Diminished cardiac contractile response to tetrahydropapaveroline in hypertension: role of β-adrenoceptors and intracellular Ca²⁺

Abstract 

Tetrahydropapaveroline (THP), a condensation product of ethanol-derived acetaldehyde, potentiates cardiac function through a β-adrenergic mechanism. It is well established that β-adrenergic activity is markedly depressed in hypertension. However, little is known about the myocardial action of THP in hypertension. In this study, the effect of THP was examined using left ventricular papillary muscles and ventricular myocytes from 10-week-old normotensive (WKY) and spontaneously hypertensive (SHR) rats. The mechanical parameters evaluated include: peak tension developed (PTD), peak twitch amplitude (PTA), time-to-PTD/PTA (TPT/TPS), time-to-90% relaxation/relengthening (RT₉₀/TR₉₀), and the maximal velocities of contraction/shortening and relaxation/relengthening (±VT/±dL/dt). Intracellular Ca²⁺ transients were measured as fura-2 fluorescence intensity changes (ΔFFI). THP (0.01–100 μM) produced a concentration-dependent increase in myocardial contraction on muscles and myocytes from both groups of animals. However, preparations from the SHR group were generally less responsive to THP than their normotensive counterparts. The increase in contractility by THP was associated with increases in ΔFFI and ±VT, and shortening of TPT/TPS and RT₉₀/TR₉₀. The role of β-adrenoceptor(s) in the mechanism of action of THP was explored using specific β-receptor subtype antagonists CGP 207.12A (β₁) and ICI 118,551 (β₂). In preparations from both WKY and SHR hearts, the THP-induced increase in cardiac contractility was either attenuated or blocked by CGP 207.12A and ICI 118,551. These results indicate that THP exhibits a positive action on myocardial contraction that is mediated, in part, through both β₁ and β₂ adrenergic receptors. This cardiac inotropic response, however, is markedly diminished in hypertension, which is due possibly to alterations in β-adrenergic signal transduction.

Keywords:  Tetrahydropapaveroline, Hypertension, Myocardial contraction, Myocyte, β-Adrenergic receptor