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CLINICAL STUDIES

Cardiac beta-adrenoceptors in chronic uremia: studies in humans and rats

Stefan Dhein, MD^*, Peter Röhnert^*, Silke Markau, MD, Emanuel Kotchi-Kotchi, PhD^*, Karin Becker, PhD^*, Ulrike Poller, MD^*, Bernd Osten, MD and Otto-Erich Brodde, PhD^*

^* Institute of Pharmacology and Toxicology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany
Department of Nephrology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany

Manuscript received August 29, 1999; revised manuscript received January 26, 2000, accepted March 30, 2000.

Reprint requests and correspondence: Dr. Stefan Dhein, Institute of Pharmacology, University of Halle-Wittenberg, Magdeburger Str. 4, D-06097 Halle (Saale), Germany
stefan.dhein{at}medizin.uni-halle.de

OBJECTIVES

The purpose of this study was to elucidate whether cardiac beta-adrenergic effects may be blunted in patients on maintenance hemodialysis (HD) and may help to explain autonomic dysfunction.

BACKGROUND

Patients on HD often suffer from autonomic dysfunction.

METHODS

We investigated the cardiovascular response of five HD patients (age: 46.1 ± 7.9 years) and six healthy volunteers (age: 48.2 ± 7.5 years) to isoprenaline, pirenzepine and phenylephrine. For analysis of underlying mechanisms of beta-adrenoceptor hyporesponsiveness, six-week-old male Wistar rats were rendered uremic by 5/6-nephrectomy (n = 9; SNX) and were killed for removal of the heart after six to seven weeks. Sham-operated rats (n = 15) served as controls.

RESULTS

In the patient study, isoprenaline (3.5, 7, 17, 35 ng/kg/min, i.v.) led to an increase in heart rate, and shortening of the heart rate corrected duration of the electromechanical systole (QS₂c), both of which were significantly reduced in HD patients. Baroreflex sensitivity was significantly reduced in HD patients. The response to low parasympathomimetic doses of pirenzepine was unchanged. In the rat study, left ventricular strips were placed in an organ bath, electrically driven and exposed to isoprenaline (10^–11 to 10^–6 mol/liter). While pD₂ values were unchanged, maximum effect at the highest concentration was significantly reduced in SNX rats. The response to carbachol was not altered, nor was the M₂-cholinoceptor density. There was no difference in beta-adrenoceptor density, or in immunodetectable amount of G_s and G_i protein. Activation of adenylyl cyclase evoked by isoprenaline was significantly reduced in left ventricular membranes of SNX rats, whereas effects of 10 µmol/liter GTP, 10 mmol/liter NaF, 10 µmol/liter forskolin and 10 mmol/liter Mn²⁺ were not altered.

CONCLUSIONS

Cardiac beta-adrenergic responses are blunted in chronic uremia due to reduced isoprenaline-dependent activation of adenylyl cyclase. This might be caused by an "uncoupling" of the receptor or by an inhibition of the receptor by uremic toxins.

Abbreviations and Acronyms   DBP = diastolic blood pressure   HD = maintenance hemodialysis   HR = heart rate   MAP = mean arterial pressure   QS2c = heart rate corrected duration of the electromechanical systole   PSL = photostimulated luminescence   SBP = systolic blood pressure   SNX = 5/6-nephrectomized rat   SOP = sham-operated rat   (-)[125I]ICYP = (-)[125I]-iodocyanopindolol   [3H]NMS = [3H]N-methyl-scopolamine

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