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PubMed1997

Differential relaxant responses of pulmonary arteries and veins in lung explants of guinea pigs.

The endothelium regulates vascular tone through release of relaxing or contracting factors, with nitric oxide (NO) being a major endothelium-derived relaxing factor. In the present study, we used a lung explant technique to determine the differential abilities and mechanisms of pulmonary arteries and veins of normal guinea pigs to relax after precontraction. Excised lungs of 15 guinea pigs were filled through the airways with 1% agarose, cut into 1-mm-thick slices, and cultured overnight. Luminal areas of vascular cross sections were measured with an image-analysis system. Vessels were precontracted with U-46619, and responses to histamine, acetylcholine (ACh), sodium nitroprusside, and papaverine were examined. We also determined the effects of N omega-nitro-L-arginine and of indomethacin on ACh-induced responses. We found that histamine relaxed arteries more than veins and that ACh relaxed only arteries. N omega-nitro-L-arginine pretreatment abolished ACh-induced relaxation of arteries and caused ACh-induced contraction of veins, whereas indomethacin markedly augmented ACh-induced relaxation of arteries (maximal relaxation: 48.5 +/- 4.7 vs. 19.2 +/- 5.1% without it) and induced a dose-dependent relaxation of veins (maximal relaxation: 17.0 +/- 4.1%). Sodium nitroprusside induced a significantly greater relaxation of arteries than veins, whereas papaverine relaxed them equally. We conclude that in guinea pigs endothelial NO-mediated relaxation is greater in pulmonary arteries than in veins and that ACh-induced NO-mediated relaxation is reduced by the simultaneous production of cyclooxygenase-derived vasoconstrictors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Involvement of nitric oxide and vasoactive intestinal peptide in the nonadrenergic-noncholinergic relaxation of the porcine retractor penis muscle.

Neurotransmitters mediating nonadrenergic-noncholinergic (NANC) relaxation were investigated in strips of porcine retractor penis muscle (RPM). Muscle tone was raised by phenylephrine (1 microM) in the presence of atropine (1 microM) and guanethidine (50 microM). Upon electrical field stimulation (1 ms, 80 V, 1-32 Hz for 10 s), the initial fast relaxation was followed by the slow relaxation. Although the fast and the slow relaxation were completely abolished by tetrodotoxin (1 microM), they showed different pharmacological sensitivities to the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 mM). The fast relaxation was markedly inhibited by L-NAME in an L-arginine reversible manner and by oxyhemoglobin (50 microM), while the slow relaxation was hardly blocked by L-NAME. L-NAME and alpha-chymotrypsin (alpha-CT, 3 U/ml) selectively inhibited the fast and the slow relaxation, respectively. Alpha-CT abolished L-NAME-resistant slow relaxation, and L-NAME completely abolished the alpha-CT-resistant fast relaxation. Alpha-CT-resistant relaxation was not significantly different from the digitally calculated L-NAME-sensitive component, and L-NAME-resistant relaxation was similar to the digitally calculated alpha-CT-sensitive component. Vasoactive intestinal peptide (VIP, 0.003-0.1 microM) relaxed porcine RPM in a concentration-dependent manner. The effect of a VIP was partially inhibited by a VIP receptor antagonist, VIP(10-28) (1 and 3 microM). L-NAME-resistant relaxation was also reduced by VIP(10-28) (3 microM) and by another putative antagonist, VIP(6-28) (1 microM), although the effects of the two antagonists were somewhat inconsistent. From the histochemical staining, it was verified that nerve bundles that showed VIP-like immunoreactivities were also positive for the NADPH diaphorase reaction. These results suggest that NO and peptide neurotransmitter(s) including VIP mediate the NANC relaxation in porcine RPM.

Animals↗
PubMed2001

The mechanism of gentisic acid-induced relaxation of the guinea pig isolated trachea: the role of potassium channels and vasoactive intestinal peptide receptors.

