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R Bolli

Publications and source records attributed to R Bolli.

184 records · Page 11Linked to original sources
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Basic and clinical aspects of myocardial stunning.

Although the pathogenesis of myocardial stunning has not been definitively established, the two major hypotheses are that it is caused by the generation of oxygen-derived free radicals on reperfusion and by a loss of sensitivity of contractile filaments to calcium. These hypotheses are not mutually exclusive and are likely to represent different facets of the same pathophysiological cascade. For example, a burst of free radical generation after reperfusion could alter contractile filaments in a manner that renders them less responsive to calcium. Increased free radical formation could also cause cellular calcium overload, which would damage the contractile apparatus of the myocytes. There is now considerable evidence that myocardial stunning occurs clinically in various situations in which the heart is exposed to transient ischemia, such as unstable angina, acute myocardial infarction with early reperfusion, exercise-induced ischemia, cardiac surgery, and cardiac transplantation. Recognition of myocardial stunning is clinically important and may impact patient treatment. Although no ideal diagnostic technique for myocardial stunning has yet been developed, thallium-201 scintigraphy or dobutamine echocardiography are available and can be useful to identify viable myocardium with reversible wall motion abnormalities. An intriguing possibility is that so-called chronic hibernation may in fact be the result of repetitive episodes of stunning, which have a cumulative effect and cause protracted postischemic left ventricular dysfunction. A better understanding of myocardial stunning will expand our knowledge of the pathophysiology of myocardial ischemia and provide a rationale for developing new therapeutic strategies designed to prevent postischemic dysfunction.

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Bifunctional role of protein tyrosine kinases in late preconditioning against myocardial stunning in conscious rabbits.

Although protein tyrosine kinases (PTKs) have been implicated in late preconditioning (PC) against infarction, their role in late PC against stunning is unknown. Furthermore, it is unknown whether PTK signaling is necessary only to trigger late PC on day 1 or also to mediate it on day 2. Thus, conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). In the control group (group I, n=7), the recovery of systolic wall thickening after the 6 occlusion/reperfusion cycles was markedly improved on days 2 and 3 compared with day 1, indicating the development of late PC against stunning. Administration of the PTK inhibitor lavendustin-A (LD-A, 1 mg/kg IV) before the first occlusion on day 1 (group II, n=7) completely prevented the late PC effect against stunning on day 2. Late PC against stunning was also abrogated when LD-A was given before the first occlusion on day 2 (group III, n=7); however, in these rabbits, the late PC effect became apparent on day 3, indicating that LD-A itself did not have any delayed deleterious actions on myocardial stunning. In group V (n=5), the sequence of 6 occlusion/reperfusion cycles resulted in a robust increase in the activity of inducible NO synthase (iNOS [assessed as Ca(2+)-independent L-citrulline formation]) and nitrite+nitrate (NO(x)) tissue levels 24 hours later (on day 2), with no concomitant change in Ca(2+)-dependent NO synthase (endothelial NO synthase and/or neuronal NO synthase) activity. Similar results were obtained on day 3 (group VIII, n=6), indicating sustained upregulation of iNOS. Administration of LD-A either on day 1 (group VI, n=5) or on day 2 (group VII, n=6) abrogated the increase in iNOS activity and NO(x) levels on day 2. LD-A had no effect on iNOS activity or NO(x) levels in the absence of PC (group X, n=5). This study demonstrates that in conscious rabbits, PTK activity is necessary not only to trigger late PC against stunning on day 1 but also to mediate the protection on day 2. This investigation also provides the first direct evidence that cardiac iNOS activity is upregulated during the late phase of ischemic PC in rabbits. Furthermore, the data indicate that PTK signaling is essential for the augmentation of iNOS activity and that PTKs modulate this enzyme at two distinct levels: at an early stage on day 1 and at a late stage on day 2. This bifunctional role of PTKs in late PC has broad implications for the signaling mechanisms that underlie the response of the heart to ischemic stress and, possibly, other stresses.

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