Spontaneous and prostaglandin- or oxytocin-induced motility of rat ovaries isolated during different stages of the estrous cycle: effects of norepinephrine

Ovaries isolated from rats in different stages of the sex cycle were explored for spontaneous or drug-induced contractile activity. The number of spontaneously active ovaries as well as the magnitude of the isometrically developed tension and frequency of contractions were greater during the periovulatory interval (late proestrus and estrus) than during early proestrus or metestrus. Furthermore, during estrus or late proestrus the left ovaries exhibited a mechanical activity significantly greater than that of the right ovaries. The oxytocin-triggered motility was clearly more marked immediately prior to ovulation (late proestrus) and greater in left ovaries than in right ovaries. In contrast, the contractions induced by prostaglandin F2alpha were similar during early proestrus and late proestrus. Ovarian contractile reactivity to norepinephrine indicated the presence in the tissue of alpha- and beta-adrenergic receptors. During early proestrus this agent stimulated the motility of left and right ovaries, whereas close to the ovulatory interval (late proestrus) it depressed the contractions of left ovaries. This last influence was blocked by propranolol. The existence of a close relationship between ovarian contractile activity and ovulation is reinforced by the present results in the rat. A tentative participation of oxytocin is also suggested. In addition, the influences of other possible regulatory agents of ovarian contraction, such as catecholamines and prostaglandins, are presented and discussed.     

Contribution of prostaglandins to the adenosine triphosphate-induced contraction of rabbit urinary bladder

1 Adenosine 5'-triphosphate (ATP) produced an initial rapid, phasic contraction and a later, slowly developing tonic contraction in the isolated detrusor of the rabbit but mainly a rapid, phasic response in the guinea-pig bladder. 2 Electrical field stimulation elicited only a rapid, phasic contraction in both rabbit and guinea-pig bladders. 3 Prostaglandin synthesis inhibition by means of indomethacin and suprofen abolished the tonic response to ATP in the rabbit detrusor, leaving the phasic part of the contraction almost unaffected. The ATP-induced contraction in guinea-pig bladder was not influenced by indomethacin. 4 The contractile response of rabbit urinary bladder to prostaglandins F2 alpha and E2 and to carbachol were not significantly influenced by indomethacin. The contractions induced by the prostaglandins were similar to the tonic response to ATP. 5 Tetrodotoxin, atropine, phentolamine, and theophylline did not alter the ATP-induced contraction. However, the calcium antagonists, nifedipine and nimodipine, abolished the phasic ATP response and greatly reduced the tonic part of the contraction. 6 Tachyphylaxis occurred on repeated addition of ATP; the response to field stimulation was progressively reduced only after indomethacin pretreatment. 7 ATP and prostaglandins may contribute to the non-adrenergic, non-cholinergic component of the excitation of rabbit and guinea-pig bladder.     

The physiology of spasticity

The contractile effects of ATP and related purine compounds on the isolated rabbit detrusor were investigated. It was found that ATP produced an initial rapid, phasic contraction followed by a slowly developing and maintained increase in tension. ADP caused a contraction closely mimicking the tonic response to ATP. The ADP induced contraction and the tonic response to ATP could both be abolished by indomethacin. beta, gamma-methylene ATP (APPCP), which is not degraded to ADP, elicited a rapid, phasic response, which could be abolished by nifedipine. AMP, dibutyryl-cAMP, and adenosine in low concentrations had no contractile effects; high concentrations of adenosine and 2-chloroadenosine, which is resistant to adenosine deaminase, decreased tone and spontaneous activity. The amplitude of the ATP induced contraction was positively correlated to the Ca2+-concentration in the extracellular medium; removal of Ca2+ abolished the ATP contraction before the responses to high K+ and carbachol disappeared. Responses to electrical field stimulation, mediated by non-cholinergic, non-adrenergic mechanisms were abolished by nifedipine and significantly reduced by indomethacin. It is concluded that in isolated rabbit detrusor, a direct contractile response can be elicited only by tripolyphosphates (ATP and APPCP), and that the diphosphate moiety ADP stimulates synthesis of prostaglandins The similarity between the effects of stimulation of non-cholinergic, non-adrenergic neurones and the phasic response to ATP supports the view that in rabbit detrusor ATP may be involved in excitation.     

