The α-adrenoceptor-mediated actions of chloroethylclonidine

• 1.1. Chloroethylclonidine (CEC) has an affinity for all 6 subtypes of α-adrenoceptor, but binds irreversibly particularly to α_1B-, α_1D-, α_2C-, and α_2A/D-adrenoceptors.
• 2.2. Functionally, CEC behaves as an irreversible α₁-adrenoceptor antagonist, reducing the maximum response to noradrenaline (NA), and shows subtype selectivity in that α_1A-adrenoceptors are relatively insensitive to CEC. CEC also behaves as an irreversible α₂-adrenoceptor agonist, both prejunctionally in the rat vas deferens and postjunctionally in the dog saphenous vein.
• 3.3. In the rat aorta, CEC does not produce direct contractions, but following exposure to CEC concentrations of NA of 10 μM and above produce contractions resistant to α_1- and α₂-adrenoceptor blockade. We have investigated this phenomenon in detail.
• 4.4. Receptor protection experiments were carried out in the rat aorta, in which the protecting agent was present prior to and during exposure to CEC. The component of the contraction to NA resistant to α-blockade was still present following receptor protection with the α₁-adrenoceptor antagonist prazosin, but absent following receptor protection with NA and reduced following receptor protection with α₂-adrenoceptor antagonists. The resistant response may represent an irreversible agonist interaction between CEC, NA, and normally silent α₂-adrenoceptors, that cannot be affected by subsequent competitive antagonism, but that can be prevented by receptor protection with the agonist NA prior to CEC.
• 5.5. CEC has two major classes of action at α-adrenoceptors: irreversible antagonism at α₁-adrenoceptors, and irreversible agonism at α₂-adrenoceptors. Both actions can be demonstrated in the rat aorta.

     

Stimulant actions of Δ 9-Tetrahydrocannabinol in mice

⁹-Tetrahydrocannabinol (THC) augments the locomotor activity produced by methamphetamine (0.5 mg/kg) in aggregated mice. THC-induced augmentation was dose related and lasted for a two-hour period. Maximal effective dosage of THC was 15 mg/kg with higher dosages of 30 and 60 mg/kg producing a decrease from maximum in locomotor activity. THC, 15 mg/kg, also increases locomotor activity among aggregated animals treated with saline. However, the increase was much less than the methamphetamine augmentation. In similar studies using isolated mice THC produced only a dose-related decrease in locomotor activity among both methamphetamine-treated and saline-treated animals. THC, 60 mg/kg, had no effect on methamphetamine-induced lethality in aggregated mice. However, at 15 mg/kg, THC significantly enhanced the lethality of methamphetamine. THC did not after methamphetamine lethality in isolated mice. Distribution studies using ¹⁴C-methamphetamine indicated that neither THC nor isolation of animals affected tissue concentration or disappearance of ¹⁴C material. Previously reported synergistic interaction between amphetamine and THC is related to aggregation of the animals rather than drug treatment. Since THC at low doses can stimulate motor activity in saline-treated animals, amphetamine may act only to amplify the behavioral activity produced by low doses of THC.     

Mechanisms underlying the vasoconstrictor actions of prostaglandins E

AIM: To investigate the cellular,mechanisms wherebyprostaglandin E_2 and other EP_3-receptor agonists (eg Sulprostone )contract vascular smooth muscle. METHODS: Isometrictension was recorded from ring preparations of guinea pig aorta.rabbit renal artery and human intrapulmonary artery in the presenceof indomethacin 1 μmol·L~(-1). RESULTS: On all threeprepartions the maximal contractile response to sulprostone (EC_50)=10-25 nmol·L~(-1) ) was less (40％. 7％.60％ ) than thatof U-46619 (TP agonist) or phenylephrine. Contractions werealmost abolished by removal of Ca~(2 ) from the bathing f1uid and byCd~(2 ) (500 μmol·L~(-1) ). but were usually unaffected by L-typeCa~(2 ) channel blockers and by PKC inhibitors (calphostin C.     

Participation of opioid system in acupuncture actions on immunosuppression by morphine and trauma

Acupuncture therapy is an effective method in traditional Chinese medicine. Substantial studies have shown that acupuncture can ameliorate a diverse collection of ailments that     

Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key?

Agonists of the peroxisome proliferator activated receptor gamma (PPAR(gamma)) are currently used for treatment of type 2 diabetes due to their insulin sensitizing and glucose metabolism stabilizing effects. More recently some of these same agonists were shown to exert anti-inflammatory and anti-proliferative effects as well. Although PPAR(gamma) agonists can operate via receptor-mediated events occurring at the genomic level, thereby causing long lasting changes in gene expression patterns, recent studies demonstrate non-genomic as well as genomic actions, and receptor-dependent as well as receptor-independent effects of the thiazolidinedione (TZD) class of PPAR(gamma) agonists. In this review we will summarize data describing some of these novel, receptor independent actions of TZDs, review evidence that TZDs directly influence mitochondrial function, and attempt to reconcile how changes in mitochondrial function could contribute to other receptor-independent actions of these drugs.     

