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. 

Kaumann, A. J., and Marano, M. (1982). On equilibrium dissociation constants for complexes of drag receptor subtypes Selective and nonselective interactions of partial agonists with two P-adrenoceptor subtypes mediating positive chronotropic effects of (-) isoprenaline in kitten atria. Nannyn Schmiedebeberg s Arch. Pharmacol. 219 216—221. 

The histamine H2-receptor (359 amino acids) is best known for its effect on gastric acid secretion. Histamine H2-receptor activation, in conjunction with gastrin and acetylcholine from the vagus, potently stimulate acid secretion from parietal cells. High concentrations of histamine are also present in cardiac tissues and can stimulate positive chronotropic and inotropic effects via H2-receptor stimulation and activation of adenylyl... 

MTX caused a contraction of vascular smooth muscle and positive inotropic, positive chronotropic and arrhythmogenic effects on cardiac muscle. The effect of MTX was little affected by various receptor blockers, a Na channel blocker or a catecholamine depleting agent. Further, MTX had no effect on the enzymes which were related to Ca movements, such as Na , K -ATPase, cyclic AMP phosphodiesterase, and sarcoplasmic reticulum Ca -ATPase. These results would eliminate the possible involvement of an indirect action elicited by the release of chemical mediators and direct modifications of their receptors, Na channels, or various enzymes as a major mechanism of action of MTX. 

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. 

Another mechanism to maintain CO when contractility is low is to increase heart rate. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of norepinephrine on P-adrenergic receptors in the heart. Sympathetic activation also enhances contractility by increasing cytosolic calcium concentrations. SV is relatively fixed in HF, thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both systolic and diastolic function. 

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). 

Vasopressin levels are increased during hypotension to maintain blood pressure by vasoconstriction. However, there is a vasopressin deficiency in septic shock. Low doses of vasopressin increase MAP, leading to the discontinuation of vasopressors. However, routine use of vasopressin is not recommended because of lack of evidence of efficacy. Vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects and may result in decreased cardiac output and hepatosplanchnic flow. Vasopressin use may be considered in patients with refractory shock despite adequate fluid resuscitation and high-dose vasopressors.24,27-28... 

Chronotropic Affecting pulse rate, or referring to changes in heart rate. 

Isoproterenol (104) is an important agent for classification because of its selective p-receptor agonist activity. It is of special interest that its chronotropic (increase in heart rate) and inotropic (increase in force of contraction) effects exceed that of epinephrine it is also used in the management of mild to moderate asthma due to its bronchodilating effect, resulting in increased vital capacity of the lungs. 

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.

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

Beta-1, beta-2, and beta-3 adrenergic receptors are G-protein-coupled receptors. Beta-1 and beta-2 receptors mediate the positive inotropic, chronotropic, and dro-motropic effects of the endogenous catecholamines epinephrine and norepinephrine. The beta-3 subtype seems to play a role in regulating thermogenesis and lipid mobilization in brown and white adipose tissue. Several coding and promoter polymorphisms of these receptors have been identified. Clinical studies in asthma... 

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 answer is d. (Katzung, p 130J Epinephrine has a positive ionotropic and chronotropic effect on the heart because of its pradrenergic activity It also has a-adrenergic activity that causes vasoconstriction in the vascular beds. These actions result in a rise in systolic blood pressure. Epinephrine also has p2-adrenergic activity, which causes vasodilation in skeletal muscle. Because of this latter effect, total peripheral resistance can fall, resulting in a drop in diastolic pressure, particularly at low doses of epinephrine. 

Dopamine produces dose-dependent hemodynamic effects because of its relative affinity for cq-, /Jr, /J2-, and Dr (vascular dopaminergic) receptors. Positive inotropic effects mediated primarily by / -receptors become more prominent with doses of 2 to 5 mcg/kg/min. At doses between 5 to 10 mcg/kg/min, chronotropic and -mediated vasoconstricting effects become more prominent. Especially at higher doses, dopamine alters several parameters that increase myocardial oxygen demand and potentially decrease myocardial blood flow, worsening ischemia in some patients with coronary artery disease. 

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. 

Chronotropism and inotropism Isolated atrium/papillary muscle/ isolated hearts Sugiyama et al.,-86 Voss et al.87... 

Sugiyama, A., Kobayashi, M., Tsujimoto, G., Motomura, S., and Hashimoto, K., The first demonstration of CGRP-immunoreactive fibers in canine hearts coronary vasodilator, inotropic and chronotropic effects of CGRP in canine isolated, blood-perfused heart preparations, Jpn. J. Pharmacol, 50, 421-427, 1989. 

Voss, H.P., Shukrula, S., Wu, T.S., Donnell, D., and Bast, A., A functional beta-2 adrenoceptor-mediated chronotropic response in isolated guinea pig heart tissue selectivity of the potent beta-2 adrenoceptor agonist TA 2005, /. Pharmacol. Exp. Ther., 271, 386-389, 1994. 

Lorenzo PS, Rubio MC, Medina JH, Adler-Graschinsl E. (1996). Involvement of monoamine oxidase and noradrenaline uptake in the positive chronotropic effects of apigenin in rat atria. EurJ Pharmacol. 312(2) 203-7. 

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