Role of PAdrenergic Receptor Subtypes in Regulating Cardiac Function

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3.1. Basal Cardiovascular Function

Targeted deletion of Pr, P2-, and both Pr and P2-ARs in mice has no significant impact on resting heart rate, blood pressure, or cardiac output (28-30,35) (Table 1) (data from mice lacking all three P-ARs is not available yet). These results suggest that P1- and P2-ARs are not required for maintaining normal resting heart rate and blood pressure or for baseline contractile function in the mouse. They differ somewhat from experiments using antagonists to disrupt PAR function acutely, suggesting some compensation occurs with the disruption of P-AR genes. For example, downregulation of cardiac muscarinic receptors observed in P^-AR-KO mice may counterbalance the lack of adrenergic stimulation in maintaining the resting heart rate (30).

3.2. Chronotropic and Inotropic Response to Sympathetic Stimulation

The relative role of P-AR subtypes in modulation of cardiac chronotropy was tested with the nonselective P-AR agonist isoproterenol administered to P-AR-KO mice. Wild-type mice show a robust 200 beats per min increase in heart rate associated with an approx 30 mmHg drop in mean blood pressure. In PrAR-KO mice, the heart rate response is attenuated by approx 50% (28). This residual response is not mediated directly by cardiac P2-ARs but by P2-AR-mediated vasodilation. The hypotensive effect of activating vascular P2-ARs leads to a baroreflex-mediated withdrawal of vagal tone. The chronotropic response to isoproterenol in PrAR-KO mice can be blocked by atropine, a muscarinic receptor antagonist (35).

The lack of P2-AR involvement in cardiac chronotropy is further evidenced by the normal heart rate response to isoproterenol in P2-AR-KO mice (29). In P:/ P2-AR-KO mice, the heart rate response to isoproterenol is even more severely attenuated because these mice have diminished peripheral vasodilation and hence a smaller baroreflex response than do PrAR-KO mice (30). The remaining small baroreflex component in P:/P2-AR-KO mice is caused by an enhanced P3-AR-mediated peripheral vasodilation (30). These results are in agreement with experiments using isolated, spontaneously beating atria (30) and cultured neonatal myocytes isolated from each of these knockout strains (24). Together, these data suggest that the PrAR is the primary receptor responsible for sympathetic regulation of cardiac chronotropy in adult mice.

Isolated right ventricular tissues were used to measure the contribution of PAR signaling to contractility. Cardiac inotropy was monitored in isolated, paced right ventricular muscle strips. Preparations from PrAR-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 Pj-AR-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, +dP/dt was reduced by 20% and -dP/dt was reduced by 12% in P^P2-AR-KO mice compared to wild-type mice (30).

aThese results are consistent with the ineffectual stimulation of cardiac adenylyl cyclase by P2-ARs in PrAR-KO mice. This observation is somewhat surprising, however, given the fact that, in both native human myocardium and heterologous expression systems, the P2-AR appears to couple more efficiently to adenylyl cyclase stimulation than does the P1-AR. One possible explanation is that activation of adenylyl cyclase by the P2-AR in murine hearts is inhibited by p2-AR coupling to Gj. Indeed, P2-AR-selective agonist-mediated inotropic effects on isolated adult ventricular myocytes are greatly enhanced when Gi/Go proteins are inactivated by pertussis toxin treatment (6). Of interest, transgenic mice with cardiac overexpression of P2-AR exhibit enhanced contractility and elevated adenylyl cyclase activity (27). Thus, P2-AR coupling to cardiac ionotropy can occur in murine heart when the appropriate cellular or tissue context is provided.

3.3. Role of P-AR Subtypes in the Cardiovascular and Metabolic Response to Exercise

Maximal exercise is associated with near maximal sympathetic nervous system activity and dramatic changes in heart rate, contractility, and vascular tone. Surprisingly, even though P1-ARs are essential for catecholamine stimulation of chronotropy and inotropy, P1-AR-KO mice exhibited the same exercise capacity as wild-type controls (32,36). The heart rate response to exercise in P1-AR-KO mice was markedly reduced compared to wild-type mice; yet, there were no differences between P1-AR-KO mice and wild-type mice in VO2 and VCO2 over the entire range of workloads, suggesting no difference in metabolic response to exercise and no difference in O2 extraction. Thus, P1-AR-KO mice must compensate for their slower heart rates with greater increases in stroke volume, presumably through preload-dependent mechanisms (36).

Using the same graded treadmill protocol, P2-AR-KO mice exercised for a longer duration than did wild-type mice (29). Heart rate responses to exercise were similar; however, P2-AR-KO mice became hypertensive relative to wildtype mice, probably a result of unopposed a1-AR-mediated peripheral vasoconstriction. At any given workload, VO2 tended to be slightly higher in the knockout mice, resulting in a lower respiratory exchange ratio (RER; the ratio of VCO2:VO2). RER is one indicator of substrate utilization, and this difference suggests an alteration in energy metabolism caused by the absence of P2-ARs. Normally, activation of P2-ARs enhances glycogenolysis during exercise. Therefore, P2-AR-KO mice might preferentially metabolize fat, resulting in a higher VO2. Interestingly, the body fat content is decreased in P2-AR-KO mice compared with wild-type mice (29).

Similar to P1-AR-KO mice, P1/P2-AR-KO mice are able to achieve exercise capacities equal to those of wild-type mice. Their heart rate response, like those of pj-AR-KO mice, is blunted. However, in contrast to both of the prAR-KO and P2-AR-KO mice, the P:/P2-AR-KO mice have lower levels of VO2 at all exercise workloads (30). This metabolic deficit results only from the combined deficiency of both pr and P2-ARs and could be secondary to an inability to mobilize metabolic fuels or to downstream effects that alter metabolic demands—for example, at the level of adenylyl cyclase, Na/K-adenosine triphosphatase, or the calcium channel. Collectively, these results suggest that pr and P2-ARs serve both separate and redundant metabolic functions during exercise, and that both receptors must be ablated before significant metabolic abnormalities are encountered. Despite these deficits and significant deficits in inotropy and chronotropy, Pi/P2-AR-KO mice were still able to achieve normal exercise capacity, which emphasizes the importance of preload in the response to exercise.

3.4. Role of P-AR Subtypes in the Pathogenesis of Heart Failure

Studies outlined above as well as studies using pharmacological methods showed that the PrAR is the dominant subtype regulating cardiac performance. Of interest, the PrAR has also been implicated in the pathogenesis of heart failure. It has been shown that the PrAR is selectively downregulated in cardiomyopathy (37). Some evidence suggests that P-AR downregulation plays a role in the decrease in cardiac function in heart failure. However, more compelling is evidence that chronic PrAR activation contributes to the pathogenesis of heart failure. Chronic exposure to P-agonists leads to myocyte apoptosis, fibrosis, and dysfunction (13,38). Moreover, inhibiting P-ARs with antagonists has been clinically beneficial in patients with cardiomyopathy (18). Transgenic mice with overexpressed P rAR develop a cardiomyopathy similar to that seen with chronic catecholamine infusion (26,39). In contrast, overexpressing the human P2-AR in mouse hearts can significantly increase baseline cardiac contractility (27). Deleterious effects of P2-AR are observed only at very high levels of cardiac expression (40). In fact, physiological levels of P2-AR signaling in the heart may be protective. When isoproterenol was administered to mice over 2 wk by isometric infusion pump, P2-AR-KO mice had higher mortality and more myocyte apop-tosis than did wild-type mice (41).

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