We examined some of the mechanisms by which the aspirin metabolite and the naturally occurring metabolite gentisic acid induced relaxation of the guinea pig trachea in vitro. In preparations with or without epithelium and contracted by histamine, gentisic acid caused concentration-dependent and reproducible relaxation, with mean EC(50) values of 18 microM and E(max) of 100% (N = 10) or 20 microM and E(max) of 92% (N = 10), respectively. The relaxation caused by gentisic acid was of slow onset in comparison to that caused by norepinephrine, theophylline or vasoactive intestinal peptide (VIP). The relative rank order of potency was: salbutamol 7.9 > VIP 7.0 > gentisic acid 4.7 > theophylline 3.7. Gentisic acid-induced relaxation was markedly reduced (24 +/- 7.0, 43 +/- 3.9 and 78 +/- 5.6%) in preparations with elevated potassium concentration in the medium (20, 40 or 80 mM, respectively). Tetraethylammonium (100 microM), a nonselective blocker of the potassium channels, partially inhibited the relaxation response to gentisic acid, while 4-AP (10 microM), a blocker of the voltage potassium channel, inhibited gentisic acid-induced relaxation by 41 +/- 12%. Glibenclamide (1 or 3 microM), at a concentration which markedly inhibited the relaxation induced by the opener of ATP-sensitive K(+) channels, levcromakalim, had no effect on the relaxation induced by gentisic acid. Charybdotoxin (0.1 or 0.3 microM), a selective blocker of the large-conductance Ca(2+)-activated K(+) channels, caused rightward shifts (6- and 7-fold) of the gentisic acid concentration-relaxation curve. L-N(G)-nitroarginine (100 microM), a NO synthase inhibitor, had no effect on the relaxant effect of gentisic acid, and caused a slight displacement to the right in the relaxant effect of the gentisic acid curve at 300 microM, while methylene blue (10 or 30 microM) or ODQ (1 microM), the inhibitors of soluble guanylate cyclase, all failed to affect gentisic acid-induced relaxation. D-(P)-Cl-Phe(6),Leu(17)[VIP] (0.1 microM), a VIP receptor antagonist, significantly inhibited (37 +/- 7%) relaxation induced by gentisic acid, whereas CGRP (8-37) (0.1 microM), a CGRP antagonist, only slightly enhanced the action of gentisic acid. Taken together, these results provide functional evidence for the direct activation of voltage and large-conductance Ca(+2)-activated K(+) channels, or indirect modulation of potassium channels induced by VIP receptors and accounts for the predominant relaxation response caused by gentisic acid in the guinea pig trachea.

Animals↗
PubMed1988

Antagonism of acetylcholine-mediated relaxation of rabbit pulmonary arteries by phorbol myristate acetate.

We studied the effect of 4-phorbol 12-myristate 13-acetate (PMA) on endothelium-dependent relaxation of rabbit isolated lobar pulmonary arteries contracted with phenylephrine. After full development of relaxation in response to 1.0 microM acetylcholine, addition of 10.0 nM PMA reversed relaxation rapidly and completely. This effect of PMA on acetylcholine-induced relaxation was unchanged when catalase was included in the medium. In separate groups of experiments, lobar pulmonary arteries were preincubated with 10.0 nM PMA for 20 min and then challenged with acetylcholine without washout of PMA. In these experiments PMA did not block completely the relaxation in response to addition of 1.0 microM acetylcholine. Log-concentration response curves for 0.01 to 31.6 microM acetylcholine vs. relaxation as percentage of phenylephrine-induced tone exhibited rightward shifts and depression of maxima after pretreatment with PMA. The EC50 for acetylcholine-induced relaxation was increased from 57 +/- 9.0 to 377 +/- 6.30 nM (values are mean +/- S.E.). Relaxation of lobar pulmonary arteries induced by 10.0 nM A23187 was much less sensitive to treatment with PMA than relaxation induced by acetylcholine. At least for the low concentration of PMA used here, these data are consistent with the following: 1) PMA blocks acetylcholine-induced relaxation by disrupting the link between acetylcholine receptor occupancy and the formation or release of the endothelium-derived relaxing factor, 2) PMA does not directly block the relaxant action of endothelium-derived relaxing factor on vascular smooth muscle and 3) the effect of PMA on acetylcholine-induced relaxation is not mediated by hydrogen peroxide or derived oxygen radicals.

Acetylcholine↗
PubMed1995

Modulation of vasoactive intestinal polypeptide (VIP)-mediated relaxation by nitric oxide and prostanoids in the rabbit corpus cavernosum.