Excitatory motor and electrical effects produced by tachykinins in the human and guinea-pig isolated ureter and guinea-pig renal pelvis

1. In isolated tissue experiments, neurokinin A (NKA) produced concentration-dependent contraction of human and guinea-pig ureter (pD2 = 6.7 and 7.2, respectively); an effect greatly reduced (>80% inhibition) by the tachykinin NK2 receptor-selective antagonist MEN 11420 (0.1 microM). The tachykinin NK1 and NK3 receptor agonists septide and senktide, respectively, were ineffective. 2. Electrical field stimulation (EFS) of the guinea-pig isolated renal pelvis produced an inotropic response blocked by MEN 11420 (0.01-1 microM). In the same preparation MEN 11420 (0.1 microM) blocked (apparent pK(B) = 8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor-selective agonist [betaAla8]NKA(4-10). 3. In sucrose-gap experiments, EFS evoked action potentials (APs) accompanied by phasic contractions of human and guinea-pig ureter, which were unaffected by tetrodotoxin or MEN 11420 (3 microM), but were blocked by nifedipine (1-10 microM). NKA (1-3 microM) produced a slow membrane depolarization with superimposed APs and a tonic contraction with superimposed phasic contractions. NKA prolonged the duration of EFS-evoked APs and potentiated the accompanying contractions. MEN 11420 completely prevented the responses to NKA in both the human and guinea-pig ureter. 4. Nifedipine (1-10 microM) suppressed the NKA-evoked APs and phasic contractions in both human and guinea-pig ureter, and slightly reduced the membrane depolarization induced by NKA. A tonic-type contraction of the human ureter in response to NKA persisted in the presence of nifedipine. 5. In conclusion, tachykinins produce smooth muscle excitation in both human and guinea-pig ureter by stimulating receptors of the NK2 type only. NK2 receptor activation depolarizes the membrane to trigger the firing of APs from latent pacemakers.     

Electric activity of the rat myometrium in vivo during the estrous cycle

Electric activity of the uterus was recorded by 6 chronically implanted wire electrodes in 17 unrestrained 5-day cycling rats. Results obtained during 196 h of recording revealed consistent changes in frequency, amplitude, temporal pattern and in direction and distance of propagation of electric activity. In estrus, bursts were short and of variable amplitude and frequency, while in metestrus bursts had high amplitude, longer duration and regular frequency. The activity decreased from metestrus to the first diestrous day and still more to the second diestrous day. In diestrus and proestrus long bursts appeared once to twice within an hour. In proestrus the morning level of activity was still low, but high at night, when it resembled the activity in estrus. Electric activity spread in both directions but with a higher frequency in the cervical direction in all phases of the cycle. Cervical electric activity appeared in synchrony with that of the uterine body and did not differ from it in type.     

