions created to inhibit non-oxidative ATP production from glycolysis using a glucose-free Krebs solution containing 2-deoxyglucose (10 mM), the hypoxic relaxation was enhanced from 54.5% +/- 5.0 to 77.2% +/- 4.4. Under these conditions glibenclamide (1 microM) significantly inhibited the hypoxic relaxant response from 77.2% +/- 4.2 to 55.2% +/- 4.4 and prolonged the time until half-maximal relaxation from 5.5 min +/- 0.6 to 8.1 min +/- 0.6. A low concentration of the KATP opener levcromakalim (30 nM) failed to significantly potentiate the hypoxic relaxation. The adenosine receptor blocker theophylline (1 microM) or removal of the endothelium showed no effect on the hypoxic relaxation. In normal glucose-containing Krebs solution, indomethacin (10 microM) caused a small but significant inhibition of the hypoxic relaxation from 54.5% +/- 5.0 to 41.6% +/- 3.6.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

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.

Animals↗
PubMed1992

Diabetes mellitus impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle.

The effect of alloxan-induced diabetes on the reactivity of corporeal nerves, endothelium and smooth muscle was studied in the New Zealand white rabbit. Fifteen rabbits were randomly divided into treated (n = 6) and control (n = 9) groups. The treated group was maintained for 6 weeks. Two control groups were studied. One control group (n = 3) was maintained for 6 weeks as littermate controls for diabetic group. The second control group (n = 6) was not maintained but was weight matched with the 6 week diabetic group. The reactivity of corpus cavernosum tissue from the diabetic animals and the control animals was studied in organ chambers. When tissue contraction was produced with phenylephrine for the study of relaxation to various stimuli, the tension induced was similar in the diabetic and the control groups. Relaxation of corpus cavernosum tissue to electrical stimulation of autonomic nerves as well as relaxation to the endothelium-dependent vasodilator acetylcholine were comparably unaffected in the weight matched and littermate control groups while significantly inhibited in the diabetic group. Treatment of the corporeal tissue with the cyclooxgenase inhibitor indomethacin enhanced the relaxation to electrical stimulation and to acetylcholine in the control and in the diabetic groups but did not improve the significant difference in relaxation between the two groups. Relaxation of corporeal tissue to endothelium-independent vasodilators, papaverine and nitroprusside was similar in the control groups and the diabetic groups. It is concluded that diabetes impairs neurogenic and endothelium-mediated relaxation of rabbit corpus cavernosum smooth muscle. These findings are comparable to those described in corpus cavernosum tissue from diabetic men, showing the validity of this experimental animal model. The mechanism for the nerve or endothelial dysfunction does not appear to involve alteration in cyclooxygenase products of arachidonate or the ability of the corporeal smooth muscle to relax via a cGMP-dependent mechanism. Since nitric oxide has been shown to act as the nonadrenergic noncholinergic neurotransmitter as well as endothelium-derived relaxing factor (EDRF) of the trabecular smooth muscle, it is possible that impairment of neurogenic and endothelium-dependent relaxation due to diabetes is mediated by alteration in the synthesis or availability of nitric oxide in corporeal tissue.

Acetylcholine↗
PubMed1992

Electrically-induced, nerve-mediated relaxation of rabbit urethra involves nitric oxide.

Isolated smooth muscle preparations from the rabbit urethra precontracted with noradrenaline (10(-5) M), endothelin (10(-7) M), or arginine vasopressin (10(-7) M) responded to electrical field stimulation by frequency-dependent non-adrenergic, non-cholinergic relaxations, which could be blocked by tetrodotoxin (10(-6) M). Relaxation was more pronounced in preparations precontracted by endothelin than by noradrenaline or arginine vasopressin. The electrically induced relaxations were reduced in a concentration-dependent manner by pretreatment for 30 minutes with NG-nitro-L-arginine (10(-6) to 10(-4) M) and NG-monomethyl-L-arginine (10(-5) to 10(-4) M). At the highest concentration of NG-nitro-L-arginine used (10(-4) M), relaxation was abolished and/or changed into a contraction. The effect of NG-nitro-L-arginine was reversible. NG-nitro-D-arginine had no effect. Pretreatment for 30 minutes with L-arginine (10(-3) M) slightly, but significantly, enhanced the maximum relaxation to field stimulation in noradrenaline-precontracted preparations. L-arginine pretreatment also prevented the effects of low, but not high, concentrations of NG-nitro-L-arginine. In contrast, D-arginine had no effect. Electrically induced relaxations were not significantly affected by methylene blue (10(-5) M) or superoxide dismutase (20 U/ml). Addition of nitric oxide (present in acidified solution of NaNO2) caused transient and concentration-dependent relaxations in preparations precontracted by noradrenaline. At the maximum concentration used (10(-3) M), the relaxant response averaged 67% of the tension induced by noradrenaline. Nitric-oxide-induced relaxations were not affected by NG-nitro-L-arginine or L-arginine, but were significantly inhibited by methylene blue. In preliminary experiments, effects similar to those found in rabbit urethra were also observed in isolated urethral preparations obtained from three patients. It is suggested that in the urethra, nitric oxide is involved in the mediation of relaxation evoked by electrical stimulation of nerves.

Animals↗
PubMed2001

Calcium-sensitive potassium channel inhibitors antagonize genistein- and daidzein-induced arterial relaxation in vitro.

Estradiol-17beta relaxes rabbit coronary artery rings via large conductance Ca2+-activated K+-channels (K(Ca)). Genistein and daidzein are plant-derived estrogen-like compounds. The aim of the present study was to investigate whether potassium channels participate in the genistein- and daidzein-induced arterial relaxation like they do in the case of estradiol-17beta. Endothelium-denuded superior mesenteric arterial rings from non-pregnant Wistar female rats were used. At a concentration of 10 microM, estradiol-17beta, genistein and daidzein relaxed noradrenaline precontracted arterial rings, (58 +/- 4%, 45 +/- 5% and 31 +/- 3%, respectively; (n=6-8)). Genistein- and daidzein-induced relaxations were inhibited both by iberiotoxin (1-10 nM) and charybdotoxin (30 nM), the antagonists of large conductance Ca2+-activated K+-channels (K(Ca)). Estradiol-17beta-induced relaxation was reduced by iberiotoxin (30 nM). Estradiol-17beta- and daidzein-induced relaxations were also decreased by apamin (0.1-0.3 microM), an antagonist of small conductance Ca2+-activated K+-channels. The antagonists of voltage-dependent K+-channels (K(V)) (4-aminopyridine), ATP-sensitive K+-channels (K(ATP)) (glibenclamide), or inward rectifier K+-channels (KIR) (barium) had no effect on the relaxation responses of any of the compounds studied. Estrogen receptor antagonist tamoxifen did not inhibit the relaxations. In conclusion, in the noradrenaline precontracted rat mesenteric arteries, the relaxations caused by estradiol-17beta, genistein and daidzein were antagonized by large and small conductance K(Ca)-channel inhibitors, suggesting the role of these channels as one of the relaxation mechanisms.

Animals↗