Pharmacological action of the phospholipase A2 from the venom of Trimeresurus flavoviridis on the smooth muscle of the rat stomach

Phospholipase A2 (PLA2) from the venom of the snake Trimeresurus flavoviridis produced an increase in resting tension of isolated strips of rat stomach fundus. The contractions of the fundus strips induced by the PLA2 were significantly inhibited by treatment with 10(-6) M indomethacin and in Ca2+-free medium, while treatment of the fundus strips with nordihydroguaiaretic acid caused a marked potentiation of the PLA2-induced contraction. Atropine (10(-6) M), chlorpheniramine (10(-6) M) and methysergide (10(-6) M) had no effects on the contractions induced by PLA2, while tetrodotoxin (10(-6) M) significantly potentiated the contraction. From these results, it appears that exogenously applied PLA2 may cause contraction of the rat stomach fundus through the liberation of endogenous arachidonic acid which may then be transformed into prostaglandins.     

A formyl peptide contracts guinea pig lung: role of arachidonic acid metabolites

We studied the role of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in mediating N-formyl-methionyl-leucyl-phenylalanine- (FMLP) induced contractions of guinea pig lung parenchymal strips. The cyclooxygenase inhibitors indomethacin (10(-5) M) and aspirin (3 X 10(-5) to 10(-4) M), the lipoxygenase inhibitor nordihydroguaiaretic acid (10(-5) to 3 X 10(-5) M), and the combined cyclooxygenase/lipoxygenase inhibitors 1-phenyl-3-pyrazolidinone (Phenidone) (3 X 10(-5) to 3 X 10(-4) M) and BW 755C (10(-5) to 10(-4) M) each caused a decrease in the maximum force induced by FMLP (Fmax) and an increase in the concentration of FMLP required to produce 50% of Fmax (EC50). The thromboxane synthesis inhibitor imidazole (3 X 10(-3) M) also decreased Fmax. The leukotriene D4 receptor antagonist FPL 55712 (5.7 X 10(-6) to 1.9 X 10(-5) M) increased the EC50 for FMLP, whereas desensitization of lung parenchymal strips to leukotriene B4 by pretreatment with this leukotriene (10(-7) M) had no effect on FMLP-induced contraction. After exposure to FMLP (10(-6) M), guinea pig lung produced (as determined by high-performance liquid chromatography and radioimmunoassay) leukotrienes C4 and B4, thromboxane A2 (as measured by its stable degradation product thromboxane B2), and prostaglandin F2 alpha. Lung strips not exposed to FMLP showed no evidence of leukotriene production. We conclude that thromboxane A2 and leukotriene C4 generated in response to FMLP mediate a substantial fraction of the force induced by this peptide in guinea pig lung parenchymal strips.     

Noncholinergic contractile response to nicotine in the guinea pig isolated tracheal smooth muscle

The existence of substance P immunoreactive nerves in the trachea of guinea pig is known. In this study, capsaicin induced a long-lasting and marked contraction in the guinea pig trachea and nicotine-induced contraction was partially reduced in the capsaicin-treated muscle. Furthermore, the contractile response to nicotine (10(-5) M) in the presence of atropine (10(-7) M) was abolished by a substance P antagonist, [D-Arg1, D-Pro2, D-Trp7,9 Leu11]substance P (10(-5) M). These findings suggest that noncholinergic contractile response to nicotine may be due to the release of material(s) resembling substance P in the isolated tracheal smooth muscle preparation of guinea pig.     

Mechanism of spasmolytic activity of a fraction of Sarcostemma brevistigma Wight

The effect of chloroform soluble fraction (F-A) of twigs of Sarcostemma brevistigma on contractions induced by KCl, histamine, and acetylcholine in the isolated guinea pig ileum and taenia coli smooth muscles has been evaluated. F-A (19.5 microg/ml) significantly inhibited the contraction induced by 40 mM KCl to the extent of 87.6% in the isolated guinea pig ileum. In the isolated guinea pig ileum, F-A (64.3 and 59.2 microg/ml) significantly inhibited the contractions induced by acetylcholine and histamine to the extent of 85 and 83% respectively. In the isolated guinea pig taenia coli, F-A (65.2 microg/ml) significantly inhibited the contraction induced by 40 mM KCl to the extent of 96.0%. The inhibitory effect of F-A (40 microg/ml) on the isolated guinea pig taenia coli was reduced by Bay K 8644 (10(-6) M) to the extent of 61.6 from 73.6%. These results suggest that the F-A may exhibit smooth muscle relaxant activity by blocking the Ca2+ channels.     