Calcium-sodium antagonism on the frog's heart: a voltage-clamp study

1. In double sucrose-gap voltage-clamped frog atrial fibres the influence of [Ca]o and [Na]o on membrane current and contraction was investigated. 2. The slow (secondary) inward current varied with [Ca]o but was almost insensitive to changes in [Na]o. In contrast, the phasic (transient) contraction initiated by the slow inward current was affected by both [Ca]o and [Na]o. 3. With moderate changes of [Ca]o and [Na]o from normal, the strength of phasic contraction at a given depolarization followed the [Ca]o/[Na]2o ratio approximately. This was best seen at membrane potentials near zero level. 4. Under the same conditions, tonic (sustained) contractions associated with prolonged depolarizations were strictly correlated to the [Ca]o/[Na]2o ratio at any potential. No interrelation between tonic tension and steady-state current was found. 5. With extensive changes in [Ca]o and [Na]o, the sensitivity of both phasic and tonic tension to the [Ca]o/[Na]2o ratio declined, the negative effect of [Na]o becoming smaller than was expected from this ratio. 6. In Na-free choline-Ringer, a strong contracture developed followed by a spontaneous relaxation. Starting from the relaxed state, application of depolarizing clamps gave rise to phasic contractions with a very slow relaxation while tonic contractions were apparently lacking. 7. The results are interpreted in terms of an energy-dependent carrier mechanism exchanging one Ca for two Na ions across the cell membrane. The model implies a strong asymmetry in the rate constants governing the chemical reactions on both sides of the membrane. The system is thought to operate close to equilibrium at any potential, thereby determining the steady level of myoplasmic Ca. The equilibrium itself is considered to shift upon depolarization. Assuming that [Na]i is constant, the steady level of [Ca]i is expected to be proportional to the [Ca]o/[Na]2o ratio, the scale factor being a function of membrane potential. 8. The carrier model suggests the occurrence of a depolarization-induced inward transfer of Ca which might be involved in the generation of tonic contractions. 9. The apparent lack of tonic contractions in the absence of external Na ions may be explained by a suppression of carrier-mediated Ca influx normally occurring upon depolarization. 10. The antagonistic effects of [Ca]o and [Na]o on phasic contraction are understood as being due to alterations of the Ca pumping system rather than changes in slow inward current.     

Health professionals'' responses to multiple sclerosis and motor neurone disease

The effect of vasopressin and oxytocin on the contractile activity of preparations isolated from the feline gastric corpus wall was investigated. Vasopressin (1.5 x 10(-9)-2.1 x 10(-7) M), but not oxytocin, evoked concentration-dependent tonic contractions only of longitudinal muscle strips. At the same time, vasopressin (1.5 x 10(-9)-2.1 x 10(-7) M) potentiated the magnitude of amplitudes, but not the frequency, of spontaneous contractions. Both the vasopressin V1 receptor antagonist d(CH2)5-(Me)2-Tyr-AVP and the predominantly vasopressin V2 receptor antagonist d(CH2)5, D-Ile2, Ile4-AVP, the non-selective muscarinic receptor antagonist, atropine, the predominantly selective muscarinic M1 receptor antagonist, pirenzepine, the predominantly selective muscarinic M2 antagonist, methoctramine, the predominantly selective muscarinic M3 receptor antagonist, para-fluoro-hexahydro-siladifenidol, and the calcium channel blocker, nifedipine, but not the ganglion blocking agent, mecamylamine, depressed or blocked the tonic contractions induced by vasopressin. Among the antagonists, only atropine and nifedipine inhibited the spontaneous contractions. On the other hand, the anticholinesterase, physostigmine, potentiated both the vasopressin-induced tonic and spontaneous contractions. With regard to the receptors, the vasopressin-induced tonic contractions are mediated at least in part through vasopressin V1 and V2 receptors, non-selective muscarinic and selective muscarinic M1, M2 and M3 receptors. The increase in amplitudes of spontaneous contractions is mediated only via-nonselective muscarinic receptors. Vasopressin receptors appear to be located mostly pre-synaptically, although the direct effect of vasopressin on post-synaptic receptors cannot be excluded. The pA2 values suggests rather V1a than V1b vasopressin receptor subtype involvement in tonic contractions vasopressin had produced. The tonic as well as spontaneous contractions are calcium-dependent. In addition, these results point to the existence of non-selective muscarinic receptors, which participate in the regulation of both tonic and spontaneous contractions, while muscarinic M1, M2 and M3 receptors subserve only the tonic contractions.     

The arterial blood supply of the human patella. Its clinical importance for the operating technique in vascularized knee joint transplantations

