Indomethacin alters the effects of substance-P and VIP on isolated airway smooth muscle

Both substance-P and vasoactive intestinal peptide (VIP) have previously been demonstrated to contract and relax, respectively, the isolated guinea pig trachea. In addition, substance-P and VIP have been localized within the pulmonary innervation of various species. In the present studies, substance-P was found to cause a concentration-related contraction of isolated lung parenchymal strips of the guinea pig, as well as isolated tracheal strips. VIP caused a significant concentration-related relaxation of the isolated tracheal strip, but not the lung parenchymal strip. Indomethacin, a prostaglandin synthetase inhibitor, potentiated the contractile response of the trachea to substance-P and inhibited the VIP- and isoproterenol-induced relaxation. These studies are potentially important in understanding the pathogenesis of bronchospastic disorders, since alterations in prostaglandin biosynthesis may result in hyperreactivity of airways to contractile agonists such as neurotransmitters, as well as an inhibition of relaxation induced by endogenous substances such as VIP or β agonists.     

In vitro relaxation of rabbit and human internal anal sphincter by rutaecarpine, an alkaloid isolated from Evodia rutaecarpa

Rutaecarpine, a compound extracted from the Chinese medicinal herb Evodia rutaecarpa, has been shown to possess relaxing action on vascular smooth muscle from rat thoracic aorta. The internal anal sphincter is a specialized smooth muscle regulating important anorectal physiology. To investigate the effect and underlying mechanisms of rutaecarpine on internal anal sphincter, muscle strips from rabbit internal anal sphincter were used. The results showed that rutaecarpine (1 x 10(-10) M to 1 x 10(-4) M) produced a concentration-dependent muscular relaxation effect in our preparations, which were precontracted with acetylcholine. This muscular relaxation effect was not affected by treatment with L-N(G)-nitro-arginine methyl ester (a nitric oxide synthase inhibitor), methylene blue (a guanylate cyclase inhibitor), N-ethylmaleimide (an adenylate cyclase inhibitor), or by removal of the mucosa and submucosa tissue. Pretreatment with nifedipine (a calcium channel blocker) or extracellular Ca+2 removal by ethylenediaminetetraacetic acid (EDTA) greatly attenuated the relaxation effect, suggesting that calcium ion might be involved. In experiments using strips from human internal anal sphincter, an even more prominent relaxation effect was shown. It is thus concluded that rutaecarpine caused relaxation on internal anal sphincter from rabbits and human subjects. The relaxation action was not related to NO-cGMP pathway, instead calcium ion might play an important role and shed insight into clinical implications for those anorectal disorders with hyperactive anal tone.     

Influence of pyridoxal-5'-phosphate on responses of isolated coronary arteries to noradrenaline, in the presence of pyrogallol

The effect of PLP on the noradrenaline-induced relaxation of coronary arteries was studied in vitro, after known inhibitor of COMT, Pyrogallol. Relaxation of response to noradrenaline were increased by PLP. Pyrogallol potentiated responses of coronary strips to noradrenaline and also reduced or abolished the enhancing effects of PLP. It is concluded that PLP enhances the response of coronary smooth muscle to noradrenaline by inhibiting a enzymatic pathway for the inactivation of catecolamines.     

哮喘豚鼠肺内ADM表达变化及对离体气管条张力的作用

目的：通过观察肾上腺髓质素（ADM）mRNA在豚鼠哮喘模型肺内的表达及对哮喘豚鼠离体气管条张力的影响,研究ADM在支气管哮喘（简称哮喘）发病机制中的作用。方法：用原位杂交方法检测ADM mRNA在豚鼠哮喘模型肺内的表达,用组胺诱导豚鼠离体气管条收缩后,观察不同浓度的ADM对其收缩作用影响。结果：原位杂交结果显示正常及哮喘豚鼠肺内均有ADM mRNA的表达,但哮喘组较正常组明显增多（P＜0．05）,ADM可抑制组胺诱导的哮喘豚鼠离体气管条的收缩,并呈量效关系,当浓度达10^-8mol/L时抑经达到最大,而且即使加大ADM的浓度,抑制率未继续明显增加,并对致敏气管螺旋条的舒张作用明显大于正常气管螺旋条。结论：哮喘时,肺内ADM mRNA的表达明显增多,ADM可抑制组胺诱导的豚鼠离体气管条的收缩,浓度为10^-8mol/L时抑制率达到最大。提示ADM在哮喘发病过程中起重要作用。     