The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist

L-670,596 ((-)6,8-difluoro-9-rho-methylsulfonyl benzyl-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 x 10(-9) M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 x 10(-7) M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1-5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.     

Adenosine selectively inhibits noncholinergic transmission in guinea pig bronchi

The neuromodulatory action of adenosine and ATP was investigated in isolated guinea pig bronchial strip chain preparations contracted with electrical field stimulation. The tissues were placed in organ baths containing physiological salt solution and stimulated at 8-Hz frequency, 0.5-ms pulse duration, and 30 V (approximately 100 mA) for 5 s. Electrical field stimulation evoked a biphasic contraction of bronchial muscle, consisting of an initial contraction followed by a sustained contraction, which was mediated by intramural cholinergic and noncholinergic nerve stimulations, respectively. Adenosine, at concentrations greater than M, caused a concentration-dependent inhibition in the height of the noncholinergically mediated contraction, accompanied by a very weak inhibition on the cholinergically mediated response. ATP (10(-5) to 3 x 10(-3) M) also produced a similar inhibitory effect on the noncholinergically mediated contraction, but the inhibitory potency was less than that of adenosine. The inhibitory response to adenosine was enhanced by the pretreatment with dipyridamole (2 x 10(-6) M) but antagonized with aminophylline (10(-5) M). Contractions of bronchial muscle evoked by exogenous acetylcholine (2 x 10(-6) M) or substance P (2 x 10(-7) M) were significantly inhibited by the adenosine (3 x 10(-4) M) pretreatment. These data suggest that in isolated guinea pig bronchi adenosine selectively inhibits noncholinergic neurotransmission through prejunctional P1-purinoceptors.     

Two components of contraction in guinea pig papillary muscle

Biphasic contractions were produced in guinea pig papillary muscle by inducing partial depolarization in a K+ -rich solution (22 mM) containing 10(-6) M isoproterenol. However, when the same conditions were applied to frog and rat, monophasic contractions were obtained. In the case of guinea pig, an increase in the beating frequency produced an increase in amplitude of the first component and a reduction of the second, while in frog and rat, only a decrease in the amplitude of contractions was recorded. Caffeine (10(-3) M) eliminated the first component and increased the second in guinea pig, while in the case of rat and frog it decreased the amplitude of contractions. Procaine (10(-3) M) suppressed the first component and decreased the second one. The contraction in frog appears to be similar to the second component of contraction in guinea pig, while in rat, the contraction is comparable with the first component in guinea pig. It is suggested that the calcium ions which activate the two components of contraction in guinea pig under the given experimental conditions may arise from two different sources.     

ChTX induces oscillatory contraction in guinea pig trachea: role of cyclooxygenase-2 and PGE2

We examined the possible role of cyclooxygenase (COX) in charybdotoxin (ChTX)-induced oscillatory contraction in guinea pig trachea. Involvement of prostaglandin E(2) (PGE(2)) in ChTX-induced oscillatory contraction was also investigated. ChTX (100 nM) induced oscillatory contraction in guinea pig trachea. The mean oscillatory frequency induced by ChTX was 10.7 +/- 0.8 counts/h. Maximum and minimum tensions within ChTX-induced oscillatory contractions were 68.4 +/- 1.8 and 14.3 +/- 1.7% compared with K(+) (72.7 mM) contractions. ChTX-induced oscillatory contraction was completely inhibited by indomethacin, a nonselective COX inhibitor. Valeryl salicylate, a selective COX-1 inhibitor, did not significantly inhibit this contraction, whereas N-(2-cyclohexyloxy-4-nitro-phenyl)-methanesulfonamide, a selective COX-2 inhibitor, abolished this contraction. Exogenously applied arachidonic acid enhanced ChTX-induced oscillatory contraction. SC-51322, a selective PGE receptor subtype EP(1) antagonist, significantly inhibited ChTX-induced oscillatory contraction. Exogenously applied PGE(2) induced only a slight phasic contraction in guinea pig trachea, but PGE(2) induced strong oscillatory contraction after pretreatment with indomethacin and ChTX. Moreover, ChTX time-dependently stimulated PGE(2) generation. These results suggest that ChTX specifically activates COX-2 and stimulates PGE(2) production and that ChTX-induced oscillatory contraction in guinea pig trachea is mediated by activation of EP(1) receptor.     

