bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular effects of ginsenosides in vitro
Authors: Chen Xiu , Gillis C. Norman , Moalli Richard
Published: July 2012

Ginsenosides (saponins extracted from Panax ginseng) elicit qualitatively and quantitatively different responses in isolated, contracted ring preparations of different blood vessels from rabbits, dogs and humans.

Ginsenosides themselves did not affect the tone of ‘resting’ isolated blood vessels directly, but contracted slightly the renal vein of rabbits at the maximum concentration tested. The mixture caused relaxation of the noradrenaline (NA) or prostaglandin F2α (PGF2α‐induced contraction of the pulmonary artery and intrapulmonary artery of rabbits, and the PGF2α‐induced contraction of the canine mesenteric vein.

Ginsenosides potentiated, in a concentration‐dependent manner, the contractile responses of renal veins of dogs and rabbits to PGF2α

The reason for such heterogeneous responses of different blood vessels to ginsenosides in unknown. It is suggested that either potentiation of contraction or relaxation of contracted blood vessels might be mediated by interaction with endogenous vasoactive substances. The potentiation of PGF2α‐induced contraction may be related to the reduction of renal blood flow observed in anaesthetized dogs. The simultaneous contraction and relaxation effects may explain its biphasic actions on blood pressure.
Anti‐arrhythmic effects of (‐)‐carnitine chloride and its acetyl analogue on canine late ventricular arrhythmia induced by ligation of the coronary artery as related to improvement of mitochondrial function
Authors: Imai Shoichi , Matsui Kazuki , Nakazawa Mikio , Takatsuka Naoki , Takeda Keisuke , Tamatsu Hirokuni
Published: July 2012

Using the two‐stage coronary ligation method, first described by Harris, (1950), anti‐arrhythmic effects (AAE) of (‐)‐carnitine chloride (LCC) and acetyl (‐)‐carnitine chloride (ALCC) were studied in conscious unrestrained dogs in comparison with those of disopyramide (D). Two‐stage ligation of the coronary artery resulted in a significant decrease in the myocardial free carnitine content.

Intravenous administration of LCC (300 mg kg−1) and D (5 mg kg−1) suppressed the ventricular arrhythmia induced by coronary ligation after 24 hours. ALCC (300 mg kg−1) was found to be less potent.

An improvement of the mitochondrial function (respiratory control index (RCI) and oxidative phosphorylation rate (OPR)) was noted with LCC and ALCC and there was a linear correlation between AAE expressed as reduction of arrhythmic ratio and improvement in the OPR, whereas there was no improvement in mitochondrial function after D.

Plasma carnitine concentration was increased after administration of LCC, attaining the value of around 8 mm at 10 min after 300 mg kg−1. At 60 min, the plasma carnitine concentration was still about half as high as at 10 min. After ALCC, both acetyl carnitine and free carnitine were found in the plasma. The concentration of the former was decreased after attaining a peak value of around 0.2 mm at 10 min, while the plasma concentration of free carnitine was gradually increased.

The anti‐arrhythmic effects of LCC and ALCC were ascribed to the improvement of mitochondrial oxidative phosphorylation, while effects other than the improvement of the mitochondrial activity were suggested as mechanisms of anti‐arrhythmic effects of D.
The actions of cirazoline on the rat vas deferens
Authors: Docherty J.R. , McGrath J.C.
Published: July 2012

The pre‐ and postsynaptic effects of the α1‐agonist cirazoline were assessed in epididymal and prostatic portions of the rat isolated vas deferens.

Cirazoline produced a postsynaptic α1‐adrenoceptor mediated potentiation of the isometric contraction to single pulse field stimulation in both prostatic and epididymal portions.

In epididymal portions, nifedipine (10 μM) greatly attenuated the postsynaptic α1‐receptor mediated potentiation of nerve mediated contractions, uncovering a presynaptic inhibitory action of cirazoline.

No evidence was found for α2‐antagonism by cirazoline. It is concluded that the previously reported antagonism of the presynaptic inhibitory effects of clonidine was due to postsynaptic potentiation of nerve‐mediated responses by cirazoline.
Post‐natal development of functional neurotransmission in rat vas deferens
Authors: MacDonald A. , McGrath J.C.
Published: July 2012

Responses of the rat vas deferens to drugs and to field stimulation were examined in sexually immature rats.

The vasa from immature rats often exhibited spontaneous contractions and displayed greater sensitivity to the contractile effects of α‐adrenoceptor agonists.

The responses of the vasa from immature rats to single pulse field stimulation lacked the adrenergic component of the response although the non‐adrenergic component was present. The responses were antagonized by α2‐adrenoceptor agonists. In the presence of cocaine, an adrenergic component of the response did appear.

During trains of pulses the pre‐ and postjunctional effects of adrenergic transmission which are found in adult rats were absent in vasa from immature rats.

Electron microscopic studies showed no qualitative differences in adrenergic innervation in vasa from immature and adult rats.

It is concluded that a state of ‘pre‐innervation supersensitivity’ associated with a lack of functional adrenergic transmission exists in the vas deferens of immature rats. The supersensitivity disappears and functional transmission develops during the period in which testosterone secretion increases in the rat. The reason for the lack of functional transmission at a time when the innervation appears to be morphologically mature is not clear but may be due to the noradrenaline release mechanism not being fully operative.
Pardaxin produces postjunctional muscle contraction in guinea‐pig intestinal smooth muscle
Authors: Primor Naftali
Published: July 2012

The action of pardaxin (PX), a toxin isolated from the secretion of the Red Sea flatfish, Pardachirus marmoratus, was studied on longitudinal muscle of guinea‐pig ileum.