The polypeptide VIP has been proposed as an inhibitory nonadrenergic, noncholinergic (NANC) neurotransmitter involved in the relaxation of cavernosal smooth muscle during erection. However, the specific mechanism(s) by which VIP exerts its effect is unknown. To determine whether VIP is involved in NANC-mediated cavernosal relaxation, strips of corpus cavernosum from New Zealand White rabbits were hung in tissue baths; atropine and guanethidine were added to block cholinergic and adrenergic neurotransmission, respectively. The tissue was then submaximally precontracted with norepinephrine (NE) and relaxed by electrical field stimulation (EFS; 10 V square waves, 0.5 msec. duration, 10 second trains at 5, 15 and 40 Hz) before and after preincubation with the VIP antagonist, VIP 10-28. To evaluate the role of nitric oxide (NO) and prostaglandins on the relaxant effect of VIP in the corpus cavernosum, the strips were contracted with NE and subsequently relaxed with cumulative doses of VIP (10(-10) to 10(-6) M.). After VIP dose-response curves were obtained, the strips were preincubated with N omega-nitro-L-arginine (NOARG, an inhibitor of nitric oxide synthase, 10(-4) M.) and the VIP dose-response curve was repeated. Indomethacin (10(-5) M.) was added to one-half of the NOARG treated strips to inhibit prostaglandin synthesis. VIP 10-28 inhibited EFS-induced relaxation (p < 0.05) and produced dose-dependent relaxation, which was inhibited by NOARG (p < 0.05). In contrast, the VIP-induced relaxation was more pronounced in the presence of indomethacin (p < 0.05). Moreover, indomethacin substantially reversed the NOARG inhibition of VIP relaxation (p < 0.05). These results suggest that VIP is a mediator of NANC cavernosal relaxation and that NO synthesis is involved in VIP-induced NANC relaxation in the corpus cavernosum. In addition, the presence of vasoconstrictive prostanoids modulates this VIP-mediated NANC relaxation. Therefore, VIP appears to contribute to NANC neurally mediated cavernosal relaxation, and its mechanisms of relaxation are dependent on prostanoid and involve the generation of NO.

Animals↗
PubMed2002

Altered effect of cyclopiazonic acid on endothelium-dependent relaxation in femoral arteries from hypertensive rats.

The function of endoplasmic reticulum in hypertensive vascular endothelium has not been intensively studied. The current study was designed to investigate a role of intracellular Ca2+ stores in endothelium-dependent relaxations to acetylcholine using femoral arteries obtained from Wistar-Kyoto (WKYs) and spontaneously hypertensive rats (SHRs). Rings were prepared from the femoral arteries and changes in isometric tension were recorded. Endothelium-dependent relaxations induced by acetylcholine in rings contracted with serotonin were identical in WKYs and SHRs. Cyclopiazonic acid (CPA) inhibited the relaxation in SHRs but not in WKYs. In WKYs, acetylcholine evoked smaller relaxations in rings contracted with KCl than in those contracted with serotonin, whereas in SHRs the relaxation was not affected by the contractile agonists used. The relaxation in rings contracted with KCl was abolished by Nw-nitro-l-arginine methyl ester (l-NAME) and was reduced by CPA to a similar extent in both strains. In rings contracted with serotonin, l-NAME abolished the relaxation in SHRs, but the inhibitor only partially reduced the relaxation in WKYs. CPA did not alter the relaxation in the presence of l-NAME. Endothelium-independent relaxations to sodium nitroprusside were not affected by CPA. These results suggest that acetylcholine relaxes rat femoral arteries by releasing both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF). In SHRs, the relaxation is preserved, but the release of EDHF is absent. CPA inhibits the relaxation mediated by nitric oxide, but not EDHF and, thus, inhibits the relaxation in SHRs but not in WKYs. Functional alteration of endoplasmic reticulum in the hypertensive endothelium cannot be detected.

Acetylcholine↗
PubMed1970

Relaxations of the isolated portal vein of the rabbit induced by nicotine and electrical stimulation.

1. A pharmacological analysis of the inhibitory innervation of the isolated portal vein of the rabbit has been made.2. In untreated preparations, transmural stimulation elicited a long-lasting relaxation at low frequencies (0.2-1 Hz); at higher frequencies a contraction followed by a prolonged after-relaxation occurred. Tetrodotoxin abolished the contractions but a higher dose was required to abolish the relaxations. Veratrine lowered the threshold of stimulation for producing relaxations in the untreated vein. The relaxations were unaffected by hyoscine or hexamethonium. They were reduced or altered by antagonists of alpha-adrenoceptors for catecholamines and by adrenergic neurone blockade. They were sometimes slightly reduced by antagonists of beta-adrenoceptors.3. In the presence of antagonists of alpha-adrenoceptors, electrical stimulation elicited relaxations which increased with frequency of stimulation and became maximal at 20-30 Hz. These relaxations were partially reduced by antagonists of beta-adrenoceptors, or by adrenergic neurone block; the antagonisms were more pronounced at the higher frequencies of stimulation. Noradrenaline also caused relaxations which were abolished by beta-adrenoceptor blocking drugs. Cocaine increased the sensitivity to noradrenaline by 7-8 fold after alpha-adrenoceptor blockade but had little or no effect on the relaxations induced by electrical stimulation at high frequencies.4. In the presence of antagonists of alpha- and beta-adrenoceptors, or adrenergic neurone blocking agents, or in veins taken from rabbits pretreated with reserpine, electrical stimulation elicited rapid relaxations which were greatest at 20-30 Hz. These relaxations were increased by veratrine and abolished by tetrodotoxin or by storing the vein for 9 days at 4 degrees C. They were unaffected by antagonists of acetylcholine, or by dipyridamole.5. Prostaglandins E(1), E(2) and F(2alpha) inhibited contractions elicited by electrical stimulation and noradrenaline, but in higher doses caused contractions themselves.6. Nicotine (10(-6)-10(-5) g/ml) relaxed the portal vein; higher concentrations elicited mixed inhibitory and excitatory effects. All these effects were abolished by tetrodotoxin, cocaine, hexamethonium or storage. The contractor effects were abolished by drugs or procedures that blocked adrenergic mechanisms.7. The relaxations produced by nicotine in untreated preparations and in veins from rabbits pretreated with reserpine were mediated mainly by a non-adrenergic non-cholinergic nervous mechanism. Relaxations induced by nicotine in the presence of antagonists of a-adrenoceptors were only partially antagonized by antagonists of f3-adrenoceptors.8. It was concluded that all the effects of nicotine and transmural stimulation were mediated by nerves. Part of the inhibitory effects was mediated by non-adrenergic, non-cholinergic nerves.

