Effects on Smooth Muscle

Adenosine has long been known to cause dilatation of coronary blood vessels, and Berne 24, 25) and others 26) have suggested that adenosine produced within the heart might help to regulate coronary blood flow in this way. Thus, factors which reduce myocardial oxygen tension, such as decreased coronary blood flow, hypoxia, or increased myocardial metabolic activity, accelerate adenine nucleotide breakdown and impair resynthesis. The result is formation of adenosine, which interacts with the vascular smooth muscle cells to cause dilatation and consequently increased blood flow, increased oxygen tension, and removal of adenosine. Although Berne proposed that the adenosine is produced in the myocardial cells and reaches the coronary arterioles via the interstitial space, Baer and Drummond 26) have shown that adenylate can be dephosphorylated rapidly by the coronary vasculature itself. 

The duration of coronary dilatation by adenosine is controlled in part by the active adenosine deaminase of the heart, and certain clinically useful vasodilators are believed to act through inhibition of adenosine deamination. Thus dipyridamole (Persantin), or 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine is a smooth muscle relaxant used particularly as a coronary vasodilator it also increases cardiac oxygen consumption. It decreases nucleotide breakdown, causes an accumulation of adenosine in hypoxic heart muscle, and increases blood adenosine concentrations by decreasing its uptake by erythrocytes. Papaverine is also reported to decrease adenosine uptake by erythrocytes, and inhibition of adenosine deamination by ouabain has also been reported. 

Adenine nucleotides also cause smooth muscle to contract, and Daniel and Irwin 27) believe that this is due to their effects on calcium ion movement in and out of the muscle. Whether this is a physiologically significant effect is not clear. 

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It is a powerful antagonist of histamine, antagonizing its effect on smooth muscle of the bronchioles, bladder and partially the intestines and preventing the dilation of capillaries. Promethazine is used in the treatment of allergic reactions. 

P-Adrenoceptors have been subdivided into P - and P2-adrenoceptors. A third subset called nontypical P-adrenoceptors or P -adrenoceptors have been described but are stiU the subject of debate. In terms of the interactions with various subsets of P-adrenoceptors, some antagonists are nonselective in that they antagonize the effects of activation of both P - and P2-adrenoceptors, whereas others are selective for either P - or P2-adrenoceptors. P - and P2-adrenoceptors coexist in almost all organs but generally, one type predominates. The focus herein is on the clinically relevant P -adrenoceptor-mediated effects on heart and on P2-adrenoceptor-mediated effects on smooth muscles of blood vessels and bronchioles, the insulin-secreting tissue of the pancreas, and skeletal muscle glycogenolysis for side effects profile (36). 

Reseaich in physiology caiiied out in the 1930s established that the lipid fraction of semen contains small fflnounts of substances that exert powerful effects on smooth muscle. Sheep prostate glands proved to be a convenient source of this material and yielded a mixture of structurally related substances refened to collectively as prostaglandins. We now know that prostaglandins are present in almost all animal tissues, where they cany out a variety of regulatory functions. 

Natriuretic peptides are a family of peptide hormones. All of them contain a 17-amino acid long ring that is closed by a disulfide bond between two cysteine residues. ANP (atrial natriuretic peptide) is mainly expressed in the atria of the heart, whereas BNP (B-type natriuretic peptide) is synthesized in the ventricular myocardium. CNP occurs mainly in the endothelium and is thought to have a paracrine function. ANF and BNF lower blood pressure by a direct effect on smooth muscle and on the salt retention in the kidney. Natriuretic peptides bind and activate particulate guanylyl cyclases. 

A large number of diugs interfere with the smooth muscle contraction. These compounds lower blood pressure and are referred to as antihypertensive. In this section, only those coumpounds will be mentioned that have a direct effect on smooth muscle tone. Phenylephrine is an agonist on most smooth muscles and activates ax adrenoceptors. Carbachol is an agonist on some smooth muscles and activates contraction through muscarinic receptors. Blockers of the ax-adrenoceptors such as prazosin and urapidil are competitive inhibitors of the ax-receptor in vascular and bladder smooth muscle. Phenoxybenzamine is an ineversible blocker of ax receptors and phentol-amine blocks ax and a2 receptors. Ca2+ channel blockers such as the dihydropyiidines, phenylalkyla-mines and benzothiazepines lower smooth muscle tone by blocking the L-type calcium channel. 