Cooling-induced contraction of guinea pig tracheal smooth muscle

Cooling of isolated guinea pig tracheal smooth muscle from 38 to 28 degrees C over 2.25 min produced a transient contraction followed by sustained relaxation. The cooling-induced contraction was blocked either by pretreatment with ouabain at concentrations of 10(-5) M or greater or by substitution of normal physiological salt solution with K-free solution. In contrast, the contractile response to cooling was not inhibited by pretreatment with phentolamine (10(-5) M), atropine (10(-5) M), tetrodotoxin (3 X 10(-7) M), diphenhydramine (10(-5) M), cromolyn sodium (10(-3) M), indomethacin (3 X 10(-7) M), nifedipine (10(-7) M), or verapamil (3 X 10(-6) M). Addition of NaHCO3 to the bath during cooling, preventing a change in pH of the physiological salt solution, did not affect the cooling-induced contraction. It is concluded that cooling of isolated guinea pig trachea produces a transient ouabain-sensitive contraction, and that the data suggest the contraction is mediated by inhibition of Na-K-ATPase in the smooth muscle rather than through neuronal stimulation or chemical mediator release.     

Contraction of guinea pig lung parenchyma by pancreatic type phospholipase A2 via its specific binding site.

Porcine pancreatic group I phospholipase A2 (PLA2-I) induced contraction of guinea pig parenchyma in a concentration-dependent manner. Its EC50 value was similar to the Kd value calculated from the specific binding of 125I-labeled porcine PLA2-I in the membrane fraction of guinea pig lung. Type-specific action of PLA2's and homologous desensitization strongly implicated the involvement of PLA2-I-specific sites in the activation process. Thromboxane A2 was found to be the main product from lung tissue by PLA2-I action and the contractile response by PLA2-I was specifically suppressed by thromboxane A2 receptor antagonists and cyclooxygenase inhibitor, but not by leukotriene receptor antagonist and H1 blocker. These findings indicate that PLA2-I-induced contractile response may depend on the secondarily produced thromboxane A2, thus providing a new aspect of PLA2-I from the pathophysiological standpoint.     

Neuropeptide Y inhibits relaxations of the guinea pig uterine artery produced by VIP

Interactions between neuropeptides contained in autonomic vasodilator neurons supplying the guinea pig uterine artery were investigated in isolated segments of the artery precontracted with prostaglandin F2 alpha. Neither somatostatin-14 (10(-6) mol.l-1) nor dynorphin A(1-17) (10(-6) mol.l-1) had direct effects on vascular tone, and did not affect relaxations produced by guinea pig vasoactive intestinal peptide (gpVIP). Both the porcine and the guinea pig forms of neuropeptide Y (NPY; 10(-7)-10(-5) mol.l-1) caused transient contraction of the precontracted arteries. NPY also inhibited relaxations of the artery produced by gpVIP, an action which was not directly related to the NPY contractions. NPY caused both a concentration-dependent rightward shift in the gpVIP concentration-response curve, and a reduction in size of the maximum relaxation to gpVIP. NPY (10(-6) mol.l-1) also produced a rightward shift in the concentration-response curves for the vasodilators forskolin and glyceryl trinitrate, but did not reduce the maximum relaxations to these compounds. Thus NPY, which is colocalized with VIP in vasodilator neurons supplying the uterine artery, can greatly reduce the vasodilator potency of VIP.     

Contribution of Na+ and membrane depolarization to contraction induced by adrenaline in the guinea pig vas deferens

The contribution of Na+ and membrane depolarization to biphasic contractions induced by adrenaline were investigated in the smooth muscle of guinea pig vas deferens. Adrenaline (5 X 10(-6) M) produced an initial small contraction (first contraction) followed by a large tonic contraction (second contraction) with subsequent rhythmic activity. The entire response to adrenaline was largely inhibited by phentolamine (5 X 10(-6) M). By adding an appropriate concentration of Mn2+ (2 X 10(-4) M) or nifedipine (3 X 10(-7) M), a Ca2+ blocker, the second contraction was strongly reduced, accompanied by abolishment of the rhythmic contraction, whereas the first contraction was virtually unaffected. However, the first contraction was markedly suppressed by a higher concentration of Mn2+. All contractions produced by adrenaline were greatly reduced in Ca2+-free solution containing 0.5 mM EGTA. By lowering external Na+ concentration, the first contraction was markedly increased without greatly affecting the second contraction. By exposure to Na+-free isotonic high K+ solution, which elicited a greater depolarization of the membrane, the first contraction produced by adrenaline was also greatly potentiated, while the second and rhythmic contractions were eliminated. These results suggest that the adrenaline-evoked first contraction may be due to an influx of membrane bound Ca2+ which is independent of membrane depolarization, while the second (rhythmic) contraction is due to an influx of extracellular Ca2+ which is dependent upon depolarization.     