Adrenergic alpha-Antagonists↗
PubMed1994

Relaxant effects of isoproterenol in isolated cardiac muscle: influence of loading patterns.

The purpose of this study was to test the hypothesis that loading patterns (i.e., loading sequence, total load, and preload) modulate the relaxant effects of isoproterenol. The effects of isoproterenol (10(-6) M) on peak rate of force decline (-dF/dt) were studied in rat left ventricular papillary muscle (n = 24) with respect to two sequences of relaxation: the classical, isotonic-isometric sequence, in which tension fall occurs at initial muscle length, and the physiological, isometric-isotonic sequence, in which tension fall occurs at end-systolic muscle length. The influences of muscle load and initial length were accounted for in the evaluation of relaxation rate by plotting -dF/dt against the entire range of loads both at preload = maximum length (Lmax) and 90% Lmax. The main results are the following: 1) in the classical, isotonic-isometric sequence of relaxation, and whatever the preload, the magnitude of the relaxant effect of isoproterenol increased with load; 2) after reversal into the physiological, isometric-isotonic sequence of relaxation, the relaxant effect of isoproterenol behaved independently of load level in muscle preloaded at Lmax; 3) conversely, in muscle preloaded at 90% Lmax and relaxing according to the physiological sequence, the relaxant effect of isoproterenol increased with load; and 4) the peak relaxant effect of isoproterenol was proportionally higher in the physiological sequence of relaxation than in the classical one and occurred at a similar level of load, whatever the loading sequence and whatever the preload level. Our results indicate that loading patterns finely modulated the relaxant effects of isoproterenol and that muscle length, both before the contraction phase and at the onset of relaxation phase, influenced the effects of isoproterenol on myocardial relaxation rate.

Animals↗
PubMedDate not supplied

Endothelium-independent relaxations to acetylcholine and A23187 in the human umbilical artery.

The effects of acetylcholine (ACh) and A23187 on ring preparations from the human umbilical artery (HUA) were investigated and compared with the rat aorta (RA). The results from the HUA demonstrate that: (1) At both high (pO2 > 600 mm Hg) and low O2 tension (pO2 < 55 mm Hg), ACh and A23187 relaxed precontracted rings in a concentration-dependent and endothelium-independent manner. Changes in pO2 did not influence the responses of the HUA to either relaxant. (2) Relaxation responses of the HUA to either ACh or A23187 were insensitive to methylene blue (50 microM), L-nitro-arginine methyl ester (100 microM), indomethacin (10 microM) and nordihydroguaiaretic acid (50 microM). Relaxations initiated by ACh were also atropine-resistant. (3) Meclofenamic acid (3 microM) suppressed the relaxations to A23187, but not ACh. (4) Regardless of pO2 superoxide dismutase (100 U/ml) potentiated the relaxant effects of ACh, whereas mannitol (60 mM) enhanced ACh-initiated relaxations at high but not low pO2. (5) Ouabain (30 nM), high potassium (HK+, 60 mM) and tetraethylammonium (20 mM) inhibited responses to ACh. (6) Na(+)-free physiological saline solution inhibited both relaxations and oscillations initiated by either ACh or A23187. (7) Both nitroglycerin and exogenous nitric oxide (NO) fully, and 8-bromoguanosine 3',5'-cyclic monophosphate partially, relaxed the HUA, and LY83583 (10 microM) reversed such relaxations. (8) In the RA, relaxation responses to ACh and A23187 were endothelium-dependent and sensitivity was reduced under high versus low pO2 conditions. We conclude that in the HUA, unlike in the RA, ACh and A23187 mediate their responses via an endothelium- and NO-independent process(es), perhaps involving the release of a muscle-derived relaxing factor. ACh-initiated relaxations are mediated by activation of Na+,K(+)-ATPase, and subsequent hyperpolarization via K+ efflux, whereas A23187-mediated relaxations result from the synthesis of an indomethacin-resistant cyclooxygenase product.

