Basal Smooth Muscle Tone Research Articles

Smooth muscle regional contribution to vaginal wall function.

Pelvic organ prolapse is characterized as the descent of the pelvic organs into the vaginal canal. In the USA, there is a 12% lifetime risk for requiring surgical intervention. Although vaginal childbirth is a well-established risk factor for prolapse, the underlying mechanisms are not fully understood. Decreased smooth muscle organization, composition and maximum muscle tone are characteristics of prolapsed vaginal tissue. Maximum muscle tone of the vaginal wall was previously investigated in the circumferential or axial direction under uniaxial loading; however, the vaginal wall is subjected to multiaxial loads. Further, the contribution of vaginal smooth muscle basal (resting) tone to mechanical function remains undetermined. The objectives of this study were to determine the contribution of smooth muscle basal and maximum tone to the regional biaxial mechanical behaviour of the murine vagina. Vaginal tissue from C57BL/6 mice was subjected to extension-inflation protocols (n = 10) with and without basal smooth muscle tone. Maximum tone was induced with KCl under various circumferential (n = 5) and axial (n = 5) loading conditions. The microstructure was visualized with multiphoton microscopy (n = 1), multiaxial histology (n = 4) and multiaxial immunohistochemistry (n = 4). Smooth muscle basal tone decreased material stiffness and increased anisotropy. In addition, maximum vaginal tone was decreased with increasing intraluminal pressures. This study demonstrated that vaginal muscle tone contributed to the biaxial mechanical response of murine vaginal tissue. This may be important in further elucidating the underlying mechanisms of prolapse, in order to improve current preventative and treatment strategies.

497 Dapoxetine inhibits erectile responses to stimulation of cavernous nerve in rats: A new hypothesis for its effects on ejaculation

INTRODUCTION AND OBJECTIVES: Selective Serotonin Reuptake Inhibitors (SSRI) like paroxetine and fluoxetine are known to induce erectile dysfunction in humans and rats. Dapoxetine, a selective SSRI, is approved in Europe for the management of premature ejaculation. The aim of this study was to assess the impact of dapoxetine on (1) erectile responses induced by electrical stimulation (ES) of the cavernous nerve and (2) on smooth muscle relaxations induced by sodium nitroprusside (SNP) or sildenafil (SF) in the isolated corpus cavernosum (CC). METHODS: Wistar rats were anaesthetized with urethane. The carotid artery, penis and jugular vein were catheterized for blood pressure and intracavernous pressure recordings (BP and ICP) and drug injection, respectively. The right cavernous nerve was mounted on bipolar stimulating electrodes. ES (3, 6 and 9 Hz) were performed before and at 4, 24, 44 and 64 min after intravenous (i.v.) injection of 1 or 3 mg/kg dapoxetine or saline in 3 independent groups of 6 animals. ICP values were normalized to BP. For in vitro experiments, CC strips from Wistar rats were mounted under 0.5 g of tension in organ baths with a modified Krebs solution. After 60 min of equilibration, dapoxetine 1 mM (or its solvent) was incubated for 20 min. Strips were then exposed to norepinephrine 30 mM. When contractions reached a plateau, cumulative concentration-response curves to SNP, SF or their common solvent were constructed. RESULTS: Erectile responses were dose-dependently decreased by dapoxetine from 4 to 44 min post-dosing at all frequencies of ES. The mean of ICPmean/BP at 6 Hz was 0.47 0.01 in the 3 groups before injection. At 44 min post-injection, ICPmean/BP at 6 Hz was 0.43 0.06, 0.30 0.08 and 0.13 0.04 after vehicle, 1 mg/kg and 3 mg/kg dapoxetine (P<0.01 vs vehicle) respectively. Similar decreases were observed for ICPmax/BP. On the isolated CC, dapoxetine had no inhibitory effect on SNP or SF-mediated relaxations up to 1 mM. In addition, dapoxetine had no contractile or relaxant effects on the basal smooth muscle tone up to 10 and 100 mM, respectively CONCLUSIONS: Erectile responses were inhibited by dapoxetine at 1 and 3 mg/kg i.v. This inhibitory activity might be one of the mechanisms by which dapoxetine delays ejaculation in patients suffering from premature ejaculation. Furthermore, in vitro studies demonstrated that the inhibitory activity of dapoxetine on penile erection cannot be explained by an action at the peripheral level, suggesting a central nervous system-related mechanism.