Pardaxin contracted the ileum and subsequently abolished muscle contraction to 5‐hydroxytryptamine (5‐HT), but did not affect the responses to acetylcholine (ACh) and substance P(SP).

Pardaxin‐induced contraction was only partially suppressed by atropine and not affected by tetrodotoxin or morphine. Preparations desensitized to 5‐HT or SP responded normally to pardaxin.

Pardaxin‐induced contractions were normal in K+‐depolarizing Krebs Ringer solution and not affected by black widow spider venom.

It is concluded that the pardaxin‐induced muscle contractions are not mediated through the release of neurotransmitters and do not involve 5‐HT, SP or ACh receptors, but are due to a direct action on the muscle contractile mechanism.
The calcium antagonists PY 108–068 and verapamil diminish the effects of angiotensin II: sites of interaction in the peripheral circulation of anaesthetized cats
Authors: Hof R. P.
Published: July 2012

The sites of interaction between the vasoconstrictor angiotensin II (A II) and the calcium antagonists PY 108–068 (PY) (a dihydropyridine derivative) or verapamil (V) in different peripheral vascular beds were investigated using the microsphere method in chloralose‐urethane anaesthetized open‐chested cats.

A II was infused intravenously into 27 cats at a rate of 0.15 μg kg−1 min−1. Systemic haemodynamic variables and regional blood flow were measured immediately before and 10 min after the start of the infusion.

While the infusion of A II continued, PY (3 μg kg−1 min−1), V (30 μg kg−1 min−1) or the vehicle was infused for 10 min into 9 cats each and the effects of this combined infusion were again measured at the end of the 10 min period.

A II increased mean arterial blood pressure but decreased peripheral conductance and, to a smaller but still significant degree, cardiac output and peak acceleration of blood in the aorta (an ejection phase parameter of myocardial contractility).

The calcium antagonists reversed these effects. Cardiac output and total peripheral conductance were increased even beyond the pre‐A II level by PY.

A II constricted the vascular beds of the kidney, small intestine, liver and skin. Arterio‐venous shunt flow decreased. Vasoconstriction was also found in the stomach, spleen and in different parts of the heart with the exception of the subendocardial layer of the left ventricle, where blood flow increased and conductance remained unchanged. A II did not decrease conductance in different parts of the brain or in skeletal muscle.

The vasoconstrictor effects of A II persisted or tended to be increased in most of the vascular beds of placebo treated animals. PY 108–068 and verapamil abolished the vasoconstrictor effects of A II in most of the vascular beds with the exception of the liver, the spleen, the skin and the arterio‐venous shunts and caused vasodilatation in the heart. PY also induced vasodilatation in the brain and skeletal muscle, where A II had not induced vasoconstriction.

The pattern of attenuation of A II effects was different from the pattern of vasodilatation induced by these and other calcium antagonists in the same cat preparation not treated with a vasoconstrictor. The sites of action of this dihydropyridine derivative (PY) on the peripheral circulation thus, appear to depend not only on the vascular bed but also on the presence of a vasoconstrictor influence at the time of investigation.
The time course of muscarinic depolarization of guinea‐pig myenteric neurones
Authors: North R. A. , Tokimasa T.
Published: July 2012

Intracellular recordings were made from neurones in the myenteric plexus of the guinea‐pig ileum in vitro. Muscarinic depolarizations were evoked by brief (1–500 ms) ionophoretic applications of acetylcholine (ACh) or other agonists. Nicotinic responses to ACh evoked by the same ionophoretic pulse had short latencies and rapid rise times, indicating close proximity of the ionophoretic pipette to the neurone membrane.

The time course (duration several seconds) of the muscarinic depolarization was independent of the identity of the agonists applied (ACh, methacholine, carbachol, oxotremorine).

Hyoscine and barium were ejected onto the neurones by brief (30 ms‐1 s) pressure pulses applied to micropipettes. Hyoscine applied immediately after ACh, during the latency and rising phase of the muscarinic depolarization, did not antagonize the response to ACh. The same application of hyoscine immediately prior to ACh caused complete antagonism.

Muscarinic depolarizations evoked by continuous application of ACh (by repeated ionophoresis or perfusion) were reversed by hyoscine. The time course of this reversal was similar to the decline of the muscarinic response following a single brief application of ACh.

Barium caused a depolarization similar to that produced by muscarinic agonists in its latency, time course and temperature sensitivity, and having the same reversal potential (‐90 mV). These barium potentials were not affected by hyoscine.

It is suggested that neither diffusion of ACh to the receptors nor the kinetics of the agonist‐receptor interaction contributes significantly to the latency and prolonged time course of the muscarinic depolarization.
Action of ouabain on rat heart: comparison with its effect on guinea‐pig heart
Authors: Herzig Stefan , Mohr Klaus
Published: July 2012

The inotropic dose‐response curve of ouabain in rat cardiac ventricular strips exceeded a concentration range of two decades (1 × 10−7 M to 3 × 10−5 M) displaying an intermediate plateau phase. In guinea‐pig ventricular strips the inotropic ouabain concentrations spanned only one decade (1 × 10−7 M‐1 × 10−6 M).

Ouabain‐intoxication in guinea‐pig ventricular strips occurring at 3 × 10−6 M consisted of arrhythmia and contracture, while in rat ventricular strips at the toxic concentration of 1 × 10−4 M only a progressive increase in diastolic tension was observed.

By means of atomic absorption spectroscopy the ouabain‐induced loss of cellular potassium and gain of sodium in rat ventricular strips was detected only at concentrations of ouabain higher than 10−4 M.