Acetylcholine↗
PubMed1978

Evidence of incomplete left ventricular relaxation in the dog: prediction from the time constant for isovolumic pressure fall.

Although it has been proposed that incomplete relaxation explains certain increases in left ventricular end diastolic pressure relative to volume, there has been no clear demonstration that incomplete relaxation occurs in the intact working ventricle. To identify incomplete relaxation, left ventricular pressure-dimension relationships were studied in 10 canine right heart bypass preparations during ventricular pacing. The fully relaxed, exponential diastolic pressure-dimension line for each ventricle was first determined from pressure and dimension values at the end of prolonged diastoles after interruption of pacing. For 167 beats during pacing under widely varying hemodynamic conditions, diastolic pressure-dimension values encountered this line defining the fully relaxed state during the filling period indicating that relaxation was complete before end diastole. The time constant for isovolumic exponential pressure fall (T) was determined for all beats. For this exponential function, if no diastolic filling occurred, 97% of pressure fall would be complete by 3.5 T after maximal negative dP/dt. For the 167 beats the fully relaxed pressure-dimension line was always encountered before 3.5 T. With very rapid pacing rates (170-200 beats/min) and(or) with pharmacologic prolongation of relaxation, incomplete relaxation occurred as evidenced by the fact that the line defining the fully relaxed state was never reached during diastole (n = 15). This evidence of incomplete relaxation occurred only when the subsequent beat began before 3.5 T but did not always occur under these conditions. Thus, an increase in end diastolic pressure relative to diastolic volume may result from incomplete relaxation under conditions of sufficiently rapid heart rate or sufficiently prolonged ventricular relaxation. Incomplete relaxation does not occur when the next beat begins more than 3.5 T after maximum negative dP/dt.

Animals↗
PubMed2001

EDHF mediates the relaxation of stretched canine femoral arteries to acetylcholine.

To test the hypothesis that mechanically stretched arteries relax to endothelium-derived vasodilators, we challenged endothelium-intact dog femoral artery rings stretched from 1 to 16 g total initial tension (active force and passive elastic) with 10(-6) M acetylcholine (ACh), an endothelium-dependent dilator. The relaxation to 10(-6) M sodium nitroprusside (SNP), an endothelium-independent dilator, increased with the total initial tension. The relaxation to ACh averaged approximately 65% of the relaxation to SNP at total initial tensions of 4 to 16 g. To determine the nature of the endothelial-derived products involved, we compared the ACh-induced relaxation of stretched rings (6.5 +/- 0.2 g total initial tension) with rings chemically contracted with phenylephrine (Phe, 10(-7) to 10(-5) M) (6.5 +/- 0.3 g total initial tension). ACh-induced relaxation was evaluated before and after the inhibition of the synthesis of eicosanoids [cyclooxygenase (10(-5) M indomethacin) and lipoxygenase (10(-5) M nordihydroguariaretic acid)] and nitric oxide [nitric oxide synthase (10(-5) M Nw-nitro-L-arginine)]. The contribution of endothelium-derived hyperpolarizing factor (EDHF) was identified by blocking calcium-activated potassium channels (10(-8) M iberiotoxin). SNP (10(-6) M) relaxed stretched rings by 1.7 +/- 0.1 g and chemically-activated rings by 4.8 +/- 0.2 g. ACh relaxed stretched rings to 73 +/- 3% of the SNP relaxation and this was only attenuated in the presence of iberiotoxin. ACh relaxed Phe-activated rings to 60 +/- 3% of the SNP relaxation. This relaxation was attenuated by inhibition of the synthesis of nitric oxide and (or) eicosanoids. Therefore, ACh relaxed stretched rings through the release of EDHF whereas the relaxation of chemically activated rings to ACh involved multiple endothelium-derived vasodilators.

Acetylcholine↗
PubMed2003

Relaxant effects of different fractions of essential oil from Carum copticum on guinea pig tracheal chains.

