Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic beta-adrenoreceptor activation in rats.

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Osadchii OE, Woodiwiss AJ, Deftereos D, Norton GR

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic beta-adrenoreceptor activation in rats.

Pflugers Arch. 2007 Nov;455(2):251-60. Epub 2007 Jun 9.

PubMed ID

17558518 [ View in PubMed

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Abstract

We evaluated the relationship between myocardial norepinephrine release or inotropic responsiveness to adrenergic stimulation and intrinsic myocardial function after the progression to pump dysfunction induced by chronic beta-adrenoreceptor activation (isoproterenol [ISO], 0.1 mg/kg/day for 1 month or 6 months) in rats. Left ventricular (LV) systolic chamber dysfunction occurred after 6 months, but not after 1 month of beta-adrenoreceptor activation, as evidenced by reduced LV endocardial fractional shortening determined by echocardiography and a decrease in the slope of the LV systolic pressure-volume relations assessed in isolated, perfused heart preparations. A reduced pump function at 6 months of ISO administration was associated with chamber dilatation, while LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relations (isolated heart preparations), indices of intrinsic myocardial function, were unchanged. After 1 month of ISO administration, reduced beta1- and beta2-adrenoreceptor-mediated and sustained alpha-adrenoreceptor-mediated inotropic responses were noted. Nevertheless, increased inotropic potency of beta-adrenoreceptor agonists and upregulation of alpha-adrenoreceptor-mediated contractile responses were noted after 6 months of ISO administration. Increased adrenergic-inotropic responsiveness after 6 months of ISO administration was associated with depleted LV norepinephrine stores, as evidenced by reduced desipramine-stimulated norepinephrine concentrations in the coronary effluent. In conclusion, in the progression from compensated cardiac hypertrophy to pump dysfunction after chronic sympathetic activation, a preserved intrinsic myocardial contractility is accounted for by paradoxical upregulation of adrenergic-mediated contractile responses.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Desipramine	Beta-2 adrenergic receptor	Protein	Humans	Unknown	Antagonist	Details