Ouabain reduced the activity of Na/K‐ATPase prepared from rat and guinea‐pig cardiac ventricles to half of its maximum at 6.5 × 10−5 M in rat and 1.0 × 10−6 M in guinea‐pig, rat heart Na/K‐ATPase thus being about 60 fold less sensitive towards ouabain.

Specific [3H]‐ouabain binding to membrane suspensions prepared from rat and guinea‐pig ventricles was characterized by a similar affinity in rat (KD = 4 × 10−8 M) and guinea‐pig (KD = 13 × 10−8 M). The number of ouabain binding sites in rat membranes was only about 10% of the number found in guinea‐pig membranes. In rat the presence of additional ouabain‐binding with low affinity and high capacity seemed possible, but could not be verified for methodological reasons.

In the light of the biochemical results and binding data, the wider range of ouabain concentration exerting a positive inotropic effect in the rat may be attributed to the existence in the latter of two populations of receptors with different affinities for ouabain and different capacities. In contrast, in the guinea‐pig, there is a single population. Nevertheless it is probable that all the receptors in both species are part of the Na/K‐ATPase complex and mediate a positive inotropic effect after ouabain‐binding in an identical manner.
Effect of bumetanide, frusemide and prostaglandin E2 on the isolated perfused kidney of rat and rabbit
Authors: Foy J.M. , Nuhu S.Z.
Published: July 2012

Rat and rabbit kidneys were isolated, perfused via the renal artery with Krebs solution and perfusion pressure monitored. Dose‐response curves to noradrenaline administered as bolus doses or frequency‐response curves from transmural arterial electrical stimulation were obtained.

A 1 h continuous infusion of bumetanide (0.1 μg ml−1) increased the sensitivity of rat kidney vessels to noradrenaline, an effect also seen when bumetanide and flurbiprofen (6 μg ml−1) were simultaneously perfused. In the rabbit there was a decreased sensitivity to both electrical stimulation and noradrenaline.

A 1 h continuous infusion of frusemide (6 μg ml−1) only altered the effects of electrical stimulation. An increased sensitivity in the rat (abolished by flurbiprofen) and a decreased sensitivity in the rabbit kidney was observed.

A 1 h continuous infusion of prostaglandin (PG)E2 (2 ng ml−1) increased the sensitivity of rat kidney to both types of stimuli but caused a reduction in the responsiveness of the rabbit kidney to electrical stimuli only. Addition of flurbiprofen only slightly modified these results.

The results emphasize and confirm the fundamental difference in reactivity of the rat and rabbit kidney.

Bumetanide and frusemide, two ostensibly similar loop diuretics, show significantly different effects on these preparations suggesting that any modification by non‐steroidal anti‐inflammatory drugs cannot wholly be explained by similar PGE2 induced haemodynamic changes.
Influence of age, sex, pregnancy and protein‐calorie malnutrition on the pharmacokinetics of salicylate in rats
Authors: Varma D.R. , Yue T.L.
Published: July 2012

The influence of age, sex, pregnancy and protein‐calorie malnutrition (PCM) on the plasma t1/2, plasma clearance (Clp) and apparent volume of distribution (Vd) of sodium salicylate (62 μmol kg−1) was determined in Sprague‐Dawley rats. Female and male rats of five different age groups (ages in weeks: pups 1, weanling 3, young 8–9, adult including pregnant 14–15, old 56–60) including three age groups with PCM (8–9, 14–15 and 56–60 weeks old) were used. Plasma and urinary salicylates were assayed by h.p.l.c.

Plasma 4 was longer and Clp smaller in pups than in weanling and young rats and comparable to values for old rats; Vd of salicylate in pups was larger than in any other group of rats. Plasma t1/2 was longer and Clp as well as Vd of salicylate were smaller in adult females than in males of comparable age. Relative to nonpregnant adult females, Vd of salicylate in pregnant rats was larger but plasma t1/2 and Clp were unchanged.

In all groups of rats studied, PCM decreased the plasma t1/2 and increased the Clp of salicylate; Vd was unchanged.

Changes in salicylate pharmacokinetics were not due to any differences in serum protein‐salicylate binding or to serum testosterone levels. Ovariectomy decreased the plasma t1/2 of salicylate but castration of male rats had no significant effect. Administration of testosterone to ovariectomized female rats exerted no significant effect on salicylate pharmacokinetics.

It is concluded that the physiological state and the nutritional status can modify salicylate pharmacokinetics; in so far as the rat model reflects the human situation, these variables should be taken into account for a rational salicylate therapy.
Does amiodarone affect heart rate by inhibiting the intracellular generation of triiodothyronine from thyroxine?
Authors: Lindenmeyer M. , Spörri S. , Stäubli M. , Studer A. , Studer H.
Published: July 2012

The hypothesis that the antiarrhythmic drug amiodarone slows down the heart rate by its inhibitory action on the intracellular conversion of thyroxine (T4) to 3,5,3′ triiodothyronine (T3) was investigated. For this purpose we compared the effect of amiodarone with that of another potent inhibitor of the T4 → T3 conversion, i.e. the radiographic contrast medium iopanoic acid, on the heart rate of unanaesthetized guinea‐pigs.

Both amiodarone and, to an even greater extent, iopanoic acid induced an increase in serum 3.5′,3′ triiodothyronine (reverse T3), indicating effective inhibition of T4 → T3 conversion. Both amiodarone and iopanoic acid were accumulated in the liver and in the heart (measured as iodine).

While amiodarone induced bradycardia, iopanoic acid did not change the heart rate.

Supraphysiological amounts of exogenous T3 reverted the amiodarone induced bradycardia to near normal values. A comparable effect was observed with isoprenaline.