In previous studies, the relaxant and anticholinergic (functional antagonism), histamine(H1) inhibitory, and xanthine-like activity effect of Carum copticum have been demonstrated on guinea pig tracheal chains. To investigate the effective component(s) of this plant, responsible for the observed bronchodilatory effect, fractionation of the essential oil from Carum copticum was carried out and the relaxant effects of different fractions were examined in this study. The bronchodilatory effect of different fractions of essential oil from Carum copticum and theophylline in comparison with ethanol was examined by their relaxant effects on precontracted tracheal chains of guinea pig by 60 mM KCl (group 1) and 10 microM methacholine in two different conditions including: non-incubated tissues (group 2) and incubated tissues with 1 microM propranolol and 1 microM chlorpheniramine (group 3). In addition the relaxant effect of carvacrol was also examined on precontracted tracheal chains of guinea pig by 10 microM methacholine (group 4), (for each group, n = 5). In group 1 experiments, only theophylline and fraction 2 showed significant relaxant effect compared to that of ethanol. Fraction 2 and 3 of essential oil from carum copticum showed potent and volume (concentration) dependent relaxant effects comparable to that of theophylline in groups 2 and 3 experiments. The relaxant effects of different volumes of these two fractions were significantly higher than that of ethanol (p < 0.05 to p < 0.002 ). The volumes of fraction 1 showed relatively small relaxant effects in groups 2 and 3 experiments which were not significantly different from that of ethanol. However, the relaxant effect of different volumes of fractions 2 and 3 obtained in group 2 experiments were not significantly different from those of group 3 experiments. The volumes of fraction 4 did not show any relaxant effects. In addition volumes of carvacrol also showed comparable relaxant effect with those of fraction 2 and theophylline which was significantly greater than that of ethanol. These results indicate that the relaxant effect of essential oil from carum copticum is mainly due to its fraction 2 which is presumably carvacrol and to lesser extent due to fraction 3, and their relaxant effects are not due to anticholinergic or beta-adrenegic stimulatory effects.

Animals↗
PubMed1990

Sensory nerves, vascular endothelium and neurogenic relaxation of the guinea-pig isolated pulmonary artery.

1. In the presence of atropine and guanethidine (3 mumol/l each), electrical field stimulation (1-20 Hz) produced frequency-dependent relaxations of the histamine- (3 mumol/l) induced vascular tone in isolated rings from the guinea-pig pulmonary artery. The electrically-evoked relaxations were abolished by tetrodotoxin (1 mumol/l). The amplitude of these nerve-mediated, non-adrenergic non-cholinergic (NANC) relaxations was unaffected by removal of the vascular endothelium produced through rubbing of the internal surface. 2. Capsaicin (1 mumol/l) produced a prompt and sustained relaxation of the histamine-induced tone which was unaffected by removal of the endothelium. A second application of capsaicin 60-120 min later had no further relaxant effect, indicating desensitization. After in vitro capsaicin desensitization, the electrically-evoked NANC relaxations were abolished, both in the presence or absence of the vascular endothelium. 3. Substance P evoked a prompt and transient relaxation in precontracted arterial rings with intact endothelium and a transient small contraction in rings in which the endothelium had been mechanically removed. The selective NK-1 receptor agonist, [Pro9]-substance P sulfone closely mimicked the relaxation produced by substance P while the selective NK-2 or NK-3 receptor agonists had no relaxant effect. Tachyphylaxis to substance P did not modify the amplitude of the capsaicin-induced relaxation. 4. Human alpha calcitonin gene-related peptide (CGRP) produced a prompt and sustained relaxation both in the presence and absence of the vascular endothelium. 5. Ruthenium red (10 mumol/l) blocked the relaxation to capsaicin while leaving unaffected the relaxation to electrical field stimulation or CGRP (0.1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Further evidence for involvement of adenosine-5'-triphosphate in non-adrenergic non-cholinergic relaxation of the isolated rat duodenum.

The nature of the inhbitory non-adrenergic non-cholinergic (NANC) neurotransmitter responsible for neurogenic relaxation of rat duodenum was studied with in vitro techniques. Adenosine 5'-triphosphate (ATP)(1 mM), gamma-aminobutyric acid (GABA, 1 mM), dimethylphenylpiperazinium (DMPP, 0.1 mM) and field stimulation (60 V, 2 ms, 0.1 Hz) produced transient relaxation followed by rebound contraction. In contrast vasoactive intestinal polypeptide (VIP) (0.3 microM) and noradrenaline (1 microM) induced relaxation which set in more slowly and lasted longer. Tetrodotoxin (0.85 microM) abolished field stimulation-induced relaxation but not ATP-, VIP- or noradrenaline-induced relaxation. Nucleotide pyrophosphatase (0.25 U/ml), but not the proteolytic enzyme alpha-chymotrypsin (2 U/ml), selectively antagonized NANC relaxation. The rank order of potency of various adenine derivatives for inducing relaxation was adenosine-5'-triphosphate greater than adenosine-5'-diphosphate much greater than adenosine greater than adenosine-5'-monophosphate. ATP-induced relaxation was selectively antagonized by the putative P2 purinoceptor antagonist reactive blue 2, but unaffected by the selective P1 purinoceptor antagonist 8-phenyltheophylline. The duration of ATP- as well as beta-gamma-methylene adenosine-5'-triphosphate (a stable analogue of ATP)-induced relaxation was similar and was unaffected by indomethacin 10 microM (which abolished the rebound contraction). In those preparations whose contractile tone was increased by using a high-K+ medium the ability of ATP to elicit relaxation was markedly reduced, while GABA- and DMPP-induced relaxation was abolished. On the other hand, ATP-, GABA- and DMPP-induced relaxation of the tonic component of 5-hydroxytryptamine (5-HT)(0.1 mM)-induced contraction was similar to that observed in control conditions. These findings add further weight to the proposal that endogenous ATP is involved in determining NANC relaxation of rat duodenum.