MP47-02 DAPOXETINE INHIBITS ERECTILE RESPONSES TO STIMULATION OF THE CAVERNOUS NERVE IN RATS: A NEW HYPOTHESIS FOR ITS EFFECTS ON EJACULATION

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2014MP47-02 DAPOXETINE INHIBITS ERECTILE RESPONSES TO STIMULATION OF THE CAVERNOUS NERVE IN RATS: A NEW HYPOTHESIS FOR ITS EFFECTS ON EJACULATION Stefano Palea, Celine Rouget, Philippe Lluel, and Julien Allard Stefano PaleaStefano Palea More articles by this author , Celine RougetCeline Rouget More articles by this author , Philippe LluelPhilippe Lluel More articles by this author , and Julien AllardJulien Allard More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1455AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Selective Serotonin Reuptake Inhibitors (SSRI) like paroxetine and fluoxetine are known to induce erectile dysfunction in humans and rats. Dapoxetine, a selective SSRI, is approved in Europe for the management of premature ejaculation. The aim of this study was to assess the impact of dapoxetine on (1) erectile responses induced by electrical stimulation (ES) of the cavernous nerve and (2) on smooth muscle relaxations induced by sodium nitroprusside (SNP) or sildenafil (SF) in the isolated corpus cavernosum (CC). Methods Wistar rats were anaesthetized with urethane. The carotid artery, penis and jugular vein were catheterized for blood pressure and intracavernous pressure recordings (BP and ICP) and drug injection, respectively. The right cavernous nerve was mounted on bipolar stimulating electrodes. ES (3, 6 and 9 Hz) were performed before and at 4, 24, 44 and 64 min after intravenous (i.v.) injection of 1 or 3 mg/kg dapoxetine or saline in 3 independent groups of 6 animals. ICP values were normalized to BP. For in vitro experiments, CC strips from Wistar rats were mounted under 0.5 g of tension in organ baths with a modified Krebs solution. After 60 min of equilibration, dapoxetine 1 μM (or its solvent) was incubated for 20 min. Strips were then exposed to norepinephrine 30 μM. When contractions reached a plateau, cumulative concentration-response curves to SNP, SF or their common solvent were constructed. Results Erectile responses were dose-dependently decreased by dapoxetine from 4 to 44 min post-dosing at all frequencies of ES. The mean of ICPmean/BP at 6 Hz was 0.47±0.01 in the 3 groups before injection. At 44 min post-injection, ICPmean/BP at 6 Hz was 0.43±0.06, 0.30±0.08 and 0.13±0.04 after vehicle, 1 mg/kg and 3 mg/kg dapoxetine (P<0.01 vs vehicle) respectively. Similar decreases were observed for ICPmax/BP. On the isolated CC, dapoxetine had no inhibitory effect on SNP or SF-mediated relaxations up to 1 μM. In addition, dapoxetine had no contractile or relaxant effects on the basal smooth muscle tone up to 10 and 100 μM, respectively Conclusions Erectile responses were inhibited by dapoxetine at 1 and 3 mg/kg i.v. This inhibitory activity might be one of the mechanisms by which dapoxetine delays ejaculation in patients suffering from premature ejaculation. Furthermore, in vitro studies demonstrated that the inhibitory activity of dapoxetine on penile erection cannot be explained by an action at the peripheral level, suggesting a central nervous system-related mechanism. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e519 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Stefano Palea More articles by this author Celine Rouget More articles by this author Philippe Lluel More articles by this author Julien Allard More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Phorbol 12,13-Dibutyrate-Induced, Protein Kinase C-Mediated Contraction of Rabbit Bladder Smooth Muscle