The intracellular inhibition of the T4 → T3 conversion is not the ultimate mode of the action of the amiodarone effect on heart rate. It is thought that amiodarone interacts with T3 at its receptor or somewhere later along the pathway from the T3‐receptor interaction to the final effect of T3 on heart rate.
Prostaglandins and thromboxane in the delayed phase of shock induced by Serratia marcescens endotoxin
Authors: Parratt J.R. , Sharma N. , Zeitlin I.J.
Published: July 2012

The cardiovascular and metabolic effects of an endotoxin derived from Serratia marcescens were examined in anaesthetized, spontaneously‐breathing cats. There was a marked initial elevation of right atrial pressure (the result of pulmonary vasoconstriction) and decreases in systemic arterial pressure and in arterial PO2.

The ‘delayed’ effects of endotoxin shock in this species (1–8 h) consisted of a reduced cardiac output and decreased urinary excretion. Blood pressure and myocardial contractility (assessed from measurement of left ventricular (LV) dP/dt and LV end‐diastolic pressure) were maintained throughout this phase. There was evidence of a metabolic (lactic) acidosis largely compensated by hyperventilation.

Plasma levels (both arterial and mixed venous blood samples) of prostaglandin (PG)E2, PGF2α, 6‐keto PGF1α and thromboxane (TX)B2 were measured by radioimmunoassay techniques. Endotoxin administration caused substantial increases in the plasma levels of all four derivatives of arachidonic acid, especially between 1 and 6 h.

Separation of the endotoxin‐treated cats into survivors and non‐survivors showed that the non‐survivors had significantly higher circulating levels of PGE2, TXB2 and PGF2α. It is suggested that TXB2 and PGF2α might contribute to some of the detrimental effects of endotoxin (e.g. pulmonary, mesenteric, renal vasoconstriction; platelet aggregation with resulting organ failure) and that prostacyclin may be beneficial in endotoxin shock in this species.
The dependence of excitatory junction potential amplitude on the external calcium concentration in narcotic tolerant mouse vas deferens
Authors: Einstein R. , Lavidis N. A.
Published: July 2012

The dependence of neurotransmitter secretion on external calcium ions during development of opiate tolerance in the mouse vas deferens was studied.

The writhing response of mice to an i.p. injection of acetylcholine was inhibited by morphine. Reversal of this antinociceptive effect of morphine during chronic treatment signalled the development of tolerance.

Tolerance to morphine at the neuromuscular junction was shown as a reversal of the initial shift of the size of the excitatory junction potential (e.j.p.) vs extracellular calcium concentration relationship back towards the control without any change in the power of 2.4.

Facilitation in the amplitude of the e.j.p. occurs with low frequency (2 Hz) stimulation. The initial increase in facilitation induced by morphine was reversed by chronic morphine treatment without any change in the plateau e.j.p. amplitude achieved after a long low frequency train of impulses.

At high frequencies (10 Hz) the initial increase in e.j.p. amplitude was followed by a depression. Acute morphine administration decreased the size of the e.j.p., this was followed by an increase in facilitation and a decrease in depression. These effects were reversed after chronic morphine treatment.

Tolerance to morphine involves a counteradaptive process which restores the normal entry of calcium ions or its actions within the release sites in promoting transmitter release.
Prejunctional dopamine receptors modulate twitch responses to parasympathetic nerve stimulation in the rabbit isolated rectococcygeus muscle
Authors: Drew G.M. , Hilditch A.
Published: July 2012

Field stimulation of the parasympathetic nerves supplying the rabbit isolated rectococcygeus muscle produced individual twitch responses that were inhibited by dopamine (1 × 10−8−1 × 10−5M).

The twitch‐inhibitory effect of dopamine was reversed by haloperidol or sulpiride (1 × 10−8 − 1 × 10−5M for either) but not by phentolamine or yohimbine (up to 1 × 10−4M). Haloperidol and sulpiride were potent, specific, competitive antagonists of the twitch‐inhibitory effect of dopamine; their pA2 values were 8.39 and 7.75, respectively. In contrast, cis α‐flupenthixol, fluphenazine, bulbocapnine and thioridazine were weak or inactive against dopamine.

Concentrations of dopamine that inhibited the twitch response to parasympathetic nerve stimulation had little or no effect on contractions elicited by carbachol or by direct muscle stimulation after abolition of neuronal conduction by tetrodotoxin. Thus, the effects of dopamine on responses elicited by parasympathetic nerve stimulation seem to be exerted at a prejunctional level rather than directly on the smooth muscle.

The twitch‐inhibitory effect of dopamine was mimicked by epinine, N,N‐diethyldopamine, N,N‐di‐n‐propyldopamine, 5,6‐ADTN, N,N‐di‐n‐propyl 5,6‐ADTN, 6,7‐ADTN, apomorphine and Sandoz 27–403. Sulpiride reversed the effects of all these agonists.

N,N‐di‐n‐propyl‐6,7‐ADTN and SK & F 82526 also inhibited the twitch response but their effects were not reversed by sulpiride.

SK & F 38393 and DPI had little effect on the twitch response.

The pharmacological characteristics of the presynaptic dopamine receptors in the rabbit rectococcygeus muscle show that they resemble those in the cat heart and rabbit ear artery in some respects but there are differences that suggest that the presynaptic dopamine receptors in the rabbit rectococcygeus muscle constitute a specific subgroup of receptors.
Effects of reduced calcium ion concentration and of diltiazem on vasoconstrictor responses to noradrenaline and sympathetic nerve stimulation in rat isolated tail artery
Authors: Medgett Iain C. , Rajanayagam M. A. Sharmini
Published: July 2012

In isolated, perfused proximal segments of Sprague‐Dawley rat tail artery, idazoxan (100 nmoll1) displaced the concentration‐response curve to noradrenaline (NA) to the right. The log shift of the NA concentration‐response curve was greater at lower concentrations than at higher concentrations of NA. Idazoxan (100 nmoll−1) had no effect on responses to electrical stimulation.