Adenosine↗
PubMed1996

Calcitonin gene-related peptide (CGRP) in the circular muscle of guinea-pig colon: role as inhibitory transmitter and mechanisms of relaxation.

In the presence of 1 microM tetrodotoxin (TTX), human alpha calcitonin gene-related peptide (CGRP) produced a concentration-dependent relaxation (EC50 1.1 nM; Emax 86% of the relaxation to 1 microM isoprenaline) of mucosa-free circular muscle strips from the guinea-pig proximal colon. In the presence of TTX, the C-terminal fragment CGRP(8-37) produced a concentration (0.3-3 microM)-dependent rightward shift of the curve to CGRP. The TTX-resistant, receptor-mediated, CGRP-induced relaxation was unaffected by apamin (0.3 microM) and L-nitroarginine (L-NOARG, 100 microM), alone or in combination, as well as by glibenclamide (3 microM) or (S)-ketoprofen (10 microM). Tetraethylammonium (TEA, 1-10 mM) and cyclopiazonic acid (CPA, 3-10 microM) produced a concentration-dependent partial inhibition of the relaxant response to CGRP. The inhibitory effect of TEA on the maximal relaxation produced by CGRP was prevented by nifedipine (1 microM) which did not affect the CGRP-relaxation of its own. In the presence of atropine (1 microM), guanethidine (3 microM), SR 140,333 (0.3 microM), MEN 10,627 (1 microM), apamin (0.3 microM) and L-NOARG (100 microM), the application of 1 microM capsaicin produced a transient relaxation of the strips. This response was not reproduced upon a second application of capsaicin, 60 min later, indicating complete desensitization. CGRP(8-37) (0.3-1.0 microM) produced a partial inhibitory effect (about 50% inhibition) of the relaxant response to capsaicin. In the presence of atropine (1 microM), guanethidine (3 microM), SR 140,333 (0.3 microM), MEN 10,627 (1 microM), apamin (0.3 microM), L-NOARG (100 microM) and after capsaicin in vitro pretreatment (10 microM for 15 min), electrical field stimulation (EFS, 10 Hz for 5 s) produced a transient relaxation which was unchanged by CGRP(8-37) (1 microM) while being abolished by TTX. In sucrose gap, brief superfusion with 0.3 microM CGRP produced a TTX (1 microM)- resistant membrane hyperpolarization and relaxation: the hyperpolarization produced by CGRP was inhibited by about 50% by either TEA (10 mM) or CPA (10 microM), while being unaffected by glibenclamide (3 microM). The combined application of TEA and CPA was not more effective (65% inhibition) in inhibiting the CGRP-induced hyperpolarization than each drug alone. We conclude that CGRP produces a direct relaxation of the circular muscle of the guinea-pig proximal colon by activating receptors sensitive to blockade by CGRP(8-37). Activation of Ca-dependent potassium channels and Ca release/reuptake from internal store(s) appear both to be involved in the action of CGRP. Endogenous CGRP mediates part of the relaxant response evoked by stimulation of capsaicin-sensitive primary afferent nerves in the circular muscle of guinea-pig colon, while it is not involved in the apamin and L-NOARG-resistant nonadrenergic noncholinergic (NANC) relaxation produced by electrical field stimulation of intrinsic inhibitory nerves.

Amino Acid Sequence↗
PubMed1992

Labeling relaxation procedures: impact on adolescent's self-report of effectiveness.

Adolescents are being taught relaxation techniques by health-care professionals with increased frequency. The present study examined the effect, on self-reported relaxation, of labeling passive relaxation techniques as "hypnotic relaxation" or as "relaxation training." Subjects were 64 adolescent college students who scored above the 50th percentile, from a subject pool of 189 potential subjects, on the Spielberger Trait Anxiety Inventory. A two by two by two factorial design was utilized with sex, label (hypnotic relaxation versus relaxation training) and relaxation technique (hypnotic induction versus autogenic training) as the independent variables. Under the guise of an investigation of the physiologic correlates of relaxation, subjects were assigned at random to one of four groups. Manipulations of label and relaxation technique were presented on tape via an intercom system. The dependent variable, perceived degree of relaxation, was obtained using a form presented as a "double check" of the accuracy of the physiologic monitoring equipment to which subjects seemingly were attached. Results indicate that the label attached to relaxation techniques can have a significant effect on an individual's subjective report of relaxation depending on the subject's sex.