Contraction of bladder smooth muscle is predominantly initiated by M3 muscarinic receptor-mediated activation of the Gq/11-phospholipase C β-protein kinase C (PKC) and the G12/13-RhoGEF-Rho kinase (ROCK) pathways. However, these pathways and their downstream effectors are not well understood in bladder smooth muscle. We used phorbol 12,13-dibutyrate (PDBu), and 1,2-dioctanoyl-sn-glycerol (DOG), activators of PKC, in this investigation. We were interested in dissecting the role(s) of PKC and to clarify the signaling pathways in bladder smooth muscle contraction, especially the potential cross-talk with ROCK and their downstream effectors in regulating myosin light chain phosphatase activity and force. To achieve this goal, the study was performed in the presence or absence of the PKC inhibitor bisindolylmaleimide-1 (Bis) or the ROCK inhibitor H-1152. Phosphorylation levels of Thr38-CPI-17 and Thr696/Thr850 myosin phosphatase target subunit (MYPT1) were measured during PDBu or DOG stimulation using site specific antibodies. PDBu-induced contraction in bladder smooth muscle involved both activation of PKC and PKC-dependent activation of ROCK. CPI-17 as a major downstream effector, is phosphorylated by PKC and ROCK during PDBu and DOG stimulation. Our results suggest that Thr696 and Thr850-MYPT1 phosphorylation are not involved in the regulation of a PDBu-induced contraction. The results also demonstrate that bladder smooth muscle contains a constitutively active isoform of ROCK that may play an important role in the regulation of bladder smooth muscle basal tone. Together with the results from our previous study, we developed a working model to describe the complex signaling pathways that regulate contraction of bladder smooth muscle.

Acyclovir and guinea-pig airway smooth muscle

Acyclovir, an anti-herpes virus drug, has been reported to affect aspirin-induced asthma (AIA). Acyclovir was reported to decrease the sensitivity to aspirin in some AIA patients. Although the hypothesis that AIA is related to viral infection has been stated, there is no proof that patients with AIA are infected with a specific virus. Therefore, whether the effect of acyclovir on AIA is due to an antiviral effect is not clear. We hypothesized that acyclovir directly affects airway smooth muscle. To test this hypothesis, we examined whether acyclovir can directly contract or relax guinea-pig airway strips, and whether it can modify contraction or relaxation induced with several agents in vitro. Acyclovir did not directly affect basal smooth muscle tone and did not affect the responses to leukotriene D4, prostaglandin E2, carbachol, or KCl. We conclude that acyclovir has no direct effect on the function of guinea-pig airway smooth muscle.

Ex vivo biomechanical properties of the female urethra in a rat model of birth trauma

Stress urinary incontinence (SUI) is the involuntary release of urine during sudden increases in abdominal pressures. SUI is common in women after vaginal delivery or pelvic trauma and may alter the biomechanical properties of the urethra. Thus we hypothesize that injury due to vaginal distension (VD) decreases urethral basal tone and passive stiffness. This study aimed to assess the biomechanical properties of the urethra after VD in the baseline state, where basal muscle tone and extracellular matrix (ECM) are present, and in the passive state, where inactive muscle and ECM are present. Female rat urethras were isolated in a rat model of acute SUI induced by simulated birth trauma. Our established ex vivo system was utilized, wherein we applied intraluminal static pressures ranging from 0 to 20 mmHg. Outer diameter was measured via a laser micrometer. Measurements were recorded via computer. Urethral thickness was assessed histologically. Stress-strain responses of the urethra were altered by VD. Quantification of biomechanical parameters indicated that VD decreased baseline stiffness. The passive peak incremental elastic modulus of the distal segment in VD urethras was less than for controls (1.84 +/- 0.67 vs. 1.19 +/- 0.70 x 10(6) dyne/cm(2), respectively; P = 0.016). An increase was noted in passive low-pressure compliance values in proximal VD urethras compared with controls (9.44 +/- 2.43 vs. 4.62 +/- 0.60 mmHg(-1), respectively; P = 0.04). Biomechanical analyses suggest that VD alters urethral basal tone, proximal urethral compliance, and distal stiffness. Lack of basal smooth muscle tone, in combination with these changes in the proximal and distal urethra, may contribute to SUI induced by VD.

Development of an experimental system for the study of urethral biomechanical function.

