Association of decreased myocardial beta-receptors and chronotropic response to isoproterenol and exercise in pigs following chronic dynamic exercise.

Abstract

The effects of chronic dynamic exercise on myocardial beta-adrenergic and muscarinic cholinergic receptors and chronotropic sensitivity to isoproterenol were studied in 5 Yucatan miniswine. Right atrial and left ventricular biopsies, heart rate responses to isoproterenol, and maximal exercise treadmill testing were obtained before and after 10-19 weeks of treadmill running. Radioligand studies using 125I-iodocyanopindolol (ICYP) and 3H-quinuclidinyl benzilate (QNB) were used to determine the number of beta-adrenergic and muscarinic cholinergic receptors. Maximal oxygen consumption increased from 52 +/- 5 to 65 +/- 7 ml/kg/min (mean +/- SD; p less than 0.02), maximal workload from 530 +/- 111 to 1,074 +/- 179 KPM/min (p less than 0.01), resting heart rate decreased from 91 +/- 13 to 62 +/- 4 beats/min (p less than 0.01), heart rate at 75% of pretraining maximal workload decreased from 253 +/- 15 to 196 +/- 12 beats/min (p less than 0.01), and maximal exercise heart rate decreased from 273 +/- 6 to 254 +/- 9 beats/min (p less than 0.01). Decreased heart rate responsiveness to adrenergic stimulation was observed following chronic exercise. Maximal isoproterenol-stimulated heart rate decreased from 225 +/- 13 to 185 +/- 28 beats/min (p less than 0.05) and the slope of the isoproterenol dose-response relation decreased from 63 +/- 16 to 40 +/- 16 (p less than 0.05). Radioligand studies revealed a decrease in beta-receptor number in the right atrium following chronic exercise (61 +/- 9 vs. 34 +/- 8 fmol/mg; p less than 0.02), but receptor number in membranes from the left ventricle did not change (60 +/- 9 vs. 62 +/- 4 fmol/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Noncoordinate regulation of cardiac Gs protein and beta-adrenergic receptors by a physiological stimulus, chronic dynamic exercise.

“…For example, previous studies have indicated that longterm treadmill running of pigs results in diminished maximal heart rates during exercise and isoproterenol stimulation and a down-regulation of right atrial /3-adrenergic receptors (1). In the current studies we have extended these observations and find that, in spite of this down-regulation of p-receptors, the dose of isoproterenol yielding a 50% maximal heart rate response, the ED50, is decreased after training.…”

“…After recovery from surgery animals underwent pharmacological and exercise testing to determine heart rate response, maximal work rate, and maximal oxygen consumption. Details of surgical procedures and physiological responses to exercise have been reported previously (1). When exercise and pharmacological tests were complete animals underwent 7-9 wk of treadmill running (60 min/d, 5 d/wk, 9% grade, 100 m/min) and physiological and pharmacological tests were repeated.…”

Myocardial adrenergic denervation supersensitivity depends on a postreceptor mechanism not linked with increased cAMP production.

“…/3-Adrenergic Receptor Binding Studies Figure 5 shows the results of saturation isotherm experiments; ,BAR number was decreased by 6 Adenylyl Cyclase Assays Basal (unstimulated) adenylyl cyclase activity was lower in denervated animals (control, 89±17 pmol/ mg/min; 6-OHDA, 30±12 pmol/mg/min). Adenylyl cyclase activity is therefore reported as net increase in stimulation (basal subtracted) to adjust for differ- Gpp(NH)p-stimulated adenylyl cyclase activity was diminished markedly through a wide range of Gpp-(NH)p concentrations ( Figure 7).…”

“…For example, 2 hours after injecting adult mice with 6-OHDA, myocardial norepinephrine concentrations were decreased 95%; by 8 weeks, however, myocardial norepinephrine concentration returned to normal, suggesting regeneration of adrenergic nerve terminals. 3 In contrast, when 6-OHDA was given repeatedly during the first 10 days of life to newborn rats, myocardial norepinephrine depletion was substantial (85%) 15 weeks later, suggesting that chronic myocardial adrenergic denervation is possible if 6-OHDA is given when adrenergic neural pathways are still forming.4 Thus, our study had two goals: to develop a model of long-term, nonsurgical myocardial adrenergic denervation, and to define the relations between myocardial 3AR number, physiological responsiveness, and postreceptor elements resulting from myocardial adrenergic denervation.…”

“…To achieve these goals, we administered 6-OHDA to newborn pigs and studied the pigs 14 6-OHDA is metabolized rapidly; it has been shown that 24 hours after intravenous injection of [3H]-6-OHDA to rats, no [3H]-amines were found in heart or spleen5; therefore, toxicity related to persistent drug is not likely. All pigs remained with their mother and were weaned at the usual time (8-10 weeks).…”