Original article
Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs

https://doi.org/10.1016/j.yjmcc.2006.02.001Get rights and content

Abstract

We have previously reported that histamine H2 blockers may be cardioprotective in patients with chronic heart failure. Since both endogenous histamine and histamine H2 receptors are present in heart tissue, we tested the hypothesis that the blockade of histamine H2 receptors mediates protection against reversible or irreversible ischemia and reperfusion injury. In open-chest dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Administration of famotidine and cimetidine from 10 minutes before occlusion until after 1 hour of reperfusion reduced infarct size (17.0 ± 4.1% and 17.8 ± 2.9% vs. 36.9 ± 5.9% of the solvent group, respectively) Famotidine administration only during the reperfusion period for 1 hour also attenuated infarct size (22.5 ± 3.5%). There were no differences in either area at risk or collateral flow among the groups. In another set of experiments, we decreased coronary perfusion pressure in dogs so that the coronary blood flow decreased to 50% of the non-ischemic level. In such conditions, we observed the increases in histamine release compared with non-ischemic conditions (0.04 ± 0.03 to 0.28 ± 0.13 ng/ml, p < 0.05). Famotidine improved anaerobic myocardial metabolism gauged by both lactate extraction ratio and myocardial oxygen consumption. We conclude that the blockade of histamine H2 receptors mediates improvements in the anaerobic myocardial metabolism, and thus protects against ischemia and reperfusion injury.

Introduction

Histamine is one of the autacoids and provokes various cellular functions via the stimulation of four different G-protein-coupled receptors, i.e. histamine H1–H4 receptors [1], [2]. Histamine H2 receptors, in particular, are known to be located in gastric cells and contribute to the production of acids that may cause gastric ulcers [1], [3]. Therefore, the blockade of histamine H2 receptors has been developed as a drug for the treatment of gastric ulcers. Interestingly, we have previously reported that histamine H2 blockers may be protective in patients with chronic heart failure (CHF) using the data mining technique [4], which enables us to find unexpected effective drugs for cardiovascular diseases [4]. In human ventricular tissue, histamine H1 receptor expression was less abundant, whereas histamine H2 receptors were highly expressed [5], and stimulation of H2 receptors transduces the intracellular signals via the Gs protein, as well as beta receptors [2], [6]. Indeed, it is reported that:

  • 1.

    histamine produces a positive inotropic effect in human ventricular muscles, likely due to the exclusive activation of H2 receptors [7], [8];

  • 2.

    histamine exerts a positive chronotropic effect via the H2 receptors [9];

  • 3.

    and the blockade of histamine H2 receptors decreases cardiac output in patients with CHF [10].

    If these were the case, the blockade of histamine H2 receptors protects the hearts against ischemia and reperfusion injury where histamine would be released in such a condition; beta-blockers are cardioprotective because catecholamine is released during ischemia and reperfusion.

We tested the hypothesis that the blockade of histamine H2 receptors improves protection against ischemia and reperfusion injury in canine hearts. We also investigated whether histamine is released in response to ischemic stress and modulates the myocardial contractile and metabolic function in canine hearts with coronary hypoperfusion.

Section snippets

Instrumentation

We have previously reported the details of the instrumentation procedure [11]. In brief, healthy adult beagle dogs for laboratory use (weighing 8–13 kg) were anesthetized with an intravenous injection of sodium pentobarbital (30 mg/kg), intubated, and ventilated using room air mixed with oxygen (100% O2 at flow rate of 1.0–1.5 l/min). The arterial blood pH, pO2, and pCO2 before starting the protocol were 7.37 ± 0.03, 103 ± 4 and 37.9 ± 1.9 mmHg, respectively. The chest was opened through the left

Protocol I: Effects of the histamine H2 blocker on myocardial metabolism and coronary blood flow in ischemic hearts

After the hemodynamics stabilization, coronary arterial and venous blood were sampled for blood gas analysis, and for the measurement of histamine [12], lactate [13] and the end-product (NOx) of nitric oxide (NO) levels [14], [15]. The plasma histamine concentration was determined by the radioimmunoassay kit (SRL Co. Ltd.). Lactate extraction ratio (LER) was calculated as the coronary arterio-venous difference of the lactate concentration multiplied by 100 and divided by the arterial lactate

Effects of famotidine on myocardial anaerobic metabolism during coronary hypoperfusion

Before both CBF and CPP were reduced, there were no significant differences in the systemic hemodynamic and metabolic parameters (Table 1; Fig. 1, Fig. 2). The reduction in both CPP and CBF increased the differences in histamine levels between coronary venous and arterial blood (dVA[histamine]) from 0.04 ± 0.03 to 0.28 ± 0.13 ng/ml (P < 0.05, N = 5), and cardiac NO levels prior to the administration of either famotidine or solvent in the famotidine and control groups (Fig. 3). The administration of a

Discussion

In the current study, we demonstrated that histamine release is increased from the ischemic myocardium, and the blockade of histamine H2 receptors improves anaerobic myocardial metabolism in ischemic hearts with reduced myocardial oxygen consumption. We also showed that the blockade of histamine H2 receptors limits infarct size but the blockade of histamine H1 receptors does not. These findings demonstrate that the blockade of histamine H2 receptors is beneficial against ischemia and

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