Osadchii OE, Norton GR, McKechnie R, Deftereos D, Woodiwiss AJ. Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic ␤-adrenoreceptor activation. Am J Physiol Heart Circ Physiol 292: H1898 -H1905, 2007. First published December 8, 2006; doi:10.1152/ajpheart.00740.2006.-There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a ␤-adrenoreceptor agonist, for 3 mo to rats (0.1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic ␤-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as ␤ 1-and ␤2-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and ␤-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of ␣-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing ␤-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.isoproterenol; cardiac remodeling; contractility; inotropic responses THERE IS A STRONG RELATIONSHIP between increased cardiac chamber dimensions (cardiac dilatation) and poor clinical outcomes. In otherwise healthy people, cardiac chamber enlargement is associated with an increased morbidity and mortality (20,27) and the development of heart failure (34). Moreover, chamber dimensions predict clinical outcomes in patients with either mild or severe heart failure (19, 21, 32, 37). The contemporary explanation for the relationship between chamber dimensions and clinical outcomes is that chamber enlargement reflects a compensatory response of the failing myocardium to rest...

Abstract-The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involvesexcessive ␤-adrenoreceptor (␤-AR) stimulation. To explore whether aldosterone receptor activation contributes toward ␤-AR-induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the ␤-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg ⅐ kg Ϫ1 ⅐ day for 4.5 months. ISO administered to SHR resulted in an increased 24-hour urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, a decreased LV relative wall thickness, and increased total, noncross-linked, type I and type III myocardial collagen concentrations without further enhancing increased myocardial norepinephrine (NE) release. ISO reduced pump function without modifying intrinsic myocardial systolic function or inducing further myocyte necrosis or apoptosis. ISO only increased LV cavity volumes after prolonged periods of administration. SPIRO abolished ISO-induced chamber dilatation, wall thinning, and pump dysfunction and reduced total, noncross-linked, type I and type III myocardial collagen concentrations but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, myocardial NE release, or the degree of necrosis or apoptosis. In conclusion, these results suggest that aldosterone receptor blockade, through loadindependent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic ␤-AR activation. Key Words: remodeling Ⅲ collagen Ⅲ sympathetic nervous system Ⅲ aldosterone T here is substantial evidence to indicate that in hypertension, the transition from compensated left ventricular hypertrophy (LVH) to heart failure involves chronic ␤-adrenoreceptor (␤-AR) activation. Indeed, in LVH, increased circulating norepinephrine (NE) concentrations 1,2 as well as myocardial NE release 3 precede heart failure. Moreover, in hypertensive LVH, prolonged ␤-AR agonist administration 4 or genetically enhanced sympathetic effects 5 increase the susceptibility to decompensation without blood pressure (BP) changes. Despite data to support a notion that ␤-AR activation induces the transition to heart failure in hypertensive LVH, whether the renin-angiotensin-aldosterone system (RAAS) mediates this effect is unknown. This question arises because ␤-AR stimulation provokes the RAAS, ␤-AR blockers inhibit the RAAS in hypertension, 6 and aldosterone receptor antagonists attenuate left ventricular (LV) dilatation. 7-9 Because ␤-AR blockers have a limited impact on LVH 10 and increase the chance of new onset diabetes mellitus, 11 identification of downstream targets from ␤-ARs responsible for LV decompensation that modify LVH but not metabolic pathways is desirable. Therefore, in the present stud...

No abstract

The plasma concentration of the neuromuscular blocking drug, succinylcholine, is difficult to measure. We have measured concentrations of the breakdown product of succinylcholine, choline, to assess whether choline concentration gives an accurate measure of succinylcholine concentration. Choline concentration was measured by HPLC and electrochemical detection in two blood or plasma samples, one in which succinylcholine hydrolysis was inhibited by 10(-5) M physostigmine and another in which succinylcholine was completely hydrolysed in 20 min by 200 mU butyrylcholinesterase at 37 degrees C. The difference in choline content between the two samples gives the succinylcholine concentration. Ninety-five per cent recovery of choline was achieved. Choline standard curves were linear from 156 pmol ml-1 to 200 nmol ml-1. Within-day and between-day mean coefficients of variation for succinylcholine hydrolysis were small (mean (SD) 3.7% (1.2%) and 3.8% (1.6%), respectively). We conclude that this method of measuring succinylcholine concentration in blood is accurate, repeatable and relatively easy.

Although increases in myocardial synaptic norepinephrine concentrations contribute toward the progression to heart failure in hypertension, the stimuli for norepinephrine release are unclear. In this study we explored whether neurotensin, a neuropeptide found in heart tissue, could modify myocardial norepinephrine release in spontaneously hypertensive rats (SHR). Prior to the development of cardiac decompensation, baseline coronary effluent norepinephrine concentrations were higher in isolated heart preparations of spontaneously hypertensive rats than in Wistar Kyoto (WKY) control rat hearts. Neurotensin increased coronary effluent norepinephrine concentrations and induced positive inotropic responses, effects that were enhanced in spontaneously hypertensive rats compared with Wistar Kyoto rats. Although the neurotensin receptor antagonist, SR 48692, did not modify either baseline coronary effluent norepinephrine concentrations or left ventricular systolic function in spontaneously hypertensive rats, it dose dependently abolished neurotensin-induced cardiac norepinephrine release and contractile responses. Neurotensin-mediated inotropic responses were also abolished by co-administration of the beta-adrenoreceptor blockers, propranolol and atenolol. Inotropic responses to exogenous norepinephrine were similar in SHR and WKY rats. In summary, in the hypertensive heart there is an increased sensitivity to neurotensin's actions on myocardial norepinephrine release and subsequent contractile changes. Therefore, neurotensin receptor blockade may represent a novel therapeutic target in preventing the progression to heart failure in hypertension.