Comparison of Functional β-Adrenoceptor Heterogeneity in Central and Peripheral Airway Smooth Muscle of Guinea Pig and Man

Abstract

The nature of the β-adrenoceptor population(s) mediating the relaxation of guinea pig and human airway smooth muscle was investigated. On the basis of a preferential blockade by β₁ and β₂ selective antagonists of the relaxation induced by β₁ and β₂- selective agonists, guinea pig tracheal strip relaxation was found to be mediated both by β₁ - and β₂ - adrenoceptors, the relative participation of which depending on the relative affinities of the agonist towards these two receptors. With highly selective antagonists the noradrenaline(NA)-induced relaxation could be split up biphasically into a β₁- and a β₂ - component. In contrast, no such differential blockade was observed with the guinea pig lung parenchyma strip relaxation which is mediated by a homogenous β₂ -adreno-ceptor population. On comparison of the tracheal, the spirally cut main bronchus- and intrapulmonary airway smooth muscle strips it could be shown that both the sensitivity of NA for neuronal uptake and the apparent affinity of the relaxation by NA decreased in the direction of the lung periphery. Using the same techniques it was ascertained that the relaxation of human tracheal smooth muscle (autopsy, obtained within 6 hours after death), main bronchus and intrapulmonary smooth muscle (operation) are mediated by homogenous β₂ -adrenoceptor populations. In addition, neuronal and extraneuron-al uptake sites were not operative in these preparations, whether obtained from operation or from autopsy.     

Effects of some autonomic drugs and neuropeptides on the mechanical activity of longitudinal and circular muscle strips isolated from the carp intestinal bulb (Cyprinus carpio)

1. The mechanical responses to some autonomic drugs and neuropeptides of longitudinal muscle (LM) and circular muscle (CM) strips isolated from the carp intestinal bulb were investigated in vitro. 2. Acetylcholine and carbamylcholine caused concentration-dependent transient contraction of both LM and CM strips. Tetrodotoxin had no effect, but atropine selectively decreased the contractile responses to acetylcholine and carbamylcholine. 3. Excitatory alpha-2 and inhibitory beta adrenoceptors were present in both LM and CM strips. 4. 5-Hydroxytryptamine (5-HT) caused concentration-dependent contraction of both LM and CM strips. Tetrodotoxin, atropine and methysergide decreased the contractile responses to 5-HT. 5. Some neuropeptides (angiotensin I, angiotensin II, bombesin, bradykinin, neurotensin, somatostatin and vasoactive intestinal polypeptide) did not cause any mechanical response (contraction or relaxation) in either smooth muscle strip. 6. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) caused contraction of both LM and CM strips. However, the time course of the contraction in LM was different from that in CM. The order of potency was NKA greater than SP greater than NKB in LM strips and NKA greater than SP much greater than NKB in CM strips. In LM strips, the contractile responses to tachykinins were unaffected by spantide and methysergide, but partly decreased by tetrodotoxin and atropine. On the other hand, the contractile responses of CM strips were unaffected by tetrodotoxin, atropine, methysergide and spantide. 7. Dynorphin (1-13) (DYN), leucine-enkephalin (L-Enk) and methionine-enkephalin (M-Enk) caused concentration-dependent contraction of both LM and CM strips. The order of potency was DYN greater than M-Enk greater than L-Enk. Naloxone selectively decreased the responses to opiate peptides. 8. The present results indicate that acetylcholine, carbamylcholine, catecholamines, 5-HT, tachykinins (SP, NKA and NKB) and opiate peptides (DYN, L-Enk and M-Enk) affect the mechanical activity of LM and CM strips isolated from the carp intestinal bulb through their specific receptors.     

