Muscle myocardial activity

As discussed in the previous section, all the effects of the ANS in tissues and organs throughout the body, including smooth muscle contraction or relaxation alteration of myocardial activity and increased or decreased glandular secretion, are carried out by only three substances acetylcholine, norepinephrine, and epinephrine. Furthermore, each of these substances may stimulate activity in some tissues and inhibit activity in others. How can this... 

Vasoactive intestinal peptide, VIP an octacosa-peptide from porcine small intestine, which causes va-sodlation, lowers arterial blood pressure, increases cardiac output, enhances myocardial activity, increases glycogenolysis and relaxes the smooth muscle of trachea, stomach and gall bladder. For structure, see Secretin. 

The skeletal muscle relaxants are contraindicated in patients with known hypersensitivity. Baclofen is contraindicated in skeletal muscle spasms caused by rheumatic disorders. Carisoprodol is contraindicated in patients with a known hypersensitivity to meprobamate. Cyclobenzaprine is contraindicated in patients with a recent myocardial infarction, cardiac conduction disorders, and hyperthyroidism, hi addition, cyclobenzaprine is contraindicated within 14 days of the administration of a monoamine oxidase inhibitor. Oral dantrolene is contraindicated in patients with active hepatic disease and muscle spasm caused by rheumatic disorders and during lactation. See Chapter 30 for information on diazepam. 

CR is distributed in various organs with highest concentrations in skeletal muscle, myocardium, and brain and lesser amounts in the gastrointestinal tract, uterus, urinary bladder, and kidney ( ). The CR content of liver and red blood cells is negligible so that diseases of these tissues are unlikely to increase the serum CR activity. The serum CR level begins to increase in 2-4 hours after myocardial infarction and reaches a peak in 24-36 hours and returns to normal in about 3 days. 

The enzyme responsible for this topping-up ATP in active muscle is CK. CK is found in high concentration in muscle cells, both free within the sarcoplasm and also associated with membranes of mitochondria and the sarcoplasmic reticulum. Structurally, creatine kinase is a dimeric enzyme of B and/or M subunits, each of about 40 kDa. Three quaternary structure isoenzyme forms arise CK-MM, CK-BB and CK-MB. The predominant form in all muscles is CK-MM, but cardiac muscle also contains a significant amount of CK-MB and this isoenzyme can be used as a specific marker of myocardial damage (see Case Notes at the end of this chapter). 

Molsidomine (8.159, Fig. 8.18), a very special example of a carbamate prodrug that acts by vascular smooth muscle relaxation, is an anti-angina agent effective mainly in the treatment of myocardial ischemia [207], Molsidomine undergoes enzymatic hydrolysis in the liver to form the imine 8.160 (Fig. 8.18) [208]. This metabolite is inactive and unstable, breaking down spontaneously to the A-nitroso secondary metabolite known as Sinl A (8.161, Fig. 8.18). The latter was found to be active, but there are reasons to believe that it acts by releasing nitrogen monoxide in the form of nitroxyl (HNO), which dissociates to the nitroxide ion NO, i. e., the reduced form of NO. 

More recent studies continue to support the unique antifibrillatory activity of bretylium. Kowey et al. [38] have shown that bretylium prevented spontaneous VF and decreased the effects on VF threshold in a feline myocardial infarction model. They attributed this beneficial effect to a decrease in the dispersion of refractoriness between normal and ischaemic regions of the heart. In contrast, clofilium (14, see below), which had little effect on dispersion of refractoriness after coronary occlusion, was unable to prevent spontaneous VF. Similar results were seen in isolated tissue studies with canine subendocardial Purkinje fibres and ventricular muscle which contained both normal and ischaemic regions [39]. In these studies bretylium caused a smaller increase in dispersion of refractoriness in subendocardial Purkinje fibres than either sotalol or clofilium. In ventricular muscle tissue, bretylium decreased dispersion while sotalol and clofilium increased dispersion of refractoriness. 

Congestive heart failure In myocardial insufficiency, the heart depends on a tonic sympathetic drive to maintain adequate cardiac output. Sympathetic activation gives rise to an increase in heart rate and systolic muscle tension, enabling cardiac output to be restored to a level comparable to that in a healthy subject. When sympathetic drive is eliminated during p-receptor blockade, stroke volume and cardiac rate decline, a latent myocardial insufficiency is unmasked, and overt insufficiency is exacerbated (A). 

Mechanism of Action A cardiac inotropic agent that increases the influx of calcium from extracellular to intracellular cytoplasm. Therapeutic Effect Potentiates the activity of the contractile cardiac muscle fibers and increases the force of myocardial contraction. Slows the heart rate by decreasing conduction through the SA and AV nodes. Pharmacokinetics ... 

Direct effects on the heart are determined largely by Bi receptors, although B2 and to a lesser extent a receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. 

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

The cardiovascular effects of local anesthetics result in part from direct effects of these drugs on the cardiac and smooth muscle membranes and from indirect effects on the autonomic nervous system. As described in Chapter 14, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress myocardial contractility and produce direct arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine have been inadvertently administered into the intravascular space. 

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