Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.
Graded doses of norepinephrine and methoxamine were given to rabbits over a standard 90-minute infusion period to assess their potential for inducing myocardial injury. Lesions of myofiber necrosis and leukocytic infiltration were graded semiquantitatively in animals killed 2 days later. A close correlation was found between the dose of norepinephrine and the histological score (r = 0.912, P less than 0.001). Mean arterial pressure rose from 100 mm Hg to a maximum of 129 mm Hg, and averaged 115 mm Hg during infusion of 2 micrograms/min per kg. However, heart rate fell from 287 beats/min to average 208 beats/min. The pressure-rate product, an index of metabolic demand, showed no significant change and did not differ from saline-infused controls. Beta-adrenergic blockade with practolol (4 mg/kg) or propranolol (1 mg/kg) failed to significantly reduce cardiac injury with norepinephrine. However, alpha-adrenoceptor blockade with phentolamine (10 mg), alone or in combination with either of the beta-antagonists, markedly reduced lesion formation as reflected by the histological score (P less than 0.02). Administration of the alpha-agonist methoxamine produced dose-related increases in the intensity of myocardial injury (r = 0.938, P less than 0.01), morphologically identical with those resulting from norepinephrine. Hemodynamic changes also were comparable. Phentolamine markedly reduced methoxamine injury. It may be concluded from these studies that norepinephrine cardiomyopathy results in large part from activation of the alpha-adrenergic system in the rabbit model. Ischemia or a supply-demand mismatch are unlikely mechanisms. We speculate that alterations in myofiber Ca++ translocation, uptake, and binding induced by alpha 1-receptor activation may contribute to membrane damage.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics; D008729:Methoxamine / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology; D009638:Norepinephrine / Q000009:adverse effects*; D011817:Rabbits; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D008729:Methoxamine; D009638:Norepinephrine