Negative chronotropism

Verapamil. Verapamil hydrochloride is a pbenyl alkyl amine and is considered the prototype of the Class I calcium channel blockers. Verapamil is also a potent inhibitor of coronary artery spasm and is useful in Prinzmetal s angina and in unstable angina at rest. Verapamil produces negative chronotropic and inotropic effects. These two actions reduce myocardial oxygen consumption and probably account for the effectiveness of verapamil in chronic stable effort angina (98,99). Moreover, verapamil is an effective antihypertensive agent. 

P-blocker therapy was ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality when compared to diuretics for elderly patients (60 years of age or greater) treated for primary hypertension. Clearly, the effects of P-blockers on blood pressure are complex and difficult to ascribe to one or two mechanisms. Rather, the varied effects of negative chronotropic and inotropic properties along with reduced renin levels (Fig. 2-3) appear to result in an overall reduction in cardiac output and/or reduction in peripheral resistance. 

Closely monitor heart rate in patients treated with drugs that have negative chronotropic effects (e.g., fi-blockers, verapamil, or diltiazem) or drugs that may cause reflex tachycardia (e.g, nitrates or dihydropyridine CCBs). 

Figure 14.1 Effect of autonomic nervous system stimulation on action potentials of the sinoatrial (SA) node. A normal action potential generated by the SA node under resting conditions is represented by the solid line the positive chronotropic effect (increased heart rate) of norepinephrine released from sympathetic nerve fibers is illustrated by the short dashed line and the negative chronotropic effect (decreased heart rate) of acetylcholine released from parasympathetic nerve fibers is illustrated by the long dashed line.

More recently, the clavulones (not specified which ones) [134] were described to have potent effects on the spontaneous beating rate of cultured myocardial cells from fetal mouse hearts. At a concentration of 0.45 pM, clavulone had positive chronotropic action on these cells however, the character of this effect clearly differed from the positive ionotropic and negative chronotropic effects of the steroid glycoside ouabain or the drug Bay K 8644. Hence, these results suggest that the clavulones may possess a new mechanism of action in this assay system. 

The exact hypotensive mechanism of /1-blockers is not known but may involve decreased cardiac output through negative chronotropic and inotropic effects on the heart and inhibition of renin release from the kidney. 

Verapamil and diltiazem cause less peripheral vasodilation than dihydro-pyridines such as nifedipine but greater decreases in AV node conduction. They must be used with caution in patients with preexisting conduction abnormalities or in patients taking other drugs with negative chronotropic properties. 

As with other Class I agents, patients treated with flecainide for atrial flutter have been reported with 1 1 atrioventricular conduction due to slowing the atrial rate. A paradoxical increase in the ventricular rate also may occur in patients with atrial fibrillation who receive flecainide. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication. 

Total coronary blood flow is reduced by the (3-blockers. This effect may be due in part to the unopposed a-receptor-mediated vasoconstriction that follows (3-receptor blockade in the coronary arteries. Additional contributing factors to the decrease in coronary blood flow are the negative chronotropic and inotropic effects produced by the (3-blockers these actions result in a decrease in the amount of blood available for the coronary system. The decrease in mean blood pressure may also contribute to the reduced coronary blood flow. 

Transmembrane action potential of a sinoatrial node cell. In contrast to other cardiac cells, there is no phase 2 or plateau. The threshold potential (TP) is -40 mV. The maximum diastolic potential (MDP) is achieved as a result of a gradual decline in the potassium conductance (gK+). Spontaneous phase 4 or diastolic depolarization permits the cell to achieve the TR thereby initiating an action potential (g = transmembrane ion conductance). Stimulation of pacemaker cells within the sinoatrial node decreases the time required to achieve the TR whereas vagal stimulation and the release of acetylcholine decrease the slope of diastolic depolarization. Thus, the positive and negative chronotropic actions of sympathetic and parasympathetic nerve stimulation can be attributed to the effects of the respective neurotransmitters on ion conductance in pacemaker cells of the sinuatrial node. gNa+ = Na+ conductance. 

