Inotropic response

FIGURE 2.18 Inotropic and lusitropic responses of guinea pig left atria to (3-adrenoceptor stimulation. Panels A to C isometric tension waveforms of cardiac contraction (ordinates are mg tension abscissae are msec), (a) Effect of 0.3 nM isoproterenol on the waveform. The wave is shortened due to an increase in the rate of diastolic relaxation, whereas no inotropic response (change in peak tension) is observed at this concentration, (b) A further shortening of waveform duration (lusitropic response) is observed with 3 nM isoproterenol. This is concomitant with positive inotropic response (increase maximal tension), (c) This trend continues with 100 nM isoproterenol, (d) Dose-response curves for ino tropy (filled circles) and lusitropy (open circles) in guinea pig atria for isoproterenol, (e) Dose-response curves for inotropy (filled circles) and lusitropy (open circles) in guinea pig atria for the P-adrenoceptor partial agonist prenalterol. Data redrawn from [6]. 

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

FIGURE 2.21 Effects of desensitization on inotropic responses of guinea pig atria to isoproterenol (panel a) and prenalterol (panel b). Ordinates response as a percent of the maximal reaponse to isoproterenol. Abscissae logarithms of molar concentrations of agonist (log scale). Responses shown after peak response attained (within 5 minutes, filled circles) and after 90 minutes of incubation with the agonist (open triangles). Data redrawn from [6]. 

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. 

A dose of 7.0 /ig/kg of indolidan (i.v. administration) resulted in a 50% increase in contractility in anaesthetized dogs. A selective inotropic response has been observed with conscious dogs upon oral administration of 25 ngj kg of (23). The haemodynamic profile of (23) has been evaluated in anaesthetized dogs [78]. The acute and subchronic toxicology of indolidan has been studied (rats, dogs) [79]. 

Murrayaquinone A (107) (see Scheme 2.21) was found to produce a triphasic inotropic response of guinea-pig papillary muscle. This triphasic inotropic response is not mediated through a receptor mechanism, but through a mechanism involving ATP production (473). 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

Guinea pig Right atrium Adrenergic nerves Neurogenic inotropic response inhibition Luo et al., 1991... 

Right atrium Left atrium Adrenergic nerves Neurogenic chronotropic response Neurogenic inotropic response NA release (ES-evoked) inhibition inhibition inhibition Endou et al., 1994... 

Left atrium Afferent neurons BK-evoked inotropic response BK-evoked CGRP release inhibition inhibition Imamura et al., 1996b... 

Sethi, R., and Dhalla, N.S. 1995. Inotropic responses to isoproterenol in congestive heart failure subsequent to myocardial infarction in rats. J. Card. Fail. 1 391-399. 

Cardiac pi-receptors and atrial and ventricular P2-receptors take part in positive inotropic response. Inhibition of catecholamines at P-adrenergic receptor sites interrupts the production of cAMP and inhibits calcium influx producing a negative inotropic effect that yields a reduction in the heart rate. 

Endothelin also has effects on isolated cardiac preparations, although these are less marked than on vascular tissues. The positive inotropic response varies considerably between species [18]. In the most sensitive preparation, rabbit papillary muscle, there is little difference between the potency of ET-1, ET-2 or ET-3 [18]. There is also little difference between the small positive chronotropic responses to ET-1 and ET-3 [19]. 

Consistent with this, AB KO RV trabeculae had no significant inotropic response to PE, indicating that the D was not involved in inotropy (16). However, in studies of the AB KO isolated heart, we were surprised to find in the WT mouse heart that PE caused a PIE, the first report of this in the mouse. There was a transient NIE, then a sustained PIE, with an increase almost 20% over control. 

In summary, a,-adrenergic inotropic responses in the A KO and AB KO reveal negative contractile effects in RV trabeculae mediated by the A or the B, primarily because of decreases in Ca2+ sensitivity of the myofibrils, and positive contractile effects of the A or the B in the isolated heart, with unknown mechanism. The D in coronary arteries mediates flow reductions and secondary negative contractile effects. 

A and/or B Cardiac inotropic responses Physiological cardiac hypertrophy Cardiac adaptation to exercise and pressure overload... 

Isolated right ventricular tissues were used to measure the contribution of P-AR signaling to contractility. Cardiac inotropy was monitored in isolated, paced right ventricular muscle strips. Preparations from pr AR-KO mice failed to show any responsiveness to isoproterenol administration, while wild-type preparations showed robust inotropic responses (28). This lack of contractile response is not caused by generalized hyporesponsiveness of the contractile apparatus because prAR-KO ventricles responded normally to activators of adenylyl cyclase such as forskolin. Surprisingly, disruption of both pr and P2-ARs has only modest effects on resting left ventricular contractility in vivo. When contractility was assessed with a micromanometer-tipped catheter, -i-dP/dt was reduced by 20% and -dP/dt was reduced by 12% in p /prAR-KO mice compared to wild-type mice (30). 

All three subtypes of P-ARs are expressed in the heart (73). Despite the existence of species-related differences (reviewed in ref. 74), prARs are the predominant form of ARs. The positive chronotropic and inotropic response of the heart to catecholamine stimulation is mediated almost exclusively by prARs (75-77). Coupling of (32-ARs to cardiac contractility is less defined and species related, showing a positive effect in human hearts (77) but not affecting contractility in the mouse (75). Better defined is the role of P2-ARs in the regulation of vascular tone and blood pressure (78). P3-ARs, atypical P-ARs, are expressed in the adipose tissue, where they mediate lipolysis and thermogenesis (79,80), and in smooth muscle cells, where they mediate vasorelaxation (81). 

G. Heusch, J. Rose, A. Skyschally, H. Post and R. Schulz, Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart. Inotropic responses to postextra-systolic potentiation and intracoronary calcium, Circulation 93(8), 1556-66 (1996). 

As detailed above, this experimental model of coronary microembolization is not only characterized by a perfusion-contraction mismatch pattern, but also by reduced coronary reserve. Also, the inotropic response to intracoronary infusion of dobutaminc is diminished in microembolized myocardium.1 ... 

The heart contains primarily postsynaptic /f i-receptors, which cause increased rate and force of contraction when stimulated. This effect appears to be mediated by activation of adenylate cyclase and subsequent generation and accumulation of cAMP. Stimulation of postsynaptic cardiac i -receptors causes a significant increase in contractility without an increase in rate, an effect apparently not mediated by cAMP. The increased contractility is more pronounced at lower heart rates and has a slower onset and longer duration in comparison with /Si-mediated inotropic response. Presynaptic 2-adrenoceptors also are found in the heart and appear to be activated by norepinephrine released by the sympathetic nerve itself. Their activation inhibits further norepinephrine release from the nerve terminal. 

Klapperstuck M, Muller S, Hoffmann P. 1991. Carbon disulfide exposure attenuates adrenergic inotropic responses in rats. J Hyg Epidemiol Microbiol Immunol 35(2) 113-120. 

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