Histaminergic effect of crude papaya latex on isolated guinea pig ileal strips.

In the present study, we investigated the effect of the crude latex of Carica papaya L. (CPX) on isolated guinea pig ileal strips. CPX (0.5-512 microg/ml) caused concentration-dependent contraction of ileal strips suspended in Tyrode solution. The concentration of atropine (0.69 microM) that significantly blocked the contractile effect of acetylcholine on the isolated guinea pig ileum showed no significant effect on CPX- and histamine-induced contractions of the ileal strips. Mepyramine (87.6 nM) significantly blocked the contractile effect of histamine and CPX on the ileum. The same concentration of mepyramine, however, had no significant effect on acetylcholine-induced contraction of the isolated ileal strips. Removal of Ca2+ from the bathing medium abolished ileal contractions induced by acetylcholine, histamine and CPX. All the test substances were able to provoke ileal contractions after replacement of the Ca(2+)-free solution with Tyrode solution. Furthermore, 10(-5) M of nifedipine, a Ca(2+)-entry antagonist, reversibly inhibited the contractile effect of all the test substances on the ileal strips. Results of this study together appear to show that CPX-induced contraction of the isolated guinea pig ileum is mediated via H1-receptors and dependent on extracellular Ca2+ influx.     

Lithium does not synergize the peripheral action of cholinomimetics as seen in the central nervous system

Lithium is known to synergize the action of cholinomimetics in the CNS such that pilocarpine induces seizures in low concentration (1/13th of per se dose) in rats. The present study was undertaken to see if lithium priming also enhances the peripheral effects of acetylcholine and pilocarpine i.e. change in blood pressure in rats and contractions of the isolated guinea pig ileum. In anaesthetized rats the blood pressure was recorded from cannulated carotid artery connected through the pressure transducer to Coulbourn polygraph. The blood pressure response of pilocarpine was not different either in magnitude or in duration when administered 1, 2 and 4 h after lithium chloride (3 meq/kg) pretreatment as compared to the control. Similarly acetylcholine effect remained unchanged after lithium chloride priming. In the isolated guinea pig ileum experiments, ileum was incubated for 1 h in different concentrations of lithium chloride and effect on acetylcholine induced contractions were observed. Lithium in concentration of 2.8 x 10(-3) M had no effect on acetylcholine induced contractions while incubation with higher concentrations of 1.4 x 10(-2) M and 2.8 x 10(-2) M significant inhibition of acetylcholine contractions were observed. At this concentration, histamine induced contractions were also inhibited. The results indicate that lithium does not synergize the action of cholinomimetics in the periphery as that seen in the CNS. The inhibition of acetylcholine and histamine induced contractions in guinea pig ileum at high concentration of lithium seems to be non-specific effect.     

Neutral endopeptidase inhibitor potentiates endothelin-1-induced airway smooth muscle contraction.

To study the role of neutral endopeptidase (NEP) on endothelin-1-induced contraction of the airway smooth muscle, we examined the contractile effect of endothelin-1 in the isolated guinea pig trachea and human bronchus in the presence or absence of NEP inhibitor phosphoramidon. After incubation with phosphoramidon (10(-8) to 10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the airway tissues in organ baths. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in a concentration-dependent fashion in both guinea pig trachea and human bronchus, and it shifted the concentration-response curves to the left. Because NEP is known to cleave tachykinins, we next studied whether endothelin-1 contracts airway tissues by releasing endogenous tachykinins from bronchial C-fibers. After incubation with phosphoramidon (10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the tissues that were treated with capsaicin to deplete the tachykinins. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in the capsaicin-treated tissues, suggesting that endothelin-1 causes the contraction, at least in part, without releasing tachykinins. In contrast to the effect of phosphoramidon, captopril (an angiotensin-converting enzyme inhibitor), leupeptin (a serine protease inhibitor), and bestatin (an aminopeptidase inhibitor) did not modulate the effect of endothelin-1-induced contraction in both guinea pig trachea and human bronchus. From these results, we conclude that NEP plays an important role in regulating endothelin-1-induced contraction in the guinea pig trachea and human bronchus.     