Despite its principal mechanical function in the storage and release of urine, the biomechanical properties of the urethra have remained largely unexplored. The purpose of this study was to develop and validate an experimental model that can be used for evaluating whole urethral tissue in such a manner. Bladder-urethral specimens were excised from halothane-anesthetized female rats and mounted at in vivo length within the experimental apparatus consisting of a tissue perfusion chamber, an adjustable fluid column, and a laser micrometer. Outer diameter measurements were made at proximal, mid, and distal axial locations in response to increases in intraluminal pressure and after addition of various muscle-responsive agents. Basal smooth muscle tone and regional variations in compliance were detected through pressure-diameter responses. Chemically evoked contractile responses were measured and correspond to regional compositions of intrinsic smooth and striated muscle components. The results presented illustrate the utility of this system, which should permit a more thorough characterization of structure-function relationships and urethral biomechanical function in relation to normal and dysfunctional tissue states.

Role of nitric oxide in beta3-adrenoceptor activation on basal tone of internal anal sphincter.

Effects of activation of beta3-adrenoceptor (beta3-AR) have not been determined in the spontaneously tonic smooth muscle of the internal anal sphincter (IAS). The effects of disodium (R,R)-5-[2-[2-3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243), a selective beta3-AR agonist, on the basal smooth muscle tone and direct release of nitric oxide (NO) by circular smooth muscle strips of the opossum IAS were determined. We also examined the presence of endothelial nitric oxide synthase (eNOS) protein by Western blot studies. CL 316243 produced a concentration-dependent relaxation of the smooth muscle that remained unmodified by different neurohumoral antagonists. The smooth muscle relaxation by CL 316243 was selectively antagonized by L 748337, a beta3-AR antagonist. Such relaxation was several times longer than by isoproterenol. The effect of CL 316243 was significantly attenuated by a nonselective NOS inhibitor N(omega)-nitro-l-arginine (l-NNA) and by putative inhibitor of eNOS l-N5-(1-iminoethyl)-ornithine dihydrochloride (l-NIO). Inhibitors of iNOS [N-(3-aminomethyl)benzyl acetamide 2HCl] and nNOS [1-[2-(trifluoromethylphenyl)imidazole]] had no effect on this relaxation. Relaxation of the IAS smooth muscle induced by CL 316243 was accompanied by an increased release of NO; this was attenuated by l-NNA and l-NIO. In addition, Western blot studies revealed the presence of eNOS in the circular smooth muscle of the IAS. These data demonstrate potent and protracted IAS smooth muscle relaxation by beta3-AR activation, which is partly transduced via NOS, possibly smooth muscle eNOS. Multiple signal-transduction pathways including NOS activation may explain the characteristic IAS relaxation by beta3-AR activation. The studies may have therapeutic implications in anorectal motility disorders.

R(+)-methanandamide inhibits tracheal response to endogenously released acetylcholine via capsazepine-sensitive receptors

The effects of cannabinoid drugs on the cholinergic response evoked by electrical field stimulation (0.2 ms pulse width, 20 V amplitude, 10 Hz, 7.5 s train duration) in guinea-pig tracheal preparations were investigated. The stable analogue of the endocannabinoid anandamide, R(+)-methanandamide (10 −7–10 −4 M), produced a dose-dependent inhibition (up to 27±5% of control) of electrical field stimulation-mediated atropine-sensitive response. This effect was not blocked by the selective cannabinoid CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3 carboxamide hydrochloride (SR 141716A; 10 −6 M), and was not reproduced with the cannabinoid CB 1/CB 2 receptor agonist R(+)-[2,3-dihydro-5-methyl-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate) (WIN 55,212-2; 10 −8–10 −5 M) or the cannabinoid CB 2 receptor selective agonist 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015; 10 −8–10 −5 M); it was, on the contrary, antagonized by the vanilloid antagonist 2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3,4,5-tetrahydro-1 H-2 benzazepine (capsazepine; 10 −6 M). At the postjunctional level, neither R(+)-methanandamide nor WIN 55,212-2 nor JWH-015 did affect tracheal contractions induced by exogenous acetylcholine (10 −6 M). An inhibitory vanilloid receptor-mediated effect on the cholinergic response evoked by electrical stimulation was confirmed with the vanilloid agonist capsaicin, at doses (3–6×10 −8 M) which poorly influenced the basal smooth muscle tone of trachea. In conclusion, our data indicate that in guinea-pig trachea (a) neither CB 1 nor CB 2 cannabinoid receptor-mediated modulation of acetylcholine release occurs; (b) vanilloid VR1-like receptors appear involved in R(+)-methanandamide inhibitory activity on the cholinergic response to electrical field stimulation.