Prazosin (10 nmoll−1) displaced the concentration‐response curve to NA to the right as well as markedly reducing responses to sympathetic nerve stimulation.

The concentration‐response curve to NA, obtained after reducing the concentration of calcium ions in the Krebs solution from 2.5 to 0.6 mmoll−1, was significantly displaced to the right. Responses to sympathetic nerve stimulation were not affected by this reduction in the concentration of calcium ions.

Diltiazem (1 and 10 μmoll−1) significantly displaced the concentration‐response curve to NA to the right but had no effect on sympathetic nerve stimulation.

These in vitro results in peripheral arterial smooth muscle confirm the findings of previous in vivo studies which suggest that α2‐adrenoceptors contribute to the vasoconstrictor responses elicited by α‐adrenoceptor agonists and that these responses but not those mediated by α1‐adrenoceptors are dependent on extracellular calcium.
The in vitro pharmacology of xamoterol (ICI 118,587)
Authors: Malta E. , Mian M. Aqleem , Raper C.
Published: July 2012

The effect of xamoterol and (‐)‐isoprenaline have been compared for their activity at β‐adrenoceptor sites in a number of in vitro cardiac and smooth muscle preparations.

Xamoterol produced weak positive chronotropic effects in guinea‐pig, rat and cat atria (intrinsic activity < 0.55, (‐)‐isoprenaline = 1). Positive inotropic effects were obtained in driven left atria of the cat but were absent in guinea‐pig left atrial and right ventricular strip preparations. Agonistic effects were due to β1‐adrenoceptor stimulation.

Xamoterol was without β‐adrenoceptor‐mediated inhibitory effects in guinea‐pig ileal, tracheal and uterine preparations and in the rat vas deferens and oestrogen‐primed uterus. Weak β2‐adrenoceptor‐mediated relaxation was obtained in progesterone‐primed rat uteri.

Xamoterol produced non‐specific inhibitory effects in guinea‐pig ileal and tracheal preparations.

Xamoterol acted as a competitive antagonist at βr (pA2 range = 7.4 to 7.8) and β2‐adrenoceptors (pA2 range 5.2 to 6.2) and displaced [125I]‐iodocyanopindolol from guinea‐pig left atrial (pKD = 7.25) and uterine (pKD 5.24) membrane preparations.

It is concluded that xamoterol displays a selective affinity for β1‐adrenoceptors. Although its partial agonistic actions are more evident at β1‐adrenoceptor sites, like prenalterol, xamoterol displays a degree of tissue rather than receptor‐dependent selectivity.
Forskolin: its effects on potassium‐evoked release of vasopressin from the rat neurohypophysis
Authors: Bowman David , Hope Derek B.
Published: July 2012

The effect of forskolin, added either before or 5 min after the onset of potassium‐evoked release of vasopressin from isolated neurointermediate lobes of the rat has been investigated.

A low concentration of forskolin (1 μM), added before stimulation, enhanced the potassium‐evoked release of vasopressin throughout two successive 5 min periods of stimulation. Higher concentrations of forskolin (10–80 μM) produced no effect on the potassium‐evoked release of hormone during the first 5 min of stimulation, but inhibited release during the second 5 min period.

When added 5 min after the onset of potassium stimulation, forskolin (1–80 μM) reduced the amount of vasopressin released during the remaining 5 min of stimulation.

Forskolin produced a concentration‐dependent increase in cyclic AMP during both the control and potassium stimulation periods.

The amount of cyclic AMP generated by forskolin during potassium stimulation was less than that produced during the corresponding control periods.
The effects of a new opioid analgesic, meptazinol, on the respiration of the conscious rat
Authors: Cowlrick I.S. , Shepperson N.B.
Published: July 2012

In the conscious rat arterial PCO2 was measured as an index of respiratory status.

The opioid analgesic meptazinol (7.5–30 mg kg−1) evoked small but significant increases in arterial PCO2 which were attenuated by naloxone.

Meptazinol significantly reduced the increase in arterial PCO2 evoked by morphine.

The respiratory depression induced by meptazinol, but not that induced by morphine, was enhanced by pretreatment with atropine.

The (+)‐enantiomer, but not the (‐)‐enantiomer of meptazinol increased arterial PCO2. In contrast, only the (‐)‐enantiomer reduced the respiratory depressant effect of morphine.

It is proposed that the degree of respiratory depression induced by meptazinol is limited by its opioid antagonist and cholinomimetic properties.
Role of putative neurotransmitters in the central gastric antisecretory effect of prostaglandin E2 in rats
Authors: Puurunen Juhani
Published: July 2012

The role of putative neurotransmitters of the central nervous system in the central gastric antisecretory effect of prostaglandin E2 (PGE2) was investigated in pylorus‐ligated rats.

Pretreatment of the rats with an intracerebroventricular (i.c.v.) injection of 6‐hydroxydopamine (6‐OHDA) prevented the antisecretory effect of the i.c.v. administration of PGE2, whereas pretreatment with 5,6‐dihydroxytryptamine (5,6‐DHT) plus p‐chlorophenylalanine (PCPA) had no effect.

I.c.v.‐administered phentolamine and idazoxan antagonized the inhibition of gastric secretion induced by i.c.v. PGE2, whereas prazosin, propranolol and sulpiride injected via the same route were ineffective.

