Calcium channel cardiac

Nifedipine Block vascular calcium channels > cardiac calcium channels Reduce vascular resistance Hypertension See Chapter 12... 

Nifedipine (a dihydropyridine) Block of vascular L-type calcium channels > cardiac channels Like verapamil and diltiazem less cardiac effect Prophylaxis of angina, hypertension Oral, duration 4-6 h Toxicity Excessive hypotension Interactions Additive with other vasodilators... 

Activation Atrial preparation Biophysics Calcium channel Cardiac action potential Channel kinetics Comprehensive in vitro proarrhythmia assay Delayed rectifier Early afterdepolarisation ECG Hodgkin-Huxley ICHS7A ICHS7B In silico modelling Inactivation Inward rectifier Langendorff heart Purkinje fibre Safety assessment Sodium channel Stem cells... 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

ACE inhibitors can be administered with diuretics (qv), cardiac glycosides, -adrenoceptor blockers, and calcium channel blockers. Clinical trials indicate they are generally free from serious side effects. The effectiveness of enalapril, another ACE inhibitor, in preventing patient mortaUty in severe (Class IV) heart failure was investigated. In combination with conventional dmgs such as vasodilators and diuretics, a 40% reduction in mortaUty was observed after six months of treatment using 2.5—40 mg/d of enalapril (141). However, patients complain of cough, and occasionally rash and taste disturbances can occur. 

Some metals, such as cadmium, cobalt, and lead, are selectively car-diotoxic. They depress contractivity and slow down conduction in the cardiac-system. They may also cause morphological alterations, e.g., cobalt, which was once used to prevent excessive foam formation in beers, caused cardiomyopathy among heavy beer drinkers. Some of the metals also block ion channels in myocytes. Manganese and nickel block calcium channels, whereas barium is a strong inducer of cardiac arrhythmia. 

The trigger for all musele eontraetion is an increase in Ca eoneentration in the vicinity of the muscle fibers of skeletal muscle or the myocytes of cardiac and smooth muscle. In all these cases, this increase in Ca is due to the flow of Ca through calcium channels (Figure 17.24). A muscle contraction ends when the Ca concentration is reduced by specific calcium pumps (such as the SR Ca -ATPase, Chapter 10). The sarcoplasmic reticulum, t-tubule, and sarcolemmal membranes all contain Ca channels. As we shall see, the Ca channels of the SR function together with the t-tubules in a remarkable coupled process. 

Stimulation of mAChRs also results in the activation or inhibition of a large number of ion channels [5]. For example, stimulation of Mi receptors leads to the suppression of the so-called M current, a voltage-dependent Recurrent found in various neuronal tissues. M2 receptors, on the other hand, mediate the opening of cardiac Ikcacii) channels, and both M2 and M4 receptors are linked to the inhibition of voltage-sensitive calcium channels [5]. 

Systemic and coronary arteries are influenced by movement of calcium across cell membranes of vascular smooth muscle. The contractions of cardiac and vascular smooth muscle depend on movement of extracellular calcium ions into these walls through specific ion channels. Calcium channel blockers, such as amlodipine (Norvasc), diltiazem (Cardizem), nicardipine (Cardene), nifedipine (Procardia), and verapamil (Calan), inhibit die movement of calcium ions across cell membranes. This results in less calcium available for the transmission of nerve impulses (Fig. 41-1). This drug action of the calcium channel blockers (also known as slow channel blockers) has several effects on die heart, including an effect on die smooth muscle of arteries and arterioles. These drug dilate coronary arteries and arterioles, which in turn deliver more oxygen to cardiac muscle. Dilation of peripheral arteries reduces die workload of die heart. The end effect of these drug is the same as that of die nitrates. 

Other drugs such as the neuroleptic, haloperidol, inhibit the induction of hsp70 mRNA in rodent neurons (Sharp et al.. 1992). Although this observation needs to be confirmed in the human population, it raises the possibility that an age-dependent defect in the production of HS proteins is exacerbated by a drug which is commonly used in demented elderly patients. The potential for certain pharmacologic agents to inhibit the HS response could increase the risk for untoward effects of atherosclerosis and hypoxia. A similar concern may be raised with certain calcium channel blockers which also have been found to reduce the synthesis of HS proteins in cardiac myocytes (Low-Friedrich and Schoeppe, 1991). 

Low-Friedrich, I. Schoeppe, W. (1991). Effects of calcium channel blockers on stress protein synthesis in cardiac myocytes. J. Cardiovasc. Pharmacol. 17,800-806. 

Chymostatin-sensitive Il-generating enzyme Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Trial Collaborative Study Captopril Trial ( The Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy ) calcium channel blocking agents Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality Trial congestive heart failure, but the latest recommendations use HF for heart failure chronic kidney disease cardiac output... 

The P-blockers propranolol and timolol are FDA-approved for migraine prophylaxis, but other drugs in the class are also as effective.46 Cautious dosage titration is advised for those patients who do not have other indications for P-blocker use. Rizatriptan interacts with propranolol and thus dosages must be titrated downward, or another triptan chosen for abortive therapy.36 Comorbid reactive airway disease is a relative contraindication to P-blocker prophylaxis, and patients with cardiac conduction disturbances should be closely monitored. Calcium channel antagonists are often used when patients cannot tolerate P-blockers. They are purported to beneficially... 

Mason, R. R Campbell, S. F. Wang, S.-D. Herbette, L. G., Comparison of location and binding for the positively charged 1,4-dihydropyridine calcium channel antagonist amlopidine with uncharged drugs of this class in cardiac membranes, Molec. Pharmacol. 36, 634—640 (1989). 

The effect of stimulation of cardiac adrenoceptors is even more leisurely because several more steps follow activation of the Gs protein by the p-adrenoceptor. For example, to increase the force of cardiac contraction, we have (1) activation of adenylate cyclase by Gas-GTP, (2) formation of cAMP, (3) activation of protein kinase A by the cAMP, then (4) phosphorylation of the calcium channel protein by the kinase. As a result, it takes about 5 to 6 sec from the time the receptors are... 

Kitazawa T, Kobayashi S, Horiuti K, Somlyo AV, Somlyo AP 1989 Receptor coupled, permeabilized smooth muscle role of the phosphatidylinositol cascade, G proteins and modulation of the contractile response to Ca2+. J Biol Chem 264 5339-5342 Lopez-Lopez JR, Shacklock PS, Balke CW, Wier WG 1995 Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science 268 1042-1045 Marks AR, Fleischer S, Tempst P 1990 Surface topography analysis of the ryanodine receptor/ junctional channel complex based on proteolysis sensitivity mapping. J Biol Chem 265 13143-13149... 

Los s-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation, 115, 442-449. 

Verapamil and venous pressure, reduces cardiac load Calcium channel blocker, relaxes vascular smooth muscle... 

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