Cholinergic and nonadrenergic mechanisms in human and guinea pig airways

Electrical field stimulation (70 V, 1 ms, 0.2-500 Hz) of human bronchial strips and guinea pig tracheal chains produced contractile and relaxant responses. Contractions were blocked by atropine, 10(-6) M, and tetrodotoxin (TTX), 0.1-1.0 micrograms/ml, demonstrating a cholinergic excitatory neural component. Frequencies causing half-maximal contractile response to field stimulation (EFc 50) were 10 +/- 2 Hz for guinea pig and 13 +/- 1 Hz for human airways. Relaxations were unmasked by atropine 10(-6) M and slightly diminished by propranolol in guinea pig but not human airways, demonstrating a predominantly nonadrenergic inhibitory pathway in both species. Relaxation of intrinsic tone occurred at stimulation frequencies of 1 Hz or more. Frequencies causing half-maximal relaxation (EFi 50) were 3.5 +/- 0.3 Hz for guinea pig trachealis and 38 +/- 6 Hz for human bronchi. Following 1 microgram/ml TTX, EFi 50 values increased to 104 +/- 12 and 70 +/- 14 Hz, respectively. Frequencies of field stimulation that were inhibitable by TTX (less than or equal to 20 Hz) induced greater relaxation in guinea pig than human airways (70 vs. 10% of the maximal relaxation to 10(-2) M theophylline, respectively). The methods of analysis outlined in this study can be used to compare relative degrees of functional innervation between tissues from the same or different species.     

Comparative effects of platelet activating factor, leukotriene D4 and histamine on guinea pig trachea, bronchus and lung parenchyma

The myotropic effect of platelet activating factor (PAF), leukotriene D4 (LTD4) and histamine were compared on guinea pig pulmonary tissues. The initial administration of PAF induced a contraction of strips of trachea, bronchus and lung parenchyma. However subsequent injections were characterized by relaxation of trachea and bronchus and a highly reduced (if any) contraction of the parenchyma. The three tissues of the guinea pig respiratory system contracted strongly to leukotriene D4 and histamine. Indomethacin blocked PAF-induced relaxation of the trachea and bronchus and reduced the contraction of the lung parenchyma. The injection of PAF in the pulmonary circulation stimulated the release of substance(s) causing the contraction of the trachea, bronchus and parenchyma. This study suggests that PAF is not a direct agonist of bronchoconstriction.     

Relaxant effect of dopamine on isolated rabbit pulmonary artery

In rabbit pulmonary artery, dopamine (10(-11)-10(-5) M) produced a concentration-dependent relaxation of the arterial strips contracted with prostaglandin F2 alpha (PGF2 alpha) in the presence of prazosin (10(-6) M), yohimbine (10(-6) M), propranolol (10(-6) M), and methysergide (10(-6) M). SKF38393, an agonist for D1 or DA1 dopamine receptor, mimicked partially the concentration-response curve for dopamine, whereas LY171555 and apomorphine did not. The order of potency of dopamine antagonists on the inhibitory effect was: cis-flupenthixol greater than bulbo-capnine greater than metoclopramide greater than haloperidol. Sulpiride was inactive. Cis-flupenthixol did not block the relaxation induced by acetylcholine, adenosine, and papaverine. In the arterial strips of the rabbits pretreated with 6-hydroxydopamine, the concentration-response curve for dopamine was similar to that in non-treated rabbits. Thus it is concluded that a specific dopamine receptor is located on the postsynaptic muscle membrane of the rabbit pulmonary artery.     

Effect of prostaglandin F2 alpha on propulsive activity of the isolated segmental colon of the guinea-pig.

The effects of prostaglandin F2alpha (PGF 2alpha) on propulsive activity in segments of isolated colon and on isolated strips of guinea-pig colon were investigated. Using experimental conditions under which spontaneous propulsive activity was negligible, PGF2alpha (5X10(-8)X1X10(-6)M), added to the bathing medium increased propulsive activity in a concentration dependent manner. This increase of propulsive activity was abolished in the presence of atropine or tetrodotoxin (1X10(-7)g/ml). The contractions produced by PGF2alpha (5X10(-7) -1X10(-5)M) in isolated longitudinal and circular smooth muscle strips of guinea-pig colon were unaffected in the presence of atropine or tetrodotoxin (1X10(-7) g/ml). From these results it is concluded that under the conditions employed in this study propulsive activity stimulated by PGF2alpha may depend on the contractions of both muscle layers and stimulation of the peristalic reflex.     

