Original article
Cardiovascular
Diazoxide Provides Maximal KATP Channels Independent Protection if Present Throughout Hypoxia

https://doi.org/10.1016/j.athoracsur.2005.11.045Get rights and content

Background

It is not clear what the optimal timing of diazoxide administration for cardioprotection in human myocardium is. We aimed to establish it. We next checked whether protection depended on adenosine triphosphate (ATP)–inhibited potassium (KATP) channels.

Methods

Isolated human right atrial trabeculae were subjected to 90-minute hypoxia and 120-minute reoxygenation in vitro, followed by adding 10-4 M norepinephrine. Diazoxide (100 μΜ) was added (1) as a 10-minute preconditioning signal with 10-minute washout before hypoxia or (2) 10-minute pretreatment without washout before hypoxia or (3) throughout hypoxia or (4) 10 minutes before and throughout hypoxia or (5) during the first 20 minutes of reoxygenation only. In the control, no diazoxide was added. In another set of experiments, diazoxide (100 μΜ) was present throughout hypoxia in control, while we tried to inhibit its protective effect with glibenclamide (1