Diphenhydramine, cimetidine, naloxone and theophylline, all administered i.c.v., did not modify the antisecretory effect of i.c.v. PGE2.

The results suggest that an activation of α2‐adrenoceptors in the brain is involved in the central gastric antisecretory effect of PGE2, whereas neither central 5‐hydroxytryptamine receptors, α1‐ or β‐adrenoceptors, D2‐dopamine receptors, histamine or opioid receptors nor adenosine seem to play any role here.
Effects of pentobarbitone on acetylcholine‐activated channels in mammalian muscle
Authors: Gage Peter W. , McKinnon David
Published: July 2012

Acetylcholine‐activated single channel currents were recorded from the extrajunctional region of chronically denervated skeletal muscle of the rat by the patch clamp technique.

In control experiments, the cumulative open‐time, closed‐time and burst length distributions could be well described by the sum of two exponentials.

Pentobarbitone decreased the mean open time and increased the time constant of the fast component of the closed time distribution. These effects increased with drug concentration.

The mean burst length was relatively independent of pentobarbitone concentration over the range of concentrations used (10–500 μM).

These observations are inconsistent with a simple sequential blocking model and it is suggested that pentobarbitone has an allosteric site of action on receptor‐channel complexes that makes the open state less stable.
Desensitization of prostacyclin responsiveness in a neuronal hybrid cell line: selective loss of high affinity receptors
Authors: Leigh P. J. , MacDermot J.
Published: July 2012

The binding of [3H]‐iloprost (ZK36374) to NCB‐20 membranes revealed a single population of high affinity receptors (KD = 9.55 nM, Bmax = 431 fmol mg−1 protein) and a low affinity, non‐saturable binding component.

Desensitization of prostacyclin‐responsiveness of NCB‐20 cells is induced by culture in the presence of the stable protacyclin analogue carbacyclin. Desensitization is accompanied by an increase in the Kact value for prostacyclin (64.1 nM to 175 nM), and a reduction in the prostacyclin‐dependent increase in adenylate cyclase activity (41.2 to 15.1 pmol cyclic AMP min−1 mg−1 protein).

Desensitization is not accompanied by changes in the coupling of the catalytic (C) to the regulatory (Ns) subunit of adenylate cyclase. In addition, the physical identity of the receptor molecule (as characterized by its sensitivity to electron bombardment in the beam of a linear accelerator) is not changed by desensitization.

Desensitization of prostacyclin‐dependent activation of adenylate cyclase may be explained most simply by a loss of prostacyclin receptors. The anomalous increase in the Kact (concentration of prostaglandin giving half‐maximum enzyme activation) for prostacyclin‐stimulated adenylate cyclase was not accompanied by a substantial change in the KD of [3H]‐iloprost binding, and is explained by a loss of spare receptors.

Prostacyclin responsiveness in non‐dividing cells may be restored after desensitization by prolonged culture (up to 48 h) in the absence of carbacyclin. Resensitization is accompanied by restoration of the high affinity Kact value (143 nM to 45.5 nM), and is dependent on de novo protein synthesis.
Interaction of prostaglandin D2 with prostacyclin, carbacyclin and the hydantoin prostaglandin, BW245C, in guinea‐pig platelets
Authors: Hamid S. , Whittle B.J.R.
Published: July 2012

The anti‐aggregating actions of prostaglandin D2 (PGD2) have been compared to prostacyclin (PGI2), its stable analogue carbacyclin and a hydantoin prostaglandin, BW245C, in guinea‐pig platelets in vitro.

PGI2, carbacyclin and BW245C were potent inhibitors of ADP‐induced aggregation in guinea‐pig platelets, with ID50 values comparable to those obtained in human platelet‐rich‐plasma.

In contrast, PGD2 acted as a weak and partial inhibitor in guinea‐pig platelet aggregation, producing a bell‐shaped dose‐response relationship.

PGD2 induced a dose‐related antagonism of the inhibitory actions of BW245C, prostacyclin and carbacyclin on guinea‐pig platelets.

However, PGD2 did not antagonize the inhibitory actions of either forskolin or dibutyryl cyclic AMP on this platelet preparation.

The results suggest a non‐specific interaction of PGD2 with these prostanoid binding sites on guinea‐pig platelets.
Inhibitory effects of forskolin and papaverine on nerve conduction partially blocked by tetrodotoxin in the frog sciatic nerve
Authors: Ribeiro J.A. , Sebastião A.M.
Published: July 2012

The effects of forskolin, sodium fluoride and papaverine on compound action potentials were investigated in de‐sheathed sciatic nerve preparations of the frog.

Forskolin decreased in a concentration‐dependent manner the amplitude of compound action potentials when nerve conduction was partially blocked by tetrodotoxin (TTX). In the presence of TTX a 50% decrease in the action potential amplitude recorded was obtained with about 2.5 μM forskolin.

Sodium fluoride did not modify the amplitude of compound action potentials partially blocked by TTX.

Papaverine also decreased the amplitude of compound action potentials partially inhibited by TTX. A 50% decrease in the action potential amplitude recorded in the presence of TTX was obtained with about 10 μM papaverine.