Verapamil must be used with extreme caution or not at all in patients who are receiving p-adrenoceptor blocking agents. Normally, the negative chronotropic effect of verapamil will in part be overcome by an increase in reflex sympathetic tone. The latter is be prevented by simultaneous administration of a p-adrenoceptor blocking agent, which exaggerates the depressant effects of... 

C) Inhibition of a GABA-mediated negative chronotropic effect at the heart... 

In the heart, the effects on the parasympathetic limb predominate. Thus, cholinesterase inhibitors such as edrophonium, physostigmine, or neostigmine mimic the effects of vagal nerve activation on the heart. Negative chronotropic, dromotropic, and inotropic effects are produced, and cardiac output falls. The fall in cardiac output is attributable to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility. The latter effect occurs as a result of prejunctional inhibition of norepinephrine release as well as inhibition of postjunctional cellular sympathetic effects. 

Recently, both hirsutine (85) and dihydrocorynantheine (86) were found to be active when the effects of these compounds on the action potentials of sino-atrial node, atrium and ventricle tissues were studied with standard microelectrode techniques [65]. In sino-atrial node preparations, both compounds concentration-dependently increased cycle length, decreased the slope of the pacemaker depolarization, decreased the maximum rate of rise and prolonged action potential duration. Thus, it was for the first time shown that hirsutine and dihydrocorynantheine have direct inhibitory effects on the cardiac pacemaker. In atrial and ventricular preparations, both compounds concentration-dependently decreased the maximum rate of rise and prolonged action potential duration. Although stereochemically different, these two alkaloids exhibited no difference in their effects on various myocardial action potential parameters. Dihydrocorynantheine also displays potent a-adrenoceptor blocking activity, while hirsutine is inactive [66]. Experiments with ion channels indicate that the mechanisms for these two phenomena probably differ. The direct effects of hirsutine and dihydrocorynantheine on the action potential of cardiac muscle through inhibition of multiple ion channels may explain the negative chronotropic and antiarrhythmic activities of these two alkaloids. 

Beta blockers bind to beta-1 receptors on the myocardium and block the effects of norepinephrine and epinephrine (see Chapter 20). These drugs therefore normalize sympathetic stimulation of the heart and help reduce heart rate (negative chronotropic effect) and myocardial contraction force (negative inotropic effect). Beta blockers may also prevent angina by stabilizing cardiac workload, and they may prevent certain arrhythmias by stabilizing heart rate.40 These additional properties can be useful to patients with heart failure who also have other cardiac symptoms. 

In myocardial ischemia, several of the mechanisms presented above come into play. First, neuropeptides such as CGRP are released from cardiac sensory C fibers and subsequently release histamine from mast cells as just mentioned. Histamine then can act at least at two presynaptic H3 heteroreceptors on the C fibers to attenuate further neuropeptide release (Section 3.9), and on postganglionic sympathetic fibers to attenuate exocytotic as well as carrier-mediated noradrenaline release (Section 3.3). Both presynaptic effects are potentially beneficial. The H3 receptors are unique in this pattern of effects. Presynaptic adenosine Ai receptors, when activated, also inhibit both exocytotic and carrier-mediated noradrenaline release, but cardiac Ai receptors in addition mediate negative chronotropic and dro-motropic effects. Presynaptic 0C2-adrenoceptors, when activated, reduce exocytotic noradrenaline release but enhance carrier-mediated noradrenaline release (due to stimulation of the Na+/H+ exchanger, Imamura et al. 1996b), which is the major mode of noradrenaline release and the major arrhythmogenic risk in protracted myocardial ischemia (see Levi and Smith 2000 Koyama et al. 2003). 

Compared with other CCBs, mibefradil was found to have more negative chronotropic effects, with a significant incidence of dose-dependent first-degree AV block and sinus bradycardia. No effect on QT intervals was detected in the phase III studies. 

The ability to examine a drug effect over its full range of intensities for example, it would be impossible in the intact organism to follow negative chronotropic effects to the point of cardiac arrest. 

These are both negative chronotropes and positive inotropes, and have a narrow therapeutic index and relatively long-half life of elimination (digoxin 14-60 hours, digitoxin 30-40 hours). 

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