Evidence from a number of systems suggests that ion flux plays a role in palytoxin action. In a wide range of systems, palytoxin effects are accompanied by a change in intracellular cation levels. For example, the influx of Na and/or Ca is associated with palytoxin-stimulated contraction of cardiac and smooth muscle, the release of norepinephrine by rat pheochromocytoma (PC12) cells, and the depolarization of excitable membranes 12—15). Palytoxin also induces K efflux from erythrocytes and thus alters ion flux in a nonexcitable membrane system as well 16-19). In both excitable and nonexcitable membranes, the ultimate action of palytoxin has been shown to be dependent on extracellular cations. The palytoxin-induced effects on smooth muscle and erythroctyes can be inhibited by removing Ca from the media, and the palytoxin-induced release of norephinephrine from PC12 cells can be blocked in Na" free media (ii, 14y 18, 20, 21)... 

Patients with variant (Prinzmetal s) angina or cocaine-induced ACS may benefit from calcium channel blockers as initial therapy because they can reverse coronary vasospasm. /J-Blockers generally should be avoided in these situations because they may worsen vasospasm through an unopposed /T-blocking effect on smooth muscle. 

Sildenafil was developed. However, there are different types of PDEs (nine are known today). As discussed previously, a potent drug has to be specific. Sildenafil inhibits PDE-5, which is absent in the kidney, although sildenafil s effect on smooth muscle relaxation was confirmed. The direction of the drug changed to treating angina instead, as sildenafil relaxes the vascular muscle of the heart. 

Smooth muscle effects. The opposing effects on smooth muscle (A) of a-and p-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). ai-Receptor stimulation leads to intracellular release of Ca + via activation of the inositol tris-phosphate (IP3) pathway. In concert with the protein calmodulin, Ca + can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin. cAMP inhibits activation of myosin kinase. Via the former effector pathway, stimulation of a-receptors results in vasoconstriction via the latter, P2-receptors mediate vasodilation, particularly in skeletal muscle - an effect that has little therapeutic use. 

Histamine also acts on extravascular smooth muscles to cause contraction or relaxation. Most often, contraction is due to activation of Hj receptors and relaxation to activation of H2 receptors (32). In man, histamine causes contraction of bronchial and intestinal smooth muscles. Histamine-induced contraction of guinea pig ileum is a standard bioassay for histamine. Its effects on smooth muscle of the eye and genitourinary tract are important in some species but not in human ( ). In scombroid poisoning cases. 

Trihexyphenidyl, an antiparkinsonian drug, possesses central and peripheral anticholinergic actions, as well as a direct relaxant effect on smooth muscle. It reduces muscle rigidity and general stiffness, and has a relatively minor effect on tremors. It is used in Parkinsonism in the form of monotherapy as well as in combination with levodopa. The most common synonyms are parkopan, parkinsan, and cyclodol. 

In particular, postsynaptic Oi-blockers act on the o-receptive regions located on the smooth muscle of blood vessels and counteract the pressor, vasoconstricting effect of epinephrine and norepinephrine. In addition, they exhibit a direct relaxant effect on smooth muscle, which leads to peripheral dilation of blood vessels, which in turn raises blood pressure. However, they also exhibit a cardiostimulatory effect, which is frequently a cause of tachycardia. 

Phentolamine is also a derivative of imidazoline that exhibits a direct a-adrenoblocking, muscle-relaxant effect on smooth muscle as well as cholinomimetic, histamine, and sympathomimetic effects. The chemical variation of its stmcture permits a few of its properties to be more expressed. For example, the aforementioned tolazoline, 2-benzyl-2-imidazoline, a structural analog of phentolamine, has more of an expressed muscle-relaxant effect on smooth muscle than an a-adrenoblocking effect. 

Pharmacology Oxybutynin exerts direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. 

Methylxanthines have a number of other effects, including effects on smooth muscles and the cardiovascular system. The most notable effect on smooth muscles is relaxing the bronchi of the lungs. Theophylline is prescribed to treat mild forms of asthma. While both caffeine and theophylline will relax the bronchial smooth muscles, theophylline is used therapeutically because of its longer half-life. This allows the drug to stay in the therapeutic range longer. 

Mechanism of Action An anticholinergic agent that exerts an atropine-like action and produces an antispasmodic effect on smooth muscle, is a potent mydriatic, and inhibits salivation. Therapeutic Effect Relieves symptoms of Parkinson s disease and drug-induced extrapyramidal symptoms. 