The possibility that cyclic AMP modulates axonal excitability by interfering with the entry of sodium through the TTX‐sensitive sodium channel is discussed.
The effect of Bay K 8644 on contraction mediated by α‐adrenoceptors in the rat saphenous vein
Authors: Cheung D.W.
Published: July 2012

The effect of Bay K 8644 on the contractile responses of the rat saphenous vein to KC1, noradrenaline, methoxamine, and B‐HT 920 were studied. In all cases, Bay K 8644 potentiated the responses. These results confirmed the suggestion that α‐adrenoceptor agonists initiated contraction in the rat saphenous vein by opening the potential‐operated calcium channels.
Erythrosin B inhibits high affinity ouabain binding in guinea‐pig heart Na+‐K+‐ATPase without influence on cardiac glyoside induced contractility
Authors: Fricke Uwe
Published: July 2012

Binding of [3H]‐ouabain to guinea‐pig heart membranes enriched in Na+‐K+‐ATPase revealed two different cardiac glycoside binding sites. High affinity binding was obtained at a KD = 2.2 × 10−7 mol 1−1 (Bmax = 16.8 pmol ouabain mg−1 protein) whereas low affinity ouabain binding occurred at a KD > 10−6 mol 1−1.

To discover whether the two ouabain binding sites are functional in guinea‐pig heart muscle, erythrosin B, an inhibitor of the high affinity ouabain binding in rat brain tissue, was tested in guinea‐pig isolated heart muscle preparations. Erythrosin B proved to be a potent inhibitor of the Mg2+(Na+)‐dependent‐, as well as Na+‐K+‐activated ATPase (ID50 = 9 × 10−6 mol 1−1). Contractility of guinea‐pig isolated papillary muscles, however, was not influenced by erythrosin B in concentrations up to 1 × 10−5 mol 1−1. Only very high concentrations (4 × 10−4 mol 1−1) resulted in a slightly negative inotropic effect (about 20%).

Erythrosin B dose‐dependently inhibited [3H]‐ouabain binding to the Na+‐K+‐ATPase (KD = − 3.6 × 10−6 mol 1−1). In a concentration of 1 × 10−5 mol 1−1 the dye abolished high affinity [3H]‐ouabain binding without affecting the low affinity binding sites.

In contrast, in guinea‐pig isolated atria, no functional antagonism between erythrosin B (5 × 10−5 mol 1−1) and ouabain was observed.

As there is a coincidence between the high affinity binding (KD = 2.2 × 10−7 mol 1−1) and the concentration for half maximum inotropic effects of ouabain (ED50 = 1.6 × 10−7 mol 1−1), the lack of effect of erythrosin B on ouabain‐induced inotropy may be caused by an inaccessibility of the dye to the (internal) ATP‐site of the Na+‐K+‐ATPase.
Autoradiographic localization of β‐adrenoceptor subtypes in guinea‐pig kidney
Authors: Lew R. , Summers R.J.
Published: July 2012

The distribution of β‐adrenoceptor subtypes in slide‐mounted sections of guinea‐pig kidney has been examined by the technique of in vitro labelling combined with autoradiography.

Binding of (‐)‐[125I]‐cyanopindolol (Cyp) to kidney sections equilibrated and dissociated slowly, was saturable and stereoselective with respect to the isomers of propranolol and pindolol. These characteristics were appropriate for binding to β‐adrenoceptors.

Delineation of β‐adrenoceptor subtypes was achieved by use of betaxolol (β1‐adrenoceptors) and ICI 118,551 (β2‐adrenoceptors) and computer assisted curve fitting techniques. Both β1‐ and β2‐adrenoceptors were present in the proportions 1:2.

3H‐Ultrofilm images of (‐)‐[125I]‐Cyp binding to guinea‐pig kidney sections showed localized patches of binding in the cortex and concentrated binding in the outer stripe of the medulla. Cortical receptors were of the β1 subtype and those associated with the outer stripe of the medulla were of the β2‐adrenoceptor subtype. β1‐Adrenoceptors were concentrated over glomeruli and β2‐adrenoceptors over the straight portion of the proximal tubule.
[3H]‐rauwolscine binding to α2‐adrenoceptors in the mammalian kidney: apparent receptor heterogeneity between species
Authors: Neylon C.B. , Summers R.J.
Published: July 2012

Binding of the α2‐adrenoceptor antagonist [3H]‐rauwolscine was characterized in membrane preparations from the kidneys of mouse, rat, rabbit, dog, and man.

In all species, binding reached equilibrium within 45 min and dissociated at a single exponential rate after addition of phentolamine 10 μM.

Saturation studies showed that the affinity of [3H]‐rauwolscine was similar in all species (2.33‐3.03 nM) except man where it was significantly higher (0.98 nM). Marked differences were seen in the density of binding sites, increasing in the order: man < dog < rabbit < rat < mouse. In all cases, Hill coefficients were not significantly different from unity.

[3H]‐rauwolscine binds with low affinity (KD > 15 nM) to membranes prepared from guinea‐pig kidney. The low affinity binding is not due to the absence of particular ions in the incubation medium or to receptor occupation by endogenous agonist.

The binding in all species was found to be stereoselective with respect to the isomers of noradrenaline. However, differences were seen in the characteristics of agonist interactions with the binding site both between isomers and between species.

Marked differences in affinity of particular α‐adrenoceptor antagonists were observed for α2‐adrenoceptors labelled by [3H]‐rauwolscine. These differences were most evident with the α1‐adrenoceptor selective antagonist prazosin which displayed inhibition constants (Ki values) of 33.2, 39.5, 261, 570 and 595 nM in rat, mouse, dog, man and rabbit, respectively.

Differences are apparent in the characteristics of α2‐adrenoceptors labelled by [3H]‐rauwolscine between species and it is suggested that the differences observed for α1‐selective antagonists such as prazosin may be related to binding to additional sites in the vicinity of the α2‐adrenoceptor.
Regional variation in the sensitivity of longitudinal smooth muscle to histamine at H1‐receptors in guinea‐pig ileum and colon
Authors: Barker L.A.
Published: July 2012

The sensitivity of the distal ileum, proximal colon, medial colon, and distal colon of the guinea‐pig to histamine has been evaluated.