1 This study aimed to assess the effect of cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic reticulum calcium (Ca) pump, against contractile responses produced by selective tachykinin NK1 and NK2 receptor agonists, [Sar9]substance P (SP) sulfone and [beta Ala8]neurokinin A (NKA) (4-10), respectively, on the circular muscle of guinea-pig colon. All experiments were performed in the presence of atropine (1 microM) and indomethacin (10 microM). 2 In organ bath experiments, a submaximally equieffective concentration of the two agonists (10 nM) was selected: [Sar9]SP sulfone (10 nM) produced a biphasic contraction, the two amplitudes averaging 75 +/- 2 and 43 +/- 3% of the maximal response to KCl (80 mM) at 1 and 15 min from application of the agonist, respectively. CPA (3 microM for 60 min) slightly reduced the phasic response to [Sar9]SP sulfone (16 +/- 4% inhibition) and markedly suppressed the tonic component (89 +/- 3% inhibition). 3 The contraction produced by [beta Ala8]NKA (4-10) (10 nM) was more sustained than that induced by the NK1 receptor agonist: it averaged 69 +/- 5 and 73 +/- 4% of the response to KCl at 1 and 15 min from application of the agonist, respectively. CPA slightly and evenly depressed the response to [beta Ala8]NKA (4-10) (18 +/- 7 and 21 +/- 5% inhibition at 1 and 15 min). 4 In the presence of tachykinin NK1 and NK2 receptor antagonists (SR 140333 and MEN 10627, respectively, 1 microM each) and of L-nitroarginine (100 microM), KCl (40 mM) produced a distinct phasic and tonic contraction which was suppressed by 1 mM nifedipine. CPA (3 microM) did not affect the phasic contraction to KCl but abolished the tonic component of the response. 5 In the presence of 1 microM nifedipine, the response to [beta Ala8]NKA (4-10) was slightly depressed (32 +/- 6% inhibition) in its early component only, while the response to [Sar9]SP sulfone was abolished. CPA produced a slight inhibition (15 +/- 9 and 33 +/- 10% at 1 and 15 min, respectively) of the nifedipine-resistant response to [beta Ala8]NKA (4-10), an effect similar to that observed in the absence of nifedipine. Therefore, a large part of the response to [beta Ala8]NKA (4-10) persisted in the presence of both CPA and nifedipine. 6 In the sucrose gap, a prolonged superfusion with [Sar9]SP sulfone (0.1 microM for 5 min) produced sustained depolarization with superimposed spikes and contraction. CPA (3 microM) produced transient depolarization and contraction. In the presence of CPA, the initial responses (depolarization, spikes and contraction) to [Sar9]SP sulfone were unaffected but the sustained component of contraction was absent; the latter effect was accompanied by a suppression of spikes while the sustained depolarization was present. 7 We conclude that, during sustained depolarization produced by the NK1 receptor agonist, blockade of the sarcoplasmic reticulum Ca pump by CPA produces a faster Ca-dependent inactivation of Ca channels, thereby eliminating spikes and abolishing the tonic component of contraction. Ca mobilization/reuptake from a CPA-sensitive store seems to be of minor importance for regulating the NK2 receptor-mediated contractile responses.     

Correct blue-light regulation of pea Lhcb genes in an Arabidopsis background

The phasic contraction of the isolated guinea pig vas deferens induced by adenosine 5'-triphosphate (ATP) 1mM was significantly augmented by acidification of bathing solution induced by administration of hydrochloric acid (HCL) 10mM (pH = 6.87 +/- 0.015 (n = 5); mean +/- S.E.), while the tonic contraction induced by norepinephrine (NE) 10microM was significantly depressed by HCl 10mM. The contractile response to ATP 1mM was markedly potentiated in the presence of NE 10 microM. The potentiated contractile response to ATP 1mM in the presence of NE 10microM was significantly augmented by HCl 1mM or 10mM. The potentiating ratio of the contraction induced by ATP 1mM in the presence of NE 10microM to that induced by ATP 1mM alone was almost unaffected by the administration of HCl. Electrical field stimulation (EFS) produced a biphasic contractile response of the isolated guinea pig vas deferens; viz. the first rapid phasic contractile response and the second slow maintained tonic contractile response. The phasic contractile response to EFS was significantly augmented by HCl 10mM. These results may indicate that acidification of the medium potentiates the neurochemical transmission between the nerve terminals and the smooth muscle of vas deferens via sensitization of P2X (presumably P2X1 or P2X2) receptors existing in the smooth muscle.     