Sildenafil It is orally active selective inhibitor of phosphodiesterase type 5 useful in treatment of erectile dysfunction. It results in reduced breakdown of cyclic guanosine monophosphate (cGMP) which is responsible for nitric acid (NO) mediated vasodilatation in corpora cavernosa. Thus inducing an erectile response to sexual stimulation. It has no direct relaxant effect on smooth muscle of corpus cavernosa and has no effect in absence of sexual stimulation. 

Effect on smooth muscles Acetylcholine causes increase in tone, amplitude of contractions, peristalsis and secretory activity of the gastrointestinal tract. It causes contraction of smooth muscles of gall bladder and relaxation of sphincters of gastrointestinal and biliary tract. 

Verapamil causes peripheral vasodilation, which may be beneficial in hypertension and peripheral vasospastic disorders. Its effects on smooth muscle produce a number of extracardiac effects (see Chapter 12). 

Diphenhydramine Competitive antagonism at Hi receptors Reduces or prevents histamine effects on smooth muscle, immune cells also blocks muscarinic and adrenoceptors highly sedative IgE immediate allergies, especially hay fever, urticaria some use as a sedative, antiemetic, and antimotion sickness drug Oral and parenteral t duration 4-6 h Toxicity Sedation when used in hay fever, muscarinic blockade symptoms, orthostatic hypotension Interactions Additive sedation with other sedatives, including alcohol some inhibition of CYP2D6, may prolong action of some 13 blockers... 

Nelumbium nuciferum Gaertner N. speclosum Willd. Lian, He Ye (East Indian lotus) (leaf) Nuciferine, roemerine, anonaine, O-nornuciferine, liriodenine, anneparine, dihydronuciferine, pronuciferine, N-methylcoclaurine, N-methylisococlaurine.33 Relaxing effect on smooth muscles, increase essential body energies. 

In 1930, substance P (SP) was discovered by von Euler and Gaddum as an unidentified substance - referred to as P on tracings and protocols - present in alcoholic extracts of equine brain and intestine (von Euler and Gaddum, 1931). The early experiments were mostly concerned with its stimulating effect on smooth muscle and its vasodilator properties, later interest focussed on its role as a... 

Tertiary amines used for their antispasmodic properties are dicyclomine hydrochloride (Ben-tyl, others), oxyphencyclimine hydrochloride (daricon), flavoxate hydrochloride (Uripas), and oxyburynin chloride (Ditropan). The latter two are indicated specifically for urological disorders. These agents appear to exert some nonspecific direct relaxant effect on smooth muscle. In therapeutic doses they decrease spasm of the gastrointestinal tract, biliary tract, ureter, and uterus characteristic atropine-like effects on the salivary glands and the eye also are seen with oxybutynin. 

In general, ephedrine produces the same effects on smooth muscle as epinephrine. Inhibition of the intact gastrointestinal musculature and contraction of the splenic capsule and of pilomotor muscles are produced. Ephedrine has the same myometrial and urinary bladder actions as does epinephrine. 

Papaverine, because of its general depressant effect on smooth muscle, has been used in doses of 30 to 60 mg, subcutaneously and intravenously, in peripheral thrombosis and embolism, acute myocardial infarction, angina pectoris, bronchial asthma, renal and biliary colic, and other conditions in which relaxation of smooth muscle is desired. However, the therapeutic effectiveness of papaverine is questionable, and there is no established indication for its use. 

Narcotine was isolated by Derosne (592) and Robiquet (593) from opium. It has a mild antitussic and a relaxant effect on smooth muscles (similar to those of papaverine). The relaxant effect is about ten times smaller than that of papaverine (594-597). LaBarre and Plisnier (598, 599) found that narcotine is a better antitussic than codeine. j8-Narcotine proved to be much more effective than a-narcotine (600) the effect of the N-oxides of the two isomers was more marked than that of the base. /3-Narcotine N-oxide was much more effective than dihydrocodeine. Those substances did not increase the analgesic effect of morphine. Contrary to codeine they did not cause obstipation (601). The therapeutic dose of the hydrochloride is 25-50 mg three times daily for adults and 25 mg three times daily per os for children. For the effect of narcotine upon the cough reflex and upon the bronchial muscle, see (602-613). 

J. Jozefonvicz. 1996. Conjugates of insulin with copolymers of N-(2-hydroxypropyl) methacrylamide effects on smooth muscle cell proliferation. J. Biomed. Mater-Res. 31 265-272. 

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