The rank order of sensitivity was ileum > medial colon > proximal colon ∼ distal colon.

The mean ‐ log EC50 values at receptors in the ileum, medial, proximal, and distal colon were 6.74, 6.18, 5.79, and 5.72, respectively.

The apparent dissociation constant for the interaction of histamine with receptors in the various regions was determined.

The ‐ log Kd values at receptors in the ileum, proximal colon, medial colon, and distal colon were 4.68, 4.65, 4.62, and 4.44, respectively.

The mean apparent ‐ log Kd values for the antagonism of histamine by mepyramine were 9.0, 9.0, 9.1, and 8.9 for receptors on the ileum, proximal, medial, and distal colon, respectively.

The results of these experiments provide no evidence that histamine receptors in the colon are distinguishable from H1‐preceptors as characterized on the ileum.

The differences in sensitivity to histamine in the various regions of the intestine may be due to differences in the density of H1‐preceptors.
Actions of dihydroavermectin B1α on insect muscle
Authors: Duce I.R. , Scott R.H.
Published: July 2012

Muscle bundle 33 of the locust (Schistocerca gregaria) extensor tibiae muscle, which is sensitive to γ‐aminobutyric acid (GABA) and receives inhibitory innervation, exhibited both reversible and irreversible responses to dihydroavermectin B1α (DHAVM). These responses involved increases in Cl− permeability.

DHAVM (0.000075‐0.0075 μg ml−1) induced reversible dose‐dependent increases in Cl− permeability and partially blocked GABA‐induced Cl− conductance. These effects appear to be due to an interaction of DHAVM with the GABA receptor‐Cl− ion channel complex.

DHAVM (0.01‐1.0 μg ml−1) induced an irreversible increase in Cl− conductance which continued to rise after DHAVM application was stopped. At these concentrations DHAVM potentiated GABA‐induced Cl− conductances which were in turn reduced by microperfusion of DHAVM (0.01‐1.0 μg ml−1) during bath application of GABA.

DHAVM (0.0001‐1.0 μg ml−1) induced only irreversible increases in Cl− conductance when applied to fast muscle bundles (21–26) of the locust extensor tibiae muscle, which are GABA‐insensitive and have no inhibitory innervation.

The actions of DHAVM on locust muscle appear to involve more than one site. Reversible actions of DHAVM appear to be related to GABA sensitivity and may involve the GABA receptor‐ionophore complex. This is unlikely to be the site of action for the irreversible increases in Cl− conductance caused by DHAVM.
The relative potencies of some agonists at M2 muscarinic receptors in guinea‐pig ileum, atria and bronchi
Authors: Barlow R.B. , Weston‐Smith Penelope
Published: July 2012

The effects of some agonists on isolated preparations of guinea‐pig ileum, atria and bronchial muscle have been compared with those of carbachol. The concentrations producing comparable responses were used to estimate the equipotent molar ratio relative to carbachol.

Arecaidine propargyl ester was 4 to 5 times as active as carbachol on the ileum but more than 10 times as active as carbachol on atrial rate or atrial force, so the results confirm that this compound has a 2 to 3 fold selectivity for receptors in atria.

Ethoxyethyltrimethylammonium iodide was one‐quarter to one‐third as active as carbachol on ileum but only one‐tenth as active as carbachol on atrial rate or atrial force and so shows a 3 to 4 fold selectivity for receptors in ileum.

The other compounds tested, which included acetylcholine, methacholine, n‐pentyltrimethyl‐ammonium iodide and bethanechol showed less selectivity.

There were no obvious differences between effects on atrial rate and effects on atrial force, though with esters it was often difficult to obtain effects on atrial rate in the absence of an inhibitor of cholinesterase.

Activity on bronchial muscle was generally similar to activity on ileum.
Selective effects of thiol reagents on the binding sites for imipramine and neurotransmitter amines in the rat brain
Authors: Biassoni Roberto , Vaccari Andrea
Published: July 2012

The action of the antithyroid drugs methimazole (MMI) and propylthiouracyl (PTU) on the binding of [3H]‐imipramine, [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) (to 5‐HT1‐receptors) and [3H]‐spiperone (to 5‐HT2‐, D2‐receptors) of rat brain membranes has been examined. The synaptosomal uptake of [3H]‐5‐HT was also studied.

Micromolar concentrations of the disulphide bond reducing agents MMI, PTU, dithiothreitol (DTT) and mercaptoethanol increased both the binding of [3H]‐imipramine and the uptake of [3H]‐5‐HT. In contrast, they decreased the number of 5‐HT1‐receptors, and did not affect 5‐HT2‐ and D2‐sites.

Reaction with membrane‐bound sulphydryl (SH) groups by micromolar concentrations of N‐ethylmaleimide (NEM), hydroxymercuribenzoic acid (PCMB), or Ellman's reagent (DTNB) decreased the binding of [3H]‐imipramine, the number of 5‐HT1‐receptors, and the uptake of [3H]‐5‐HT. Millimolar concentrations of NEM were necessary in order to decrease partially 5‐HT2‐ and D2‐receptors.

The effects of NEM on imipramine recognition sites and on the uptake of 5‐HT could be prevented by DTT; protection was not obtained in other receptor systems.

Three groups of receptors have been, thus, postulated, based upon their different sensitivity towards alterations in membrane [disulphide bridges SH] equilibrium: Group I, including imipramine recognition sites and the uptake system for 5‐HT; Group II, including 5‐HT]‐receptors; Group III, including 5‐HT2‐ and D2‐receptors.