Pharmacology of peptide leukotrienes on ferret isolated airway smooth muscle

The contractile activities of peptide leukotrienes (LT) on isolated spiral strips of ferret trachea were characterized pharmacologically. LTC4 and LTD4 contracted ferret tracheal strips in a concentration-related manner and were 3- to 8-fold more potent than carbachol. In contrast, high concentrations of LTE4 evoked either weak contractions or none at all, whereas LTC4 and D4 were partial agonists compared to carbachol. In tissues which were unresponsive to LTE4, this compound antagonized contractile responses to LTC4 and D4 in an apparently competitive manner: Carbachol-induced contractions were not altered by LTE4. The cyclooxygenase inhibitor, indomethacin (5 microM), LT antagonist, FPL55712 (10 microM), atropine (1 microM), phenoxybenzamine (10 microM), and LTB4 (10 microM) failed to alter LTC4 and D4 concentration-response curves. The results indicate that ferret trachea is sensitive to the contractile activity of LTC4 and LTD4 but not LTE4. The LT-induced contractions appear to be mediated by a direct action of the LT rather than indirectly through release of secondary mediators such as thromboxane, prostaglandin, or acetylcholine. LT receptors in ferret trachea are insensitive to FPL55712 but are antagonized by LTE4.     

Comparative effects of platelet activating factor, leukotriene D4 and histamine on guinea pig trachea, bronchus and lung parenchyma

The myotropic effect of platelet activating factor (PAF), leukotriene D₄ (LTD₄) and histamine were compared on guinea pig pulmonary tissues. The initial administration of PAF induced a contraction of strips of trachea, bronchus and lung parenchyma. However subsequent injections were characterized by relaxation of trachea and bronchus and a highly reduced (if any) contraction of the parenchyma. The three tissues of the guinea pig respiratory system contracted strongly to leukotriene D₄ and histamine. Indomethacin blocked PAF-induced relaxation of the trachea and bronchus and reduced the contraction of the lung parenchyma. The injection of PAF in the pulmonary circulation stimulated the release of substance(s) causing the contraction of the trachea, bronchus and parenchyma. This study suggests that PAF is not a direct agonist of bronchoconstriction.     

Endothelium-dependent relaxation by tetraoctylammonium ions in rat isolated aortic rings

Quaternary ammonium ions are common pharmacological blockers of K+ channels. This study examined the vasorelaxant effect of tetraoctylammonium ions (TOA+) in rat isolated aortic rings. TOA+ caused a concentration-dependent transient relaxation of endothelium-intact tissues. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 3x10(-5) M) or methylene blue (3 x 10(-6) M) or removal of the endothelium abolished the TOA+-induced relaxation. L-arginine (10(-3) M ) partially antagonized the effect of L-NAME. Glibenclamide (3x10(-6) M), charybdotoxin (CTX, 10(-7) M), indomethacin (10(-5) M), or atropine (3x10(-6) M) had no effect. Both TOA+ (10(-5) M)- and acetylcholine (ACh, 10(-5) M)-induced increase in tissue content of cyclic GMP was significantly attenuated by NG-nitro-L-arginine (L-NNA, 10(-4) M) and abolished in endothelium-denuded arteries. These results indicate that TOA+ induced endothelium-dependent relaxation which is likely mediated through nitric oxide but not other endothelium-derived factors. This relaxant action seems unique for TOA+ since other quaternary ammonium ions did not cause nitric oxide-dependent relaxation.     

Evidence for a lower oesophageal sphincter in the guinea-pig

1. In vitro balloon pull-through experiments have been used to identify the guinea-pig lower oesophageal sphincter (LOS). 2. Histologically, the LOS forms a 1-2 mm ring of smooth muscle at the distal termination of the oesophagus, immediately adjacent to the gastric sling muscle. 3. Tetrodotoxin (10(-6) M) sensitive, guanethidine (10(-6) M) insensitive "on" relaxation of circular LOS muscle strips was evoked by electrical field stimulation (ES). 4. ES evoked atropine (10(-6) M) sensitive "on" contractions of gastric sling and fundus smooth muscle strips. 5. Following cessation of ES a partially atropine-sensitive "off" contraction was observed in all the smooth muscle strips. 6. The predominant response of the LOS to ES was relaxation.     

Vasoactive intestinal polypeptide induces neurogenic contraction of guinea-pig ileum. Involvement of acetylcholine and substance P.

