Positive Inotropic Effects Of Catecholamines Research Articles

Potentiation of the inotropic effects of norepinephrine and dibutyryl cyclic AMP by theophylline

The positive inotropic response of the heart to catecholamines has been postulated to result from an increase in the intracellular level of cyclic AMP (adenosine 3′,5′-monophosphate), produced by activation of myocardial adenylate cyclase. According to this hypothesis, inhibition of phosphodiesterase, the enzyme which hydrolyzes cyclic AMP to inactive 5′-AMP, should enhance the cardiac effects of catecholamines. We therefore examined the effects of theophylline, an inhibitor of cardiac phosphodiesterase, on the isometric contractile response of cat papillary muscles to varying concentrations of norepinephrine (10 −11 to 10 −5 m), cyclic AMP (10 −4 to 5 × 10 −3 m) and dibutyryl cyclic AMP (10 −5 to 5 × 10 −3 m). The latter agent is a more lipid soluble derivative of cyclic AMP which is thought to reproduce the intracellular effects of the parent compound. Cyclic AMP produced no changes in isometric contractile function either in the presence or absence of theophylline. However, at a theophylline concentration (2.5 × 10 −4 m) which caused little increase in baseline contractile function (average increment in active tension less than 10%), a marked potentiation of the positive inotropic effects of norepinephrine and dibutyryl cyclic AMP was observed. The concentration of norepinephrine producing half-maximal increases in active tension and rate of tension development decreased from 10 −7 to 10 −8 m while that of dibutyryl cyclic AMP decreased from 8 × 10 −4 to 4 × 10 −4 m. Theophylline did not alter the positive inotropic effects of increasing extracellular calcium concentration (2.5 to 10 m m), an intervention which is not thought to directly influence intracellular cyclic AMP levels. Although indirect, these findings provide further evidence that the positive inotropic effects of catecholamines are mediated via the adenylate cyclase cyclic AMP system.

Positive inotropic effects of dibutyryl cyclic adenosine 3',5'-monophosphate.

The positive inotropic effects of catecholamines have been postulated to result from an increase in the intracellular level of cyclic AMP (adenosine 3',5'-monophosphate) produced by activation of adenyl cyclase. Although lack of an inotropic effect by exogenously administered cyclic AMP has cast doubt on this hypothesis, cardiac cells are not readily permeable to cyclic AMP. The N 6 -2'-O-dibutyryl derivative of cyclic AMP is thought to enter cells more readily and is resistant to enzymatic degradation by phosphodiesterase. We examined the effects of cyclic AMP and its dibutyryl derivative on the contractile performance of isolated cat right ventricular papillary muscles. Cyclic AMP (1 x 10 -4 to 5 x 10 -3 M) had no effect on papillary muscle function. However, dibutyryl cyclic AMP caused a concentration-dependent increase in isometric tension and rate of tension development, the threshold concentration being 5 x 10 -4 M. The increments in tension (4.5 ± 0.4 g/mm 2 ) and rate of tension development (58.4 ± 5.4 g/mm 2 /sec) at peak concentration (3 x 10 -3 M) were similar to those found at peak norepinephrine concentration (10 -5 M). Dibutyryl cyclic AMP (10 -3 M) also caused a marked shift of the force-velocity curve upward and to the right. Although 10 -6 M propranolol depressed the inotropic effects of norepinephrine, it did not alter the contractile response to dibutyryl cyclic AMP. These findings are consistent with the hypothesis that the positive inotropic effects of catecholamines are mediated by cyclic AMP.

Relationship between metabolic and mechanic adrenergic stimulation of the heart under conditions of small dosage, low calcium, hypothermia and ouabain

Conditions facilitating a dissociation between the actions of noradrenaline (N) and isoprenaline (I) on phosphorylase activity (%− a) and isotonic contractions were studied in isolated perfused hearts. Hypothermia and ouabain pretreatment did not dissociate the rise in %− a from the inotropic effect of N in guinea-pig and rat hearts, but abolished the inotropic response in rabbit hearts. This is explained by high-calciuminhibition of the contractile protein, caused by the stimulant actions of hypothermia, ouabain and N on calcium uptake. Low calcium perfusion inhibited the mechanical response of guinea pig hearts to I more markedly than its effect on %− a. Changes in calcium concentration are obviously more critical for contractile than for metabolic function. Small doses of N, which augmented contraction by 30–50 per cent did not raise %− a. In contrast, a 30 per cent increase in contractility, when evoked by I, was associated with a 57 per cent raise in %− a. It is proposed, that 1 increases 3', 5'-AMP faster than N. With small doses of I (in contrast to N) a sufficient part of the same total amount of newly formed 3', 5'-AMP could thus escape degradation before it reaches the cellular target, where %− a is augmented. The results agree with the theory that 3', 5'-AMP initiates the positive inotropic effect of catecholamines as well as the rise in %− a, needed for the full development of the mechanical effect.