LIPOXYGENASE-DEPENDENT MECHANISMS IN HYPERTENSION

This study was designed to examine the contribution of lipoxygenase products to mechanisms of vascular contraction and elevated blood pressure in rats with aortic coarctation-induced hypertension. In cytosolic fractions of aortae taken from hypertensive rats, 12-lipoxygenase protein was increased as compared to normotensive controls. Aortic rings from hypertensive, but not from normotensive rats, exhibited a basal tone which was reduced 74±12 and 71±22%, respectively, by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC,10−5 mol/L) and 5,8,11-eicosatriynoic acid (ETI, 10−5 mol/L). CDC (8mg/kg sc) did not affect the blood pressure of normotensive rats but decreased that of hypertensive rats from 182±6 to 151±10 mm Hg. The blood pressure lowering effect of CDC was blunted in hypertensive rats pretreated with indomethacin or antibodies against 5,6-dihydro-prostaglandin I2. These data suggest contribution of lipoxygenase-derived products to mechanisms underlying aortic smooth muscle basal tone and elevated blood pressure in rats with aortic coarctation-induced hypertension. The vasodepressor effect of CDC depends on a mechanism involving vasodilatory prostaglandins.

Role of endogenous nitric oxide on PAF-induced vascular and respiratory effects

The role of endogenous nitric oxide (NO) on vascular and respiratory smooth muscle basal tone was evaluated in six anaesthetized, paralysed, mechanically ventilated pigs. The involvement of endogenous NO in PAF-induced shock and airway hyperresponsiveness was also studied. PAF (50 ng/kg, i.v.) was administered before and after pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v.), an NO synthesis inhibitor. PAF was also administered to three of these pigs after indomethacin infusion (3 mg/kg, i.v.). In normal pigs, L-NAME increased systemic and pulmonary vascular resistances, caused pulmonary hypertension and reduced cardiac output and stroke volume. The pulmonary vascular responses were correlated with the increase in static and dynamic lung elastances, without changing lung resistance. Inhibition of NO synthesis enhanced the PAF-dependent increase in total, intrinsic and viscoelastic lung resistances, without affecting lung elastances or cardiac activity. The systemic hypotensive effect of PAF was not abolished by pretreatment with L-NAME or indomethacin. This indicates that systemic hypotension is not correlated with the release of endogenous NO or prostacyclines. Indomethacin completely abolished the PAF-dependent respiratory effects.

The relative importance of nitric oxide and nitric oxide-independent mechanisms in acetylcholine-evoked dilatation of the rat mesenteric bed.

1. The relative contribution of nitric oxide (NO) to acetylcholine-induced smooth muscle relaxation was investigated in the rat perfused mesenteric vasculature and in isolated segments of second, third and fourth order arterial branches. 2. The EC50 values and maximal relaxation to acetylcholine were not significantly different in the sequential arterial branches, being approximately 0.05 microM and 85%, respectively. 3. The NO synthase inhibitor L-NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) reduced acetylcholine-evoked endothelium-dependent dilatation and relaxation in the perfused mesenteric bed and in isolated arterial segments. The maximum response to acetylcholine in both preparations was reduced by between 35% to 40% while the EC50 values were increased by 5-6 fold. L-NAME had no effect on basal smooth muscle tone in either case. 4. In contrast, endothelium-dependent dilatation of the perfused mesenteric bed evoked by A23187 (0.002-20 nmol), was unaffected by exposure to L-NAME. The EC50 values and maximal responses elicited by A23187 (20 nmol) before and after exposure to L-NAME were 0.96 +/- 0.5 nmol and 67.0 +/- 7.0% (n = 4), and 0.7 +/- 0.4 nmol and 70.0 +/- 5.0% (n = 4; P > 0.01), respectively. 5. Perfusion of the isolated mesenteric bed with raised K(+)-Krebs buffer (25 mM) had no effect on basal tone, but reduced the amplitude of both acetylcholine- and A23187-evoked dilatation. The maximum responses to acetylcholine (2 micromol) and A23187 (20 nmol) were reduced from 67.5 +/- 7.3% and 65.4+/-8.2% to 18.9 +/-11.0% (n=5; P<0.01) and 13.5 +/-12.0% (n=4; P<0.01), respectively.6. Exposure of the mesenteric bed to L-NAME in the presence of raised K+-Krebs further reduced the maximal response elicited by acetylcholine to only 8.9 +/- 2.8% (n =4; P< 0.01).7. These results indicate that acetylcholine-evoked vasodilatation of the rat mesenteric vasculature is mediated by both NO-dependent and -independent mechanisms. The relative contribution made by these mechanisms does not appear to differ in sequential branches of the mesenteric artery. In contrast,A23187-evoked vasodilatation appears to be mediated predominantly by a NO-independent mechanism which is sensitive to increases in the extracellular potassium concentration and may reflect the action of endothelium-derived hyperpolarizing factor (EDHF).