Uterine contractility in spontaneous and induced labour

Contractility parameters (uterine activity, contraction interval, amplitude, and frequency of contractions) were analyzed quantitatively during the active phase of first-stage of labour in 60 clinically normal term nulliparae with spontaneous or induced labour. Inductions were surgical (amniotomy alone) or by amniotomy combined with either intravenous oxytocin or prostaglandin administered intravenously (PGF 2alpha or PGE 2) or orally (PGE 2).     

Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2

We characterized modulation of the gamma-aminobutyric acid (GABA)-evoked responses of the diazepam-insensitive alpha 4 beta 2 gamma2 and alpha 6 beta 2 gamma 2 recombinant GABAA receptors. The partial agonist bretazenil potentiated the responses of both receptors with similar dose dependence but with a higher maximal enhancement at the alpha 4 beta 2 gamma 2 receptor. The bretazenil-induced potentiation was reduced by the benzodiazepine antagonist flumazenil. At a high concentration (10 microM), flumazenil was a weak potentiator of the GABA response. The partial agonist imidazenil was inactive. The imidazobenzodiazepine inverse agonist Ro 15-4513, which is known to bind with high affinity to the alpha 6 beta 2 gamma 2 receptor, potentiated the GABA responses of the alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 receptor subtypes with similar dose dependence over the concentration range of 0.1-10 microM. Methyl-6, 7-dimethoxy-4-ethyl-beta-carboline, a beta-carboline inverse agonist, had a similar potentiating effect when tested at a concentration of 10 microM. The alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 receptor-mediated currents had equal sensitivities to furosemide and Zn2+ ions, both of which reduced the GABA-evoked responses. The alpha 6 beta 2 gamma 2 receptor but not the alpha 4 beta 2 gamma 2 receptor exhibited a low level of spontaneous activity in the absence of GABA; this resting current could be directly potentiated by Ro 15-4513, methyl-6,7-dimethoxy-4-ethyl-beta-carboline, bretazenil and flumazenil and was blocked by picrotoxin. Thus, although the alpha 4 beta 2 gamma 2 receptors are insensitive to benzodiazepine binding site full agonists, such as diazepam, they can be modulated by certain ligands acting as partial and inverse agonists at diazepam-sensitive receptors and thereby contribute to the respective pharmacological profiles.     

Effects of the functional elimination of sarcoplasmic reticulum on the manganese-dependent norepinephrine-induced contractions of the guinea pig vas deferens

We investigated the effects of inhibitors of the sarcoplasmic reticulum (SR) functions on the tonic contractions induced by norepinephrine (NE) in the Ca(2+)-depleted Mn(2+)-loaded vas deferens of the guinea pig in the absence of both Ca2+ and Mn2+ (Mn(2+)-dependent NE-contraction). In control preparations without Ca(2+)-depletion and Mn(2+)-loading, either cyclopiazonic acid (CPA, 10 microM) or ryanodine (RYA, 3 microM) inhibited the initial phasic and tonic components but not the large phasic component of NE-induced contraction in normal medium containing 2.2 mM Ca2+. In contrast, CPA did not affect the Mn(2+)-dependent NE-contractions. The inhibitory effect of RYA slowly developed with each repetition of the Mn(2+)-dependent NE-contraction and the magnitude of the inhibition was slight. A23187 (10 microM) inhibited the NE-induced contractions of the control preparations in the same manner as CPA and RYA. Although A23187 did not induce contractions in the Mn(2+)-loaded preparations, A23187 augmented the Mn(2+)-dependent NE-contractions. The augmented tonic contractions returned to the resting level by washing NE and A23187. The augmentation remained for 3 successive contractions in the absence of A23187. However, the 2nd application of A23187 did not augment the contraction. These results suggest that neither Mn(2+)-release from SR nor Mn(2+)-influx from the extracellular space contributes to the Mn(2+)-dependent NE-contractions. We concluded that NE induces Mn(2+)-dependent contractions by increasing Mn2+ sensitivity of contractile processes but not by increasing intracellular Mn2+ concentration.     