Multiple actions of β-bungarotoxin on acetylcholine release at amphibian motor nerve terminals

Summary The action of -bungarotoxin (-BuTX) on spontaneous transmitter release, as monitored by miniature endplate potential (MEPP) frequency, and nerve-stimulated release, which relates directly to endplate potential (EPP) amplitude, was studied at frog sciatic nerve-sartorius muscle junctions. Three phases were found for both spontaneous and evoked release: a transient decrease followed by an increase and a later decrease leading to complete failure. The initial inhibitory phase for both spontaneous and neurally-evoked release occurred at the same time and was independent of stimulation frequency. Both the excitatory and late inhibitory phases for both types of release had a more rapid onset when stimulation frequency was increased, with the effects on evoked release occurring more rapidly than the effects on spontaneous release. Even though EPP amplitude decreased to low levels while MEPP frequency was still high, EPPs did not completely fail until the MEPPs had also declined to very low levels. In elevated K⁺ solutions, the number of quanta released after toxin application was only about half that released during the control experiment. During the terminal part of the late inhibitory phase of -BuTX action on MEPP frequency, no effect or only small transient increases were observed after La³⁺ administration, elevated [K⁺]₀, or increased osmotic pressure. The present study suggests that depolarization of nerve terminals by the toxin is responsible for initiation of the excitatory phases of both types of release followed by inhibition of nerve-evoked release, and then depletion of vesicular transmitter accounts for the eventual disappearance of both MEPPs and EPPs.Part of the results were presented at the 7th International Congress of Pharmacology (Paris, July, 1978). Supported by an NIH Biomedical Research Support Grant awarded to the Louisiana State University School of Medicine in New Orleans, USA and by grant NS 07540-9 from the National Institutes of Health.     

Biological actions and molecular effects of resveratrol,pterostilbene, and 3′-hydroxypterostilbene

Stilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and -dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene.     

Critical insights into the beneficial and protective actions of the kallikrein–kinin system

Hypertension is characterized by an imbalance between the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II AT-1 receptor antagonists (also known as sartans or ARBs) are potent modulators of these systems and are highly effective as first-line treatments for hypertension, diabetic nephropathies, and diseases of the brain and coronary arteries. However, these agents are mechanistically distinct and should not be considered interchangeable. In this mini-review, we provide novel insights into the often neglected roles of the KKS in the beneficial, protective, and reparative actions of ACEIs. Indeed, ACEIs are the only antihypertensive drugs that properly reduce the imbalance between the RAS and the KKS, thereby restoring optimal cardiovascular homeostasis and significantly reducing morbidity and the risk of all-cause mortality among individuals affected by hypertension and other cardiovascular diseases.Synopsis and bullet points

• •Hypertension, a disease derived from an imbalance between two endogenous systems, the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS)
• •Effective mediators of these two systems include the octapeptide angiotensin II (Ang II) and the nonapeptide bradykinin (BK)
• •Disease pathology involves an increase in peripheral resistance (↑PVR), an increase in cardiac output (↑CO), hypertrophy of the heart and peripheral vessels, and nephropathies.
• •Preventive measures include a healthy diet, regular exercise, smoking cessation, and limiting salt and alcohol consumption.
• •Rational therapy consists of drugs that aim not only to reduce blood pressure (BP) but also to decrease morbidity and mortality.
• •The goal of therapy is to inhibit the RAS and potentiate the KKS, both of which can be achieved with ACE Inhibitors (ACEIs), thereby restoring optimal cardiovascular homeostasis.

     

Growth hormone secretagogue actions on the pituitary gland: multiple receptors for multiple ligands?

1. Growth hormone (GH) secretion is thought to occur under the reciprocal regulation of two hypothalamic hormones, namely GH-releasing hormone (GHRH) and somatostatin (SRIF), through their engagement with specific cell-surface receptors on the anterior pituitary somatotropes. 2. In addition to GHRH and SRIF, synthetic GH-releasing peptides (GHRP) or GH secretagogue(s) (GHS) regulate GH release through the activation of a novel receptor, the GHS receptor (GHS-R). 3. The cloning of the GHS-R from human, swine and rat identifies a novel G-protein-coupled receptor involved in the control of GH secretion and supports the existence of an undiscovered hormone that may activate this receptor. 4. Varieties of intracellular signalling systems are suggested to mediate the action of GHS, which include changes in intracellular free Ca2+ ([Ca2+]i), cAMP, protein kinases A and C, phospholipase C etc. 5. With regard to the use of signalling systems by GHS, especially a new form of GHRP or GHRP-2, a clear species difference has been demonstrated, supporting the possibility of more than one type of GHS-R.     

Dual vascular actions of cardiotoxin from cobra venom: initial transient relaxation followed by contraction

AIM: To study the mechanisms of action of cardiotoxin(CTX), a basic polypeptides purified from cobra venom, on rat aortic muscle contractility. METHODS: Pharmacological approach of vascular contractility study. RESULTS: CTX (10μmol·L~(-1))-induced transient relax     

Presynaptic actions of 4-Aminopyridine and γ-aminobutyric acid on rat sympathetic ganglia in vitro

Summary Responses to bath-applications of 4-aminopyridine (4-AP) and -aminobutyric acid (GABA) were recorded intracellularly from neurones in the rat isolated superior cervical ganglion.4-aminopyridine (0.1–1.0 mmol/l) usually induced spontaneous action potentials and excitatory postsynaptic potentials (EPSPs), which were blocked by hexamethonium. Membrane potential was unchanged; spike duration was slightly increased. Vagus nerve B-and C-fibre potentials were prolonged.In 4-AP solution (0.1–0.3 mmol/l), GABA (0.1 mmol/l), 3-aminopropanesulphonic acid or muscimol evoked bursts of spikes and EPSPs in addition to a neuronal depolarization. These bursts, which were not elicited by glycine, glutamate, taurine or (±)-baclofen, were completely antagonised by hexamethonium, tetrodotoxin or bicuculline methochloride.It is concluded that: (a) 4-AP has a potent presynaptic action on sympathetic ganglia; (b) presynaptic actions of GABA can be recorded postsynaptically in the presence of 4-AP; and (c) the presynaptic GABA-receptors revealed in this condition are similar to those on the postsynaptic membrane.     

A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse

The effects of morphine and ⁹-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.