Relaxation of guinea-pig trachea by cyclic AMP phosphodiesterase inhibitors and their enhancement by sodium nitroprusside.

1. The effects of agents that elevate either cyclic AMP (the phosphodiesterase (PDE) III inhibitor siguazodan, salbutamol) or cyclic GMP (sodium nitroprusside (SNP)) on the relaxant activity of the PDE IV inhibitor, rolipram, were investigated in carbachol (0.1 microM) precontracted guinea-pig tracheal sheets. 2. Rolipram, siguazodan and SNP caused concentration-related reductions in tone of tissues precontracted with 0.1 microM carbachol (EC50 values 12.5; 2.73 and 0.35 microM respectively). Whilst the concentration-response relationship for the PDE III inhibitor, siguazodan, was monophasic that of the PDE IV inhibitor, rolipram, was biphasic. 3. The relaxant activity of rolipram was markedly enhanced in the presence of 10 microM siguazodan (EC50 < 0.01 microM), 0.1 microM salbutamol (EC50 0.03 microM) and 0.3 microM SNP (EC50 0.03 microM). In contrast, the relaxant activity of siguazodan was unaffected by SNP and only modestly enhanced by rolipram (10 microM) and salbutamol (0.1 microM). 4. The relaxant activity of SNP was enhanced by the PDE V inhibitor SK&F 96231 (30 microM: EC50 0.06 microM) and rolipram (30 microM, EC50 0.08 microM) but was unaffected by 30 microM siguazodan. 5. At concentrations up to 10 microM, neither siguazodan nor rolipram elevated tracheal cyclic AMP levels. However, the combination of 10 microM rolipram and siguazodan caused a two fold increase in the cyclic AMP content (from 2.19 to 4.36 pmol cyclic AMP mg-1 protein). SNP (0.1-10 microM) failed to produce a significant increase in tracheal cyclic AMP levels. At 0.1 microM the effect of SNP on tracheal cyclic AMP levels was significantly (P < 0.05) increased in the presence of rolipram but not siguadozan. 6. The results indicate that the relaxant effects of rolipram are markedly enhanced by agents that inhibit PDE III activity or elevate cyclic GMP. They support the hypothesis that SNP potentiates the effects of rolipram via the inhibitory action of cyclic GMP on hydrolysis of cyclic AMP by PDE III. The findings also suggest that whilst PDE III may be more significant in regulating basal smooth muscle tone in the absence of any exogenous stimulus to cyclic AMP accumulation, PDE IV activity may be more tightly coupled to the pool of adenylyl cyclase stimulated by beta2-adrenoceptor agonists.

Adenosine enhancement of adrenergic neuroeffector transmission in guinea‐pig pulmonary artery

1. Adenosine and its derivatives N6-[(R)-1-methyl-2-phenylethyl]adenosine (R-PIA) or 5'-N-ethyl-carboxamideadenosine (NECA) enhanced nerve-induced contractile responses and augmented the basal smooth muscle tone in transmurally stimulated isolated strips of the guinea-pig pulmonary artery. 2. Adenosine, R-PIA and NECA enhanced contractile responses induced by noradrenaline, whereas N6-[(S)-1-methyl-2-phenylethyl]-adenosine (S-PIA) was virtually inactive. 3. Adenosine, R-PIA and NECA inhibited the nerve stimulation evoked release of [3H]-noradrenaline. However, the total release of [3H]-noradrenaline during the periods of NECA application was increased. 4. The nucleoside effects were blocked by the adenosine receptor antagonist 8-p-sulphophenyltheophylline. 5. 8-p-Sulphophenyltheophylline inhibited nerve-induced contractions and lowered basal muscle tone in preparations not having received any exogenous purines. 6. It is suggested that the observed stimulatory effects on muscle tone and on contractile responses to transmural nerve stimulation are mainly due to action at postjunctional stimulatory A1 adenosine receptors. In addition, actions at prejunctional inhibitory A1 and stimulatory A2 adenosine receptors are evident in this preparation.