Modulatory role of protein tyrosine kinase activation in the receptor-induced contractions of the bovine cerebral artery

Changes in contractile force were measured during isometric contraction of the bovine middle cerebral artery caused by stimulation of various receptors and by application of high K+, caffeine, and protein kinase C (PKC)-activators. The protein tyrosine kinase (PTK)-inhibitors, such as genistein and tyrphostin, were applied before testing the effect on the contractions or during the maximal plateau of the contraction. The contractions induced by serotonin, prostaglandin F2 alpha, endothelin-1, and thromboxane A2 were significantly and dose-dependently depressed by the PTK-inhibitors (IC50 2-15 microM). In contrast, contractions were significantly augmented by 1 microM pervanadate, an inhibitor of phosphoprotein tyrosine phosphatase. Lineweaver-Burk plotting of the dose-response curves with an increase in inhibitor concentration indicated that the receptor affinity for each agonist remained unchanged in spite of marked depression of the responses. Although the effect was not significant, contractions induced by both high K+ and caffeine were also depressed slightly by PTK-inhibitors in the same range of concentrations used for receptor-induced contractions. Contractions induced by PKC-activators, such as 1-oleoyl-2-acetyl-sn-glycerol and phorbol-12,13-diacetate, were significantly depressed by PTK-inhibitors at concentrations similar to those used for receptor-induced contractions. The results suggest that receptor stimulations which produce sequential activation of phospholipase C and PKC can activate PTK and trigger the so-called "PTK-cascade" causing a sustained or long-lasting contraction similar to the cerebral vasospasm observed clinically.     

Effect of alpha adrenergic agonist on the rabbit ear artery contraction to serotonin: enhanced response mediated by serotonergic1-like receptors

The effect of methoxamine or phenylephrine (PHE) on the contractile response of the rabbit ear artery to serotonin was assessed by using isolated arterial rings mounted in tissue baths for the measurement of isometric force development. A contractile threshold concentration of methoxamine or PHE (10-30 nM) shifted the serotonin concentration-response curve to the left by approximately 200-fold. Neither mechanical removal of the vascular endothelium nor chemical denervation had any effect on the alpha agonist-amplified response of ear artery to serotonin. Although the response to serotonin in the absence of the alpha agonist was mediated primarily by alpha-1 adrenergic receptors, prazosin did not block the amplified response to serotonin. Ketanserin (10 nM), ritanserin (50 nM) and MDL 72222 (1 microM) also had no effect on the amplified response, ruling out the involvement of serotonergic (5-HT)2 and 5-HT3 receptors. However, methiothepin (3 nM) and 1-(1-naphthyl)piperazine (10 and 100 nM) blocked the PHE-amplified contraction of ear artery to serotonin. When the contractile response of ear artery to 5-carboxamidotryptamine was measured in the presence of a threshold concentration of alpha agonist, the concentration-response curve was shifted 8300-fold to the left. The amplified response to 5-carboxyamidotryptamine was insensitive to 10 nM ketanserin, but was blocked by 3 nM methiothepin. Sumatriptan, a selective 5-HT1 agonist, failed to induce vasoconstriction in the absence of a threshold concentration of alpha agonist. However, in the presence of PHE, sumatriptan induced a concentration-dependent contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nuclear matrix proteins and their potential applications to diagnostic pathology