In vitro effect of calcitonin on guinea pig gallbladder

Calcitonin (CT) is a 32 amino acidic polypeptide hormone which has been found in almost all species and whose effects are mainly concerned with calcium and phosphorous homeostasis. Three preparations are employed for therapeutic uses: salmon (sCT), porcine (pCT) and human CT (hCT). The sCT is the most powerful one and in human volunteers a strong relaxing effect has been shown on gallbladder (GB) basal volume and emptying in response to a meal, intraduodenal instillation of a liquid meal and i.v. cholecystokinin (CCK) infusion. Our study was aimed at investigating if a direct sCT effect could be demonstrated on smooth muscle strips from guinea pig GBs "in vitro" (organ bath). Isometric contractions were measured in response to maximal doses of acetylcholine (ACh: 10(-4) M), KCl (80 mM) and cholecystokinin octapeptide (CCK-OP: 10(-6) M), in absence and in presence of four doses of sCT (1 x 10(-9), 1 x 10(-8), 1 x 10(-7) and 1 x 10(-6) M). sCT did not affect the initial strip basal tone. ACh, CCK-OP and KCl caused, as expected, a powerful contraction of the strips, but no effect was shown when each of the sCT doses was administered before ACh (1.28+ 0.69 SEM without sCT vs 1.28g+ 0.69 with sCT; n = 6) and CCK-OP (1.46g+ 0.19 without sCT vs 1.46g+ 0.19 with sCT; n = 8) or 5 min after the induced KCl contraction. On the basis of these preliminary results, we conclude that no evidence of a direct sCT effect was found on guinea pig GBs when considering either basal smooth muscle tone or isometric contraction in response to ACh, KCl and CCK-OP. Further studies are therefore required to clarify the influence of CT on GB dynamics in vivo and to elucidate its the physiological significance.     

Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist

L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 x 10(-5)M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2-12.8 micrograms/kg)-induced bronchoconstriction in guinea pigs, and p.o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.     

Inhibition of antigen and calcium ionophore A23187 induced contractions of guinea pig airways by isoprenaline and forskolin

Isoprenaline and forskolin both inhibit contractions induced by antigen or by the calcium ionophore A23187 of guinea pig tracheal spirals and parenchymal strips. Antigen-induced airway contraction is considerably more sensitive to the inhibitory effects of isoprenaline than is A23187-induced contraction. In contrast, forskolin is equiactive as an inhibitor of antigenic and ionophoric contractions. Forskolin is a more effective inhibitor of the prolonged phase of antigen-induced tracheal contraction than of the initial peak phase, which may suggest selectivity for the lipoxygenase pathway of arachidonic acid metabolism. Isoprenaline inhibits the mechanisms of the primary peak phase and of the prolonged phase equally. Although there were little, if any, differences between normal and sensitized tissues in the modulation of A23187-induced contractions of parenchyma, distinct differences were observed in trachea. Low concentrations (10(-8)-10(-7) M) of isoprenaline and forskolin enhanced A23187-induced contraction of sensitized, but not normal trachea. Higher concentrations were inhibitory. The results demonstrate that sensitization affects the modulation by isoprenaline and forskolin of A23187-induced contraction of guinea pig trachea.     

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.     

Effects of prostaglandins and arachidonic acid on baboon cerebral and mesenteric arteries

Effects of prostaglandins (PGs) E1, E2, F2 alpha and I2 in a wide range of concentration were examined in mesenteric and cerebral arteries isolated from mature baboons. PGs E1, E2 and F2 alpha at low concentrations (10(-10) to 10(-7) M) elicited relaxation in helically cut strips of cerebral arteries precontracted with phenylephrine. In contrast, the PGs did not cause relaxation in the mesenteric artery. PGI2 (10(-9) to 10(-6) M) produced marked relaxation in both arteries. The EC25 for PGI2 in the mesenteric artery was significantly lower than that in the cerebral artery. During baseline conditions, cerebral arteries contracted in response to high concentrations (greater than 10(-7) M) of PGs E1, E2 and F2 alpha. In mesenteric arteries, a large contraction was induced by PGs F2 alpha and E2 but not by PGE1. Arachidonic acid (10(-6) M) produced an aspirin-inhibitable relaxation in both arteries to a similar extent, so that the vasodilator PG(s) formed in the two different arterial walls appear to exert a similar relaxant action. Thus, the baboon mesenteric artery was more sensitive to PGI2 for the relaxant effect than was the cerebral artery, while PGs F2 alpha, E1 and E2 caused only a contraction in the mesenteric artery but both relaxation and contraction in the cerebral artery.