Colonic α2‐adrenoceptor‐mediated responses in the pony

The motor responses of the caecum and colon to stimulation of alpha 2-adrenoceptors by xylazine and detomidine at the recommended dose levels of 0.6 and 0.1 mg/kg were investigated in three ponies. The motor changes of the left ventral colon induced by continuous intra-arterial infusion of a prostaglandin (PGF2 alpha) were used to assess the relative inhibitory effects of xylazine and detomidine in a colic model. The administration of alpha 2-agonists inhibited the spiking activity on the whole of the large intestine for 20-30 min (xylazine) or 2-3 h (detomidine). However, the detomidine-induced inhibition was preceded by a short period of increased smooth muscle basal tone as indicated by strain-gauge force transducer measurements. This pattern of activity was neither reversed nor prevented by the administration of tolazoline (10 micrograms/kg/min) intra-arterially. In contrast, inhibition of the colonic phasic and tonic motor activity by alpha 2-adrenoceptor stimulation was reversed competitively by tolazoline. The intra-arterial infusion of prostaglandin F2 alpha (10 micrograms/kg/min) induced prolonged and sustained spiking activity that might be related to signs of mild colic. Detomidine, and to a lesser extent xylazine, relaxed the whole of the large intestine and this was accompanied by alleviation of the signs of visceral pain.

Serum ionized calcium and dietary calcium in human and experimental hypertension.

Calcium and its binding protein, calmodulin, exert multiple effects that serve to regulate blood pressure in humans. From experimental work in various organ systems and cell types that are integrated to control cardiovascular function, it is evident that calcium and the calcium-calmodulin complex are essential components of diverse physiologic processes that modulate arterial pressure. The abnormal peripheral resistance that underlies essential hypertension is principally a reflection of altered vascular smooth muscle basal tone and reactivity. As such, the vascular smooth cell is prototypical of calcium’s influence on blood pressure control.1 KeywordsCalcium IntakeDietary CalciumSerum Calcium ConcentrationSerum Total CalciumBlood Pressure ProfileThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Effects of neurotensin, substance P and methionine-enkephalin on colonic motility.

The influence of neurotensin, substance P and methionine-enkephalin (met-enkephaline) on proximal and distal colonic motility was studied in anesthetized cats. When administered i.v, at a dose of 14 pmol x kg-1 x min-1, neurotensin increased basal smooth muscle tone and antiperistaltic activity in the proximal colon. After higher doses of neurotensin the basal muscle tone also increased in the distal colon. Substance P at a dose of 17 pmol x kg-1 x min-1 selectively and powerfully stimulated the distal colon, thus causing a mass contraction pattern with a concomitant decrease in peristaltic amplitude. In the proximal part of the colon 17 pmol x kg -1 x min-1 of substance P exerted an inhibitory action on the peristaltic amplitude in animals with a high level of spontaneous activity. In addition, the basal muscle tone was slightly decreased. In animals with sluggish spontaneous activity, however, no effects were detected in the proximal colon. With increasing doses of substance P forceful contractions of the proximal colon were also registered. Met-enkephalin at a dose of 40 pmol x kg-1 x min-1 increased the smooth muscle basal tone with no effect on the peristaltic activity in the proximal or distal segments. The effect on basal tone was blocked by naloxone. Thus, neurotensin, substance P and met-enkephalin have distinct motor actions on the colon. At low doses neurotensin may stimulate the churning and mixing functions of the proximal colon. Substance P exerts its major effects on the distal part with a mass contraction response and met-enkepahlin increases the basal muscle tone equally in the proximal and distal parts of the colon.