Histaminergic receptors modulate the coronary vascular response in isolated guinea pig hearts. Role of nitric oxide.

OBJECTIVE: The effects of histamine and of histamine receptor agonists and antagonists on the coronary outflow and on the generation of nitric oxide (NO) were evaluated on isolated guinea pig hearts. METHODS: Isolated guinea pig hearts were perfused for 50 min in a Langendorff apparatus with histamine (10(-7)- 10(-8) M), in the absence or in the presence of N(G)-monomethyl-L-arginine (L-NMMA, 10(-4) M), a NO synthase inhibitor and of triprolidine (3.10(-8) M) and cimetidine (10(-7) M), H(1) receptor and H(2) receptor antagonists, and with trifluoromethyl-phenylhistamine (TFMPH, 10(-7) M) and dimaprit (10(-7) M), H(1) and H(2) receptor agonists. The effects of (R)-alpha-methylhistamine (10(-7) M), a H(3) receptor agonist and of FUB 181 (10(-7) M), a H(3) receptor antagonist, were studied in the presence of bradykinin (10(-7) M). RESULTS: Histamine increases the coronary outflow and the generation of NO in a concentration-dependent fashion. The effects were completely abolished by blocking NO-synthase (NOS) with L-NMMA (10 (-4 ) M). The effects were also abolished by cimetidine (10 (-7 ) M), H (2 ) receptor antagonist, and only scarcely affected by triprolidine (3.10 (-8 ) M), H (1 ) receptor antagonist. The effects were reproduced by dimaprit (10 (-7 ) M), H (2 ) receptor agonist, and only scarcely by TFMPH (10 (-7 ) M), a selective H (1 ) receptor agonist. Bradykinin (10 (-7 ) M) produces a sustained coronary dilation paralleled by a marked increase in the generation of NO; the effects were significantly reduced by L-NMMA. The stimulation of H (3 ) receptors by (R)-alpha-methylhistamine (10 (-7 ) M) significantly reduced both effects, which reverted to normal with FUB 181 (10 (-7 ) M), an H (3 ) receptor antagonist. CONCLUSION: These results suggest that, in isolated guinea pig hearts, histamine produces coronary dilation through an H (2 )/H (3 )-dependent mechanism involving the generation of nitric oxide.

Heme oxygenase-1 and the ischemia-reperfusion injury in the rat heart.

Carbon monoxide (CO) is a signaling gas produced intracellularly by heme oxygenase (HO) enzymes using heme as a substrate. During heme breakdown, HO-1 and HO-2 release CO, biliverdin, and Fe(2+). In this study, we investigated the effects of manipulation of the HO-1 system in an in vivo model of focal ischemia-reperfusion (FIR) in the rat heart. Male Wistar albino rats, under general anesthesia and artificial ventilation, underwent thoracotomy, the pericardium was opened, and a silk suture was placed around the left descending coronary artery; ischemia was induced by tightening the suture and was monitored for 30 min. Subsequently, the ligature was released to allow reperfusion lasting for 60 min. The first group of rats was sham operated and injected intraperitoneally (i.p.) with saline. The second group underwent FIR. The third group was treated ip 18 hr before FIR with hemin (4 mg/kg). The fourth group was pretreated ip 24 hr before FIR and 6 hr before hemin with zinc protoporphyrin IX (ZnPP-IX, 50 microg/kg). Specimens of the left ventricle were taken for determination of HO expression and activity, infarct size, malonyldialdehyde (MDA) production, and tissue calcium content. FIR led to a significant increase in the generation of MDA and notably raised tissue calcium levels. Induction of HO-1 by hemin significantly decreased infarct size, incidence of reperfusion arrhythmias, MDA generation, and calcium overload induced by FIR. These effects were prevented by the HO-1 inhibitor ZnPP-IX. The present experiments show that the concerted actions of CO, iron, and biliverdin/bilirubin modulate the FIR-induced myocardial injury.

Haeme oxygenase-1 and cardiac anaphylaxis.

1. Haeme oxygenase (HO) is an enzyme mainly localized in the smooth endoplasmic reticulum and involved in haeme degradation and in the generation of carbon monoxide (CO). Here we investigate (1) whether the inducible isoform of HO (HO-1) is expressed in the isolated heart of the guinea-pig and (2) the functional significance of HO-1 on the response to antigen in isolated hearts taken from actively sensitized guinea-pigs. 2. Both the HO-1 expression and activity are consistently increased in hearts from guinea-pigs pretreated with hemin, an HO-1 inducer (4 mg kg(-1) i.p., 18 h before antigen challenge). The administration of the HO-1 inhibitor zinc-protoporphyrin IX (ZnPP-IX, 50 micromol kg(-1), i.p., 6 h before hemin) abolished the increase of both the HO-1 expression and activity. 3. In vitro challenge with the specific antigen of hearts from actively sensitized animals evokes a positive inotropic and chronotropic effect, a coronary constriction followed by dilation and an increase in the amount of histamine in the perfusates. In hearts from hemin-pretreated animals, antigen challenge did not modify the heart rate and the force of contraction; the coronary outflow was significantly increased and a diminution of the release of histamine was observed. The patterns of cardiac anaphylaxis were fully restored in hearts from animals treated with ZnPP-IX 6 h before hemin. 4. In isolated hearts perfused with a Tyrode solution gassed with 100% CO for 5 min and successively reoxygenated, the response to antigen was similar to that observed in hearts from hemin-pretreated animals. 5. Pretreatment with hemin or the exposure to exogenous CO were linked to an increase in cardiac cyclic GMP levels and to a decrease of tissue Ca(2+) levels. 6. The study demonstrates that overexpression of HO-1 inhibits cardiac anaphylaxis through the generation of CO which, in turn, decreases the release of histamine through a cyclic GMP- and Ca(2+)-dependent mechanism.