The sympathetic nervous system controls lipolysis in fat by activation of four adrenergic receptors: beta1, beta2, beta3, and alpha2. During pregnancy, maternal metabolism presents anabolic and catabolic phases, characterized by modifications of fat responsiveness to catecholamines. The contributions of the four adrenergic receptors to adipocyte responsiveness during pregnancy have never been studied. Our aim was to evaluate the influence of pregnancy on adrenergic receptor-mediated lipolysis in rabbit white adipocytes. Functional studies were performed using subtype-selective and non-selective adrenergic receptor agonists. Overall adrenergic responsiveness was measured with the physiological agonist epinephrine. Non-adrenergic agents were used to evaluate different steps of the lipolytic cascade. The alpha2- and beta1/beta2-adrenergic receptor numbers were determined with selective radioligands. Non-adrenergic agents revealed that pregnancy induced an intracytoplasmic modification of the lipolytic cascade in inguinal but not in retroperitoneal adipocytes. Pregnancy induced an increase in beta1- and specially beta3-mediated lipolysis. The amounts of adipocyte beta1/beta2- and alpha2-adrenergic receptors were increased in pregnant rabbits. Epinephrine effects revealed an increased contribution of alpha2-adrenergic receptor-mediated antilipolysis in adipocytes from pregnant rabbits. These results indicate that pregnancy regulates adipocyte responsiveness to catecholamines mainly via the alpha2- and beta3-adrenergic pathways. Pregnancy induces an intracytoplasmic modification of the lipolytic cascade, probably via hormone-sensitive lipase, with differences according to fat location.-Bousquet-Mélou, A., C. Mu?oz, J. Galitzky, M. Berlan, and M. Lafontan. Pregnancy modifies the alpha2-beta-adrenergic receptor functional balance in rabbit fat cells.     

The prostaglandin E2 and F2 alpha receptor genes are expressed in human myometrium and are down-regulated during pregnancy

Prostaglandin (PG) E2 and PGF2 alpha are believed to play important roles in the myometrial contraction and the initiation of labor. Myometrial contraction by these prostanoids is mediated mainly through EP3 and FP, which are specific receptors to PGE2 and PGF2 alpha, respectively. During normal pregnancy, uterine myometrium are relaxed until term. To explore the involvement of EP3 and FP in the myometrial relaxation during pregnancy, we examined the EP3 and FP gene expressions in nonpregnant and pregnant myometrium obtained by hysterectomy for gynecological diseases. In all samples examined, expressions of EP3 and FP genes were detected. During pregnancy, the expression of EP3 gene in human myometrium was significantly reduced, to 60% of that in nonpregnant myometrium. The expression of FP gene in human myometrium also decreased during pregnancy to 55% of that in nonpregnant myometrium. In the myometrium from the nonpregnant women taking combined oral contraceptives, the gene expressions of EP3 and FP were not significantly changed as compared to those in nonpregnant controls. The down-regulation of EP3 and FP during pregnancy may play a role in the relaxation of myometrium and thus in the maintenance of normal pregnancy in humans.     

Cocaine acutely increases rat myometrial contractile activity by mechanisms other than potentiation of adrenergic pathways

OBJECTIVE: We hypothesized that cocaine acutely increases contractile activity in isolated rat myometrium and that this effect is solely caused by potentiation of adrenergic pathways. STUDY DESIGN: Isometric contractions were measured in myometrium isolated from virgin and day-18 pregnant Sprague-Dawley rats. Frequency, duration, amplitude, and integrated area were compared before and after the addition of cocaine (10(-6) to 10(-4) mol/L) by means of analysis of variance and Duncan's multiple-range test. The effects of alpha-adrenergic receptor antagonists (prazosin 10(-6) mol/L and yohimbine 10(-6) mol/L) and beta-adrenergic receptor antagonist (DL-propranolol 2 x 10(-6) mol/L) were assessed. RESULTS: Contraction duration, expressed relative to control, increased acutely after cocaine (10(-5) mol/L) administration in pregnant (1.70 +/- 0.20) and nonpregnant (1.36 +/- 0.24) myometrium (mean +/- SE, p < 0.05), as did integrated area (pregnant 3.47 +/- 0.97, nonpregnant 2.48 +/- 0.66) (mean +/- SE, p < 0.05). These effects were not completely inhibited by adrenergic blockade. CONCLUSION: Cocaine acutely increases the duration and integrated area of spontaneous contractions in isolated rat myometrium by mechanisms not completely explained by inhibition of catecholamine reuptake and potentiation of adrenergic pathways.     

