The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors

Abstract

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism

“…These data indicate that desensitization of β-AR is mainly due to the down-regulation of β 1 -ARs. These results are consistent with past reports, 4,36 but contrary to the findings of Arioglu 7 et al, who reported that decreased positive inotropic responses to both isoprenaline and noradrenaline in isolated papillary muscle but unchanged β 1 -AR mRNA expression in hypothyroidism. Of note, Arioglu’s group was the first to measure hypothyroidism-induced changes in β 3 -AR.…”

“…2, 5, 7, 8 Consistent with past experimental and clinical reports, these animals showed increased SNS activation, with significantly decreased heart rate, stroke volume, cardiac output, ejection fraction, and increased Ea without significant change in V ED (Table 1). 3, 4, 31 The relative unchanged V ED may be related hypothyroidism produced LV atrophy.…”

“…2, 5, 7, 8 The major new findings are: 1) Chronic hypothyroidism produces increased activation of the sympathetic nervous system (SNS), followed by direct depression of LV contractile function and impaired LV filling. This was associated with defects in cardiomyocyte contraction, relaxation and [Ca 2+ ] i regulation with diminished β-AR inotropic reserve.…”

“…Recent evidence suggests that altered nitric oxide synthase (NOS) isoform activations and impaired cardiac β-adrenergic receptors (AR) subtype-mediated signal pathways may be important in hypothyroid-associated cardiomyopathy. 4, 7, 8 However, the findings concerning the expression and function of three NOS isoforms and different cardiac β-AR subtypes, in particular β 1 - and β 3 -AR in hypothyroidism are limited and conflicting.…”

Beta-3 Adrenoceptors as New Therapeutic Targets for Cardiovascular Pathologies

“…A recent study reports a significant increase in ß 3 -AR mRNA expression, although BRL37344-induced negative inotropic effect was decreased [47]. The reduced BRL37344-induced negative inotropic effect could be at least partly explained by alteration of downstream ß 3 -AR signaling pathway.…”