Adolescent↗
PubMed2004

Mental relaxation improves long-term incidental visual memory.

Experimental evidence has linked increased arousal to enhanced memory retention. There is also evidence that procedures reducing arousal, i.e., mental relaxation, might improve memory, but conflicting results have been reported. To clarify this issue, we studied the effects of a single session of relaxation training on incidental visual long-term memory. Thirty-two relaxation-naive subjects viewed 280 slides without being told that there would be subsequent memory testing. Afterwards, subjects listened to a 12 min relaxation tape; 16 subjects relaxed by following the instructions (relaxation group), and the other 16 subjects pressed a button whenever a body part was mentioned (control group). While listening to the relaxation tape, high frequency heart rate variability (HRV) was greater and low frequency HRV was lower in the relaxation group, implying effective relaxation and increasing parasympathetic activation. The relaxation group had superior memory retention 4 weeks later (p = .004), indicating enhancement of long-term memory performance. This effect could not be explained by retroactive interference experienced in the control group because short-term memory performance immediately after the tape was slightly better in the control group. Retention of materials acquired after the relaxation session remained unaffected, suggesting relaxation has retrograde effects on memory consolidation. Our data demonstrate a favorable influence of relaxation on at least this aspect of learning. Our data also extend previous knowledge on the beneficial effects of ascending parasympathetic stimulation on memory retention in that enhanced long-term memory consolidation may also occur in the presence of central and descending parasympathetic activation triggered by willful psychomotor activity.

Adult↗
PubMed1998

Purinoceptor subtypes mediating contraction and relaxation of marmoset urinary bladder smooth muscle.

1. The effects of adenosine triphosphate (ATP), adenosine diphosphate (ADP), alpha,beta-methylene-ATP (alpha,beta-MeATP) and 2-methylthio-ATP (2-MeSATP) on longitudinally orientated smooth muscle strips from marmoset urinary bladder were investigated by use of standard organ bath techniques. 2. After being mounted in superfusion organ baths, 66.7% (n=249) of marmoset detrusor smooth muscle strips developed spontaneous tone, 48.2% of all strips examined developed tone equivalent to greater than 0.1 g mg(-1) of tissue and were subsequently utilized in the present investigation. 3. On exposure to ATP, muscle strips exhibited a biphasic response, a rapid and transient contraction followed by a more prolonged relaxation. Both responses were found to be concentration-dependent. ADP and 2-MeSATP elicited a similar response (contraction followed by relaxation), whereas application of alpha,beta-MeATP only produced a contraction. The potency order for each effect was alpha,beta-MeATP> >2-MeSATP> ATP>ADP (contractile response) and ATP=2-MeSATP> or = ADP> > alpha,beta-MeATP (relaxational response). 4. Desensitization with alpha,beta-MeATP (10 microM) abolished the contractile phase of the response to ATP, but had no effect on the level of relaxation evoked by this agonist. On the other hand, the G-protein inactivator, GDPbetaS (100 microM) abolished only the relaxation response to ATP. Suramin (general P2 antagonist, 100 microM) shifted both the contractile and relaxation ATP concentration-response curves to the right, whereas cibacron blue (P2Y antagonist, 10 microM) only antagonized the relaxation response to ATP. In contrast, the adenosine receptor antagonist, 8-phenyltheophylline (10 microM), had no effect on the relaxation response curve to ATP. 5. Incubation with tetrodotoxin (TTX, 3 microM) or depolarization of the muscle strip with 40 mM K+ Krebs failed to abolish the relaxation to ATP. In addition, neither Nomega-nitro-L-arginine (L-NOARG, 10 microM) nor methylene blue (10 microM) had any effect on the relaxation response curve. However, tos-phe-chloromethylketone (TPCK, 3 microM), an inhibitor of cyclicAMP-dependent protein kinase A (PKA), significantly (P<0.01) shifted the curve for the ATP-induced relaxation to the right. 6. It is proposed that marmoset detrusor smooth muscle contains two receptors for ATP, a classical P2X-type receptor mediating smooth muscle contraction, and a P2Y (G-protein linked) receptor mediating smooth muscle relaxation. The results also indicate that the ATP-evoked relaxation may occur through the activation of cyclicAMP-dependent PKA.

Adenosine Diphosphate↗