Sex differences to myocardial ischemia and β-adrenergic receptor blockade in conscious rats

Abstract

Lujan HL, DiCarlo SE. Sex differences to myocardial ischemia and ␤-adrenergic receptor blockade in conscious rats. Am J Physiol Heart Circ Physiol 294: H1523-H1529, 2008. First published February 8, 2008 doi:10.1152/ajpheart.01241.2007.-We recently documented sex differences in the susceptibility to reperfusion-induced sustained ventricular tachycardia and ␤-adrenergic receptor blockade in conscious rats. However, the effect of sex on ischemia-induced ventricular arrhythmias and ␤-adrenergic receptor blockade is underinvestigated. Therefore, we tested the hypothesis that gonadal hormones influence the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion as well as the response to ␤-adrenergic receptor blockade. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Male and female intact and gonadectomized (GnX) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, as well as a Doppler ultrasonic flow probe to measure cardiac output and a snare around the left main coronary artery. The VAT was determined in conscious rats by pulling on the snare. The VAT was significantly longer in intact females (5.56 Ϯ 0.19) vs. intact males (4.31 Ϯ 0.14 min). This sex difference was abolished by GnX. Specifically, GnX decreased the VAT in females (4.55 Ϯ 0.22) and increased the VAT in males (5.14 Ϯ 0.30 min). Thus male sex hormones increase and female sex hormones decrease the susceptibility to ischemia-induced sustained ventricular tachycardia. ␤-Adrenergic receptor blockade increased the VAT in intact males and GnX females only. Thus gonadal hormones influence the response to ␤-adrenergic receptor blockade. Uncovering major differences between males and females in the pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments. cardiovascular risks; arrhythmia ISCHEMIA-INDUCED TACHYARRHYTHMIAS that culminate in ventricular fibrillation (19) are the leading cause of death in industrially developed countries (36). Despite the clinical relevance of ischemia-induced arrhythmias, very little experimental data are available regarding sex-specific responses. Specifically, Humphreys and colleagues (20), in the pentobarbital sodium-anesthetized rat as well as isolated rat heart, reported that females experienced fewer arrhythmias than males during myocardial ischemia.Other investigators using different mechanisms to induce arrhythmias also reported a sex difference. For example, Du and colleagues (14), in the in situ perfused rat heart model with chronic infarction and failure, documented that ventricular arrhythmias, triggered by sympathetic activation, were less frequent in female than in male rats. Similarly, Teplitz and colleagues (46), in the pentobarbital sodium-anesthetized rat, reported that male rat hearts are more susceptible than female hearts to epinephrine-induced arrhythmias and more than twice as many male rats di...

Age and Ovariectomy Abolish Beneficial Effects of Female Sex on Rat Ventricular Myocytes Exposed to Simulated Ischemia and Reperfusion

“…Our results indicate that intracellular Ca 2+ dysregulation is a major mechanism that contributes to the increased sensitivity of OVX hearts to ischemia and reperfusion injury [15], [23], [25], [54]. Interestingly, Ca 2+ dysregulation in OVX myocytes may help explain the increased propensity for reperfusion arrhythmias observed in aromatase knockout mice, which exhibit both estrogen suppression and testosterone elevation [14].…”

Sex-dependent gene regulatory networks of the heart rhythm

“…For instance, the higher expression of the adrenergic receptors Adra1b and Adrb1 in males vs females may explain why females are less affected than males by Adra1a – Adra1b double KO (O’Connell et al 2006) and the influence of gonadal hormones on Adrb1 blockade (Lujan and Dicarlo 2008). By contrast, Adrbk1 was higher in females than in males supporting the hypothesis that disruption of the Adrbk1/PI3K complex preserves β-adrenergic receptor levels and signaling ability by altering the intracellular trafficking of β-adrenergic receptors (Perrino and Rockman 2007).…”

Dichloroacetate selectively improves cardiac function and metabolism in female and male rainbow trout

“…High concentrations of lactate are known to exert deleterious effects on the recovery of the heart after reperfusion (50). Interestingly, male rats are more susceptible to postischemic contractile dysfunction than female rats (2,8,47), and male rainbow trout preparations do not preserve contractile function as well as female rainbow trout preparations after hypoxia and reoxygenation (present study and Ref. 7).…”

“…Hearts from young adult female rats are generally less susceptible to postischemic contractile dysfunction than age-matched male hearts (2,8,47), and experimental removal of systemic estrogen via ovariectomy is associated with poor recovery of contractile recovery after an ischemic insult (74). Specific mechanisms for sexbased differences in cardiovascular responses to acute ischemic events remain to be defined but may be modulated by systemic levels of estrogen (16), possibly through actions on cardiomyocyte Ca 2ϩ handling (57).…”