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In this report we investigate the molecular mechanisms that contribute to tissue damage following ischemia and ischemia coupled with reperfusion (ischemia/reperfusion) in the rat heart and kidney. We observe the activation of three stress-inducible mitogen-activated protein (MAP) kinases in these tissues: p38 MAP kinase and the 46- and 55-kDa isoforms of Jun N-terminal kinase (JNK46 and JNK55). The heart and kidney show distinct time courses in the activation of p38 MAP kinase during ischemia but no activation of either JNK46 or JNK55. These two tissues also respond differently to ischemia/reperfusion. In the heart we observe activation of JNK55 and p38 MAP kinase, whereas in the kidney all three kinases are active. We also examined the expression pattern of two stress-responsive genes, c-Jun and ATF3. Our results indicate that in the heart both genes are induced by ischemia and ischemia/reperfusion. However, in the kidney c-Jun and ATF3 expression is induced only by ischemia/reperfusion. To correlate these molecular events with tissue damage we examined DNA laddering, a common marker of apoptosis. A significant increase in DNA laddering was evident in both heart and kidney following ischemia/reperfusion and correlated with the pattern of kinase activation, supporting a link between stress kinase activation and apoptotic cell death in these tissues.

Atropine produces cardioacceleration in conscious dogs partly by reversing the pre-existing parasympathetic cardioinhibition and partly by inducing "excess tachycardia" (ET). Because ET occurs independently of adrenergic mechanisms, the present study sought to determine whether ET is generated by a positive chronotropic action of endogenous histamine on pacemaker cell H1 receptors. ET was antagonized in conscious dogs by the H1-receptor antagonists pyrilamine, diphenhydramine, chlorpheniramine and promethazine (1-5 mg/kg i.v.), but not the H2-receptor antagonist cimetidine (2-10 mg/kg i.v.). Pyrilamine (0.1 mg/kg i.v.), but not cimetidine (4 mg/kg i.v.), also eliminated a histamine tachycardia (31 +/- 4.1 beats/min) produced by injecting histamine (22 +/- 14.2 micrograms) into the sinus node artery after pharmacological autonomic blockade. The 30-fold greater dose of pyrilamine required to antagonize ET than histamine tachycardia suggests a nonantihistaminic, and possibly a local anesthetic mechanism of action on ET. Indeed, lidocaine, procaine, propranolol and pyrilamine antagonized ET in doses corresponding to the known relative local anesthetic potencies of these agents. The same doses of pyrilamine, lidocaine and procaine had significantly less effects on a comparable beta adrenergic tachycardia produced by intravenous isoproterenol infusion (0.1-0.5 micrograms/kg/min i.v.) after hexamethonium (10 mg/kg i.v.). The results indicate that H1-receptor blockers antagonize ET because of their local anesthetic effects and not their antihistaminic properties. The results also suggest that the ionic pacemaker mechanisms generating ET and beta adrenergic tachycardia are different.