Pharmacological properties of the natural marine product furospongin-1

1. The natural marine product, furospongin-1 (6, 12 and 24.5 mumol/L) significantly inhibited contractions of segments of guinea-pig ileum induced by submaximal concentrations (0.1 mumol/L) of acetylcholine (ACh) and histamine. Furospongin-1 (24.5 and 36.7 mumol/L) reduced both the phasic and tonic components of a contraction induced by 30 mumol/L K+ solution in the absence and presence of atropine (1 mumol/L), mepyramine (1 mumol/L) and phentolamine (1 mumol/L). Furospongin-1 also decreased basal tension and the amplitude of spontaneous phasic contractions of guinea-pig ileum. 2. The mitochondrial ATP synthase inhibitor oligomycin (0.3, 1 and 3 mumol/L) had a similar concentration-dependent action, reducing basal activity and contractions evoked by histamine and ACh. Oligomycin also reduced both the phasic and tonic components of a contraction induced by 30 mmol/L K+ solution in the absence and presence of atropine (1 mumol/L), mepyramine (1 mumol/L) and phentolamine (1 mumol/L). 3. Furospongin-1 (6 and 37.6 mumol/L) and oligomycin (3 mumol/L) had no effect on contractions of chemically skinned guinea-pig ileum longitudinal muscle segments. In this same tissue, furospongin-1 (6, 12 and 24.5 mumol/L) and oligomycin (0.3, 1 and 3 mumol/L) concentration-dependently reduced tissue levels of ATP. 4. In lyzed bovine mitochondria, oligomycin (0.1, 0.3, 1 and 3 mumol/L) inhibited conversion of ATP to ADP whilst furospongin-1 (6, 12 and 24.5 mumol/L) and carbonyl cyanide m-chlorophenylhydrazone (0.5 mmol/L) had no significant effect on ATP breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prejunctionally mediated inhibition of neurotransmission by isoprenaline in rat vas deferens

Effects of isoprenaline on monophasic contractions evoked by electric field stimulation were studied in rat isolated prostatic vas deferens. Isoprenaline reduced electrically evoked contractions (EC50: 0.27 +/- 0.05 microM), and propranolol concentration-dependently antagonized the effect of isoprenaline. In contrast, isoprenaline (0.3-3 microM) did not affect the contractile response induced by exogenous noradrenaline or ATP, while forskolin (100 nM) attenuated agonist-induced contraction. In some tissues, adrenergic and purinergic components of the electrically evoked contraction were isolated by exposure to alpha,beta-methylene ATP (3 microM) and prazosin (3 microM), respectively. Isoprenaline induced a greater inhibition of purinergic than adrenergic component of the electrically evoked contraction. Iberiotoxin (50 nM), glibenclamide (3 microM), 4-aminopyridine (0.3 mM) and tetraethylammonium ions (1 mM) attenuated the effect of isoprenaline. These results indicate that isoprenaline-induced inhibition of the electrically evoked (both purinergic and adrenergic) contraction was mediated primarily through activation of prejunctional beta-adrenoceptors, which probably inhibited release of contractile transmitters from sympathetic nerves supplying vas deferens. Lack of effect of isoprenaline on agonist-induced contraction does not favour a functional role of beta-adrenoceptors in vas smooth muscle.     

Blockade of endotoxin-induced cecal hypoperfusion and ileus with an alpha 2 antagonist in horses

Stimulation of alpha 2 adrenergic receptors inhibits colonic motility and may constrict some peripheral vascular beds. Endotoxemia elicits release of sympathetic neurotransmitters and increases sympathetic nerve activity, which may result in stimulation of alpha 2 adrenergic receptors. The objective of this study was to determine whether blockade of alpha 2 adrenergic receptors would restore cecal motility and blood flow during endotoxemia in horses. Strain-gauge force transducers and ultrasonic flow probes were used to measure cecal and colonic mechanical activity and lateral cecal arterial blood flow. Intravenous infusion of endotoxin (cumulative dose of 0.03 mg/kg) significantly decreased cecal and right ventral colon contractile activity and lateral cecal arterial blood flow. Slow IV infusion of yohimbine (cumulative dose of 75 micrograms/kg) significantly attenuated those effects of endotoxin. On the basis of our findings, we concluded that endotoxemia causes cecal and proximal colonic ileus and cecal hypoperfusion via a mechanism that involves alpha 2 adrenergic receptors.