Relaxing effect of pharmacologic interventions increasing cAMP in rat heart

Abstract

The relationship between cAMP and relaxation was studied in the isolated rat heart beating at constant rate and perfused at constant coronary flow. After treatment during 1 min with different positive inotropic interventions, cyclic nucleotide levels (cAMP and cGMP) and cAMP-dependent protein kinase activity were determined in heart homogenates. Glucagon, norepinephrine, and isoproterenol increased cAMP from 0.503 +/- 0.025 pmol/mg wet wt to 1.051 +/- 0.099, 0.900 +/- 0.064, and 0.982 +/- 0.138, respectively. Simultaneously glucagon, norepinephrine, and isoproterenol increased cAMP-dependent protein kinase activity ratio from 0.21 +/- 0.02 to 0.45 +/- 0.04, 0.33 +/- 0.02, and 0.34 +/- 0.02, respectively. The ratio between maximal velocities of contraction and relaxation (+T/-T) was significantly decreased by these interventions, whereas time to peak tension (TTP) was shortened by norepinephrine and isoproterenol. High calcium, ouabain, and paired stimulation did not affect cAMP levels, TTP, or +T/-T. A striking correlation was found between cAMP-dependent protein kinase activity and relaxation induces, i.e., TTP, -T, or +T/-T (r = +/- 0.7 to -0.9). Results suggest that inotropic interventions increasing cAMP levels might be primarily affecting intracellular mechanisms causing relaxation.

Dissociation between contraction and relaxation: The possible role of phospholamban phosphorylation

“…23,000 was localized to a band of Mr betwen 11,000 and 12,000 (Fig. As already described (5,19,24), ISO produced a relaxant effect, evidenced by the proportional greater increase in -T than in +~i" (i.e. This behavior is typical of phospholamban, and the two proteins of different molecular weights are thought to be the high and low molecular forms of this protein (17,23).…”

“…However, differences in relaxation can occur despite identical changes in contraction (5,19,24), suggesting that the two processes can be modified separately: experiments from our own laboratory (5,24) have shown that the ratio between both maximal velocities (+T/-~i') can be decreased following pharmacological interventions which increase cAMP and cAMPdependent protein kinase activity. Whenever maximal velocity of contraction increases, maximal velocity of relaxation also increases.…”

“…In one of them (15), it was suggested that phospholamban phosphorylation appears to be more closely related to alterations in myocardial relaxation than to the positive inotropic action of isoproterenol. Previous experiments from our laboratory (5,24) have shown, on the other hand, that when myocardial contractility was enhanced by pharmacological interventions, which increase cAMP and cAMP-dependent protein kinase activity, myocardial relaxation was increased to a greater extent. Moreover, we have recently shown (25) that this dissociation between contraction and relaxation was still more evident when the negative inotropic effect of calcium blockers was overcome either by increasing extracellular calcium or by 15-adrenergic stimulation.…”

Cardiac and vascular effects of diltiazem, dobutamine and amrinone, drugs used after myocardial revascularization

“…High speed records (0.25 s/frame) were used in order to measure peak developed force (F) and, on its first derivative (dF/ dt), maximal velocity of contraction (+dF/ dt max ) and maximal velocity of relaxation (-dF/dt max ). The +dF/dt max /-dF/dt max ratio was calculated to evaluate the relative effect of each intervention on velocities of contraction and relaxation, with its decrease being considered evidence of a positive lusitropic (or relaxant) effect and its increase being considered evidence of a negative lusitropic (or antirelaxant) effect (7,8).…”

Lusitropic effects of α- and β-adrenergic stimulation in amphibian heart

“…In mammalian heart, the positive inotropic effect of ct and [3-adrenergic agents is coupled with different changes in relaxation. Whereas 13-adrenergic agonists cause a relaxant (positive lusitropic) effect [1][2][3], a-adrenergic stimulation evokes a negative lusitropic action [4]. Although both in-*Fellow of CONICET terventions appear to increase the amplitude ofcytosolic Ca 2 § transient, they have opposite effect on myofilament responsiveness to Ca :+-.…”