ELSEVIER Positive Inotropic Effect of Angiotensin II. Increases in Intracellular Ca2+ or Changes in Myofilament Ca2+ Responsiveness? Alicia Mattiazzi Centro de Investigaciones Cardiovasculares, Facultad de Medicina, (1900) La Plata, Argentina Although it is well known that Angiotensin II (Ang II) has a direct positive inotropic effect in several species, the mechanisms of this action are still poorly understood. The aim of this review is to analyze the possible subcellular mechanisms underlying Ang II-induced positive inotropic action. The binding of Ang II to its receptor triggers a complex signal transduction cascade that stimulates the intracellular formation of two second messengers, inositol 1,4,5triphosphate (IP,), and 1,2, diacylglycerol (DAG). IP, triggers the release of Ca’+ from intracellular stores in several cell types and has been shown to increase myofilament Ca2* sensitivity. DAG activates protein kinase C (PKC), an enzyme that catalyzes the phosphory- lation of different cellular proteins, including several proteins of the myofibrils. Distinct ionic transporters, like the Na+/H’ antiporter and the Na+-independent Cl-/HCO,- exchanger, implicated in the regulation of intracellular pH, and the Naf/Ca2’ exchanger which contribute to the intracellular Ca2+ homeostasis, have been shown to be activated by a PKC-dependent mechanism. Thus, either one of the Ang II-induced second messengers, that is, IP, and DAG, has the potential to affect myocardial contractility by modifying either intracellular Ca2+, myofilament Ca2+ responsiveness, or both. As described herein, the available data do not allow a definitive single model to explain the mechanism of the Ang II-induced positive inotropic effect. Moreover, it is possible that the final action of Ang II on myocardial inotropism is the end product of a complex interaction of several of the mechanisms triggered by the hormone. 0 1997 Elsevier Science Inc. Key Words: Positive inotropic interventions; Myocardial contractility; Calcium; Myofilament calcium responsiveness; Intracellular pH; Angiotensin II Introduction Angiotensin II (Ang II) is an octapeptide having multiple physiologic actions, most of which are directly or indirectly related to the cardiovascular system. Ini- tially identified as a powerful vasopressor (Braun MenCndez et al., 1940; Page and Helmer, 1940), the hormone was later found to have also direct actions on the heart, among which are inotropic and chronotropic effects (Koch-Weser, 1965; Kobayashi et al., 1978; Kass and Blair, 1981; Allen et al., 1988; Baker and Aceto, 1989; Moravec et al., 1990; Ishihata and Endoh, 1993; Ikenouchi et al., 1994; Ishihata and Endoh, 1995; Mat- tiazzi et al., 1997). In addition to these acute actions, Ang II also has long-term effects which include the expression of genes responsible for cell growth (Neyses et al., 1993). Received January28, 1997;revised and accepted April 1, 1997. Journal of Pharmacological and Toxicological Methods 37. 205-214 (1997) 0 1997 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York. NY 10010 The development of our present-day knowledge on Ang II stems from the observations of Bright (1836) who postulated an association between renal disease and hypertension. Later on, Tigerstedt and Bergman (1898) found that a substance obtained from kidney extracts caused an increase in blood pressure. It is now known that this substance, named renin, is a proteolytic enzyme which hydrolyzes angiotensinogen, an ol,-globulin nor- mally present in blood, to produce the decapeptide angiotensin I. Angiotensin I is, in turn, cleaved by a peptidase, the so-called converting enzyme, to form the active octapeptide Ang II. This vasoactive agent pro- duced by renin was discovered independently in 1940, by Braun MenCndez et al., in Argentina, who named the substance hypertensin and by Page and Helmer, in the USA, who chose the name angiotonin. In 1958, the two groups agreed to rename this agent arzgiotensin. In the last decade, it has become apparent that there exist localized renin-angiotensin systems in different tissues 1056-8719/97/$17.00 PII SlO56-8719(97)00020-S