The effect and mode of action of vasoactive intestinal polypeptide (VIP), a peptidergic neuromodulator in the gastrointestinal nervous system, were investigated in isolated muscle strips of the guinea-pig ileum. VIP induced concentration-dependent (20 nM-1 microM) contractions of longitudinal ileal strips. TTX (1 microM), a mixture of atropine (3 microM) and spantide (30 microM), a mixture of atropine (3 microM) and omega-conotoxin GVIA (100 nM), somatostatin (60 nM) and dynorphin (100 nM) abolished the effect of VIP. In most cases a small relaxation became evident. Desensitization to substance P in the presence of atropine prevented VIP-induced contraction. A partial inhibition was observed in the presence of atropine (3 microM), spantide (30 microM), omega-conotoxin GVIA (100 nM), beta-endorphin (265 nM), met-enkephalin (1100 nM) and a mixture of spantide (30 microM) and omega-conotoxin GVIA (100 nM). The action of VIP was not significantly modified by guanethidine (3 microM) or hexamethonium (150 microM). In circular ileal strips VIP (10-300 nM) caused concentration-dependent relaxations through a direct myogenic effect. These results indicate that the VIP produced contractions of the guinea-pig ileum are exclusively neurally mediated and involve a cholinergic as well as a noncholinergic-nonadrenergic (NANC) pathway. It is concluded that besides acetylcholine (Ach) VIP releases the peptidergic transmitter substance P from postganglionic nerve fibers of myenteric plexus. Opioid peptides and somatostatin modulate the activity of cholinergic and peptidegic nerves in the guinea-pig ileum. The release of substance P appears to depend completely on N-type voltage sensitive calcium channels.     

姜黄素对小鼠离体十二指肠平滑肌舒缩活动的影响

目的:本研究采用小鼠离体十二指肠平滑肌观察姜黄素对胃肠道蠕动的影响,探讨其作用机制。方法:取小鼠离体十二指肠平滑肌条,放入37℃Krebs液浴槽中,通入95%氧气和5%二氧化碳混合气体,分组进行下列实验:对照组和分别加入10-40 M姜黄素组,测量记录十二指肠平滑肌的自主收缩变化;另取一组平滑肌条,分对照组、乙酰胆碱组、乙酰胆碱+姜黄素组、阿托品组、阿托品+姜黄素组,采用张力换能器连接多通道生理信号采集处理系统,测量比较十二指肠平滑肌舒缩的变化。结果:小鼠十二指肠平滑肌加入姜黄素孵育后,其自主收缩幅度有明显下降(P0.01),而且降低的幅度与姜黄素剂量相关;给与乙酰胆碱引起十二指肠收缩后,再加姜黄素孵育,十二指肠平滑肌的收缩幅度明显的下降(P0.01);给予阿托品引起小鼠平滑肌舒张后,再给予姜黄素孵育,平滑肌收缩幅度进一步降低。结论:姜黄素对小鼠离体十二指肠平滑肌具有直接舒张作用。     

Natriuretic peptides cause relaxation of human esophageal mucosal muscle

Natriuretic peptides have been demonstrated to cause relaxation of the human gallbladder muscle through interaction with natriuretic peptide receptor-B (NPR-B/NPR2). Effects of natriuretic peptides in the human esophageal muscle were unknown. To investigate the effects of natriuretic peptides in the human esophagus, we measured relaxation of muscularis mucosae strips isolated from the human esophagus caused by C-type natriuretic peptide (CNP), brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and des[Gln(18), Ser(19), Gly(20), Leu(21), Gly(22)]ANP(4-23) amide (cANP(4-23)), a selective natriuretic peptide receptor-C (NPR-C) agonist. In endothelin-1 or carbachol-contracted mucosal muscle strips, CNP caused moderate, sustained and concentration-dependent relaxation. BNP caused a very mild relaxation whereas ANP and cANP(4-23) did not cause any relaxation. CNP was much more potent than BNP and ANP in causing relaxation. These suggest the existence of NPR-B mediating relaxation. The CNP-induced relaxation was not affected by tetrodotoxin or atropine in endothelin-1-contracted esophageal strips and not by tetrodotoxin in carbachol-contracted strips, indicating a direct effect of CNP on the human esophageal muscularis mucosae. Taken together, these results demonstrate that natriuretic peptides cause relaxation of the muscularis mucosae of the human esophagus and suggest that the relaxation is through interaction with NPR-B. Natriuretic peptides may play an important role in the control of human esophageal motility.     

