Peripheral localization

Cannabinoids and their synthetic and endogenous analogs are best known for their prominent psychoactive properties, but their cardiovascular effects were also recognized as early as the 1960s. The most important component of these effects is a profound decrease in arterial blood pressure, cardiac contractility, and heart rate (Lake et al. 1997a,b Hillard 2000 Kunos et al. 2000,2002 Randall et al. 2002 Ralevic et al. 2002 Hiley and Ford 2004). Although several lines of evidence indicate that the cardiovascular depressive effects of cannabinoids are mediated by peripherally localized CBi receptors, cannabinoids can also elicit vascular and cardiac effects, which are independent of CBi and CB2 receptors, as discussed in detail later in this chapter. 

Nu, peripherally local Nusselt number in the fully developed region for a given boundary condition... 

Figure 24.2 Epi-fluorescence micrographs demonstrating the distribution of actin filaments in (a) racket-like and (b) disk-like DMPC-CL vesicles only front views are shown. The actin encapsulated in these vesicles had been labeled with tetramethylrhodamine maleimide. The peripheral localization of actin within both types of the vesicles is evident (bar length 10 pm), (c) Schematic drawings of the mode of actin filaments inside the racket-like (left) and the disklike (right) vesicles. Actin filaments reside in the shaded area the lines in the area represent actin filaments, the alignment of which had been deduced from polarization microscopy.

CGRP is widely distributed throughout the peripheral and central nervous systems and is found ia sensory neurons and ia the autonomic and enteric nervous systems. In many iastances CGRP is co-localized with other neuroregulators, eg, ACh ia motor neurons, substance P, somatostatin, vasoactive intestinal polypeptide (VIP), and galanin ia sensory neurons. It is also present ia the CNS, with ACh ia the parabigeminal nucleus and with cholecystokinin (CCK) ia the dorsal parabrachial area. CGRP functions as a neuromodulator or co-transmitter. 

As a neurotransmitter in the sensory nervous system, high levels of substance P are found in the dorsal horn of the spinal cord as well as in peripheral sensory nerve terminals. However, substance P also plays a significant role as a neuromodulator in the central, sympathetic, and enteric nervous system. NKA and NKB are also localized selectively in the CNS. 

Lidocaine hydrochloride [73-78-9] (Xylocaine), is the most versatile local anesthetic agent because of its moderate potency and duration of action, rapid onset, topical activity, and low toxicity. Its main indications are for infiltration, peripheral nerve blocks, extradural anesthesia, and in spinal anesthesia where a duration of 30 to 60 min is desirable. Because of its vasodilator activity, addition of the vasoconstrictor, epinephrine, increases the duration of action of Hdocaine markedly. It is also available in ointment or aerosol preparations for a variety of topical appHcations. 

Benzonatate [104-31 ] (46) is a unique compound which appears to have both central and peripheral antitussive effects. Stmcturally it is a derivative of ji)-aminoben2oic acid and contains a long poly(ethylene glycol) side chain. The peripheral effects ate the result of local anesthetic action on the pulmonary stretch receptors. Clinical activity was first reported in 1955 (65). 

Oxolamine [959-14-8] (57) is sold in Europe. It is an oxadiazole, and its general pharmacological profile is described (81). The compound possesses analgesic, antiinflammatory, local anesthetic, and antispasmodic properties, in addition to its antitussive activity. Although a central mechanism may account for some of the activity, peripheral inhibition of the cough reflex may be the dominant effect. The compound has been shown to be clinically effective, although it is less active than codeine (82,83). The synthesis of oxolamine is described (84). 

In 1998, the FDA approved fibrin sealant for three specific indications. These include hemostasis at the time of cardiac surgical operations [8] (Fig. 2) as well as at the time of operative procedures to treat splenic trauma. The application of the fibrin sealant which consists of normal biologic components in the body s clotting cascade creates a localized clot which further enhances inherent clotting ability. Although approved for these specific hemostatic indications only, fibrin sealant is useful as a hemostat in a wide variety of off-label clinical situations as well [9,10]. These include such applications as hemostasis for liver trauma or resection [11], vascular anastomoses [12], tonsillectomy [13], peripheral joint replacement [14], dental extractions [15], and bum debridement [16]. 

C-fibre afferents from the aitways contain peptide tachykinin transmitters such as substance P (SP) and neurokinins A and B (NKA and NKB). Stimulation of these nerves can also cause local release of these mediators at their peripheral terminal, allowing them to enhance the activity of the RARs. SP, NKA and NKB act at the tachykinin receptors (NK4-NK3), and so understandably, antagonists for NK2 in particular appear promising in cough. 

The surrounding redness caused by the vasodilatation of local blood vessels in the skin (hyperaemia). Histamine released at the site of contact acts on sensory nerve endings in the skin. Impluses travel along the axon to other peripheral branches of the same neuron to cause release of vasodilataory peptide neurotransmitters from nerve endings serving a wider area of skin than the initial contact point. Impluses reaching the CNS are interpreted as itch and pain. 

Local anaesthetics are drugs that reversibly interrupt impulse propagation in peripheral nerves thus leading to autonomic nervous system blockade, analgesia, anaesthesia and motor blockade in a desired area of the organism. 

The amide local anaesthetic lidocaine may also be used as an antianhythmic for ventricular tachycardia and exra-systoles after injection into the blood circulation. Drugs with high lipid solubility such as bupivacaine cannot be used for these purposes because their prolonged binding to the channel may induce dysrhythmias or asystolic heart failure [3]. Systemically applied lidocaine has also been used successfully in some cases of neuropathic pain syndromes [4]. Here, electrical activity in the peripheral nervous system is reduced by used-dependent but incomplete sodium channel blockade. 

Neuromedin U is a neuropeptide which is widely distributed in the gut and central nervous system. Peripheral activities of neuromedin U include stimulation of smooth muscle, increase in blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. The actions of neuromedin U are mediated by G-protein coupled receptors (NMU1, NMU2) which are coupled tO Gq/11. 

NK3rs are preferentially expressed in the CNS. At the peripheral level, NK3rs have been localized in the enteric nervous system, nerve terminals, and autonomic ganglia, but also on other tissues. At the peripheral level, it remains to be explained the mismatch between NK3r expression and the apparent lack of expression of NKB there are, however, physiological conditions... 

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