Antagonism of relaxation to isoproterenol caused by agonist interactions

The interaction of contractile agonists on the relaxation elicited with isoproterenol (ISO) was studied in 112 tracheal smooth muscle (TSM) strips from 20 dogs in vitro. Strips were contracted to the same active target tension (TT) with acetylcholine (ACh), histamine (HIS), serotonin (5-hydroxytryptamine, 5-HT), potassium chloride (KCl), or the combinations of ACh + HIS, ACh + 5-HT, HIS + KCl, HIS + 5-HT (50% TT from each agonist). Although a less potent agonist, adding HIS to cause 50% of the TT reduced the concentration of ACh to elicit the remaining 50% TT and substantially altered relaxation by ISO compared with HIS alone [concentration required to achieve 50% relaxation (RC50) = 9.2 +/- 2.4 X 10(-8) vs. 9.0 +/- 4.4 X 10(-9) M to HIS alone; P less than 0.003]. Relaxation for TSM strips contracted with ACh + HIS was comparable to that elicited from the same TT with ACh alone, although concentrations required in combination were lower than for either agonist alone. Trachealis strips contracted equivalently with KCl + HIS also had augmented contraction and attenuated relaxation (RC50 = 3.7 +/- 0.8 X 10(-8) M; P less than 0.015 vs. HIS alone). However, combinations of 5-HT + ACh and 5-HT + HIS did not alter relaxation to ISO from that elicited by the weaker agonist alone. We demonstrate that TSM relaxation depends on the combination of agonists eliciting contraction and may be inhibited substantially by interactions among contractile agonists.     

Differentiation between bronchodilation and universal adenosine antagonism among xanthine derivatives

Relaxant effects and adenosine-antagonism of 3-propyl-xanthine (enprofylline) and 10 different methyl-xanthines were examined in isolated guinea-pig tracheas. The chemical structural requirements for tracheal relaxation were found to be different from those for adenosine antagonism by the xanthine derivatives. All xanthines produced relaxation: Enprofylline was about 5 times more potent than theophylline. However, only xanthines with a methyl in the 1-position consistently antagonized the relaxant effect of adenosine. --Theophylline over a wide range of concentrations (30-900 microM) produced a concentration dependent and surmountable antagonism at nervous adenosine receptors (isolated guinea-pig myenteric-plexus preparations). The same concentrations of enprofylline were almost devoid of antagonism at these adenosine receptors. In mice theophylline (6-24 mg/kg given intraperitoneally) dose-dependently increased locomotor activity while enprofylline (2-48 mg/Kg) was without effect on behaviour. "Non-blocking" xanthines such as enprofylline may be potent bronchodilators but lack many theophylline-like actions. We, therefore, forward the hypothesis that universal adenosine antagonism is both unnecessary and undesirable with xanthine antiasthmatics.     

Beta-adrenergic relaxation of dog trachealis: contractile agonist-specific interaction

The phenomenon of contractile agonist-dependent relaxation by isoproterenol (ISO) of active tension elicited by acetylcholine (ACh), histamine (HIS), serotonin (5-HT), and potassium chloride-substituted Krebs-Henseleit solution (KCl) was studied in 210 tracheal smooth muscle (TSM) strips from 28 mongrel dogs in vitro. All TSM strips were contracted to similar active tensions [target tension (TT) = 50% of the maximal active tension elicited by 127 mM KCl] with ACh, HIS, 5-HT, or KCl and relaxed with either ISO, forskolin (FSK), N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (db-cAMP), or 3-isobutyl-1-methylxanthine (IMX). The concentrations of ISO causing 50% relaxation from TT (RC50) were ACh (2.9 +/- 1.1 x 10(-6) M) greater than 5-HT (8.4 +/- 1.5 x 10(-8) M) approximately KCl (8.1 +/- 2.1 x 10(-8) M) greater than HIS (1.6 +/- 0.2 x 10(-8) M). FSK and IMX relaxed TSM in the same rank order of potency as ISO. In contrast to the contractile agonist-dependent relaxation elicited by ISO, FSK, and IMX, db-cAMP was nearly equipotent in relaxing similarly contracted strips. These results are consistent with contractile agonist-specific interaction with cAMP production by ISO and FSK. These data demonstrate that the phenomenon of contractile agonist-dependent relaxation by ISO is not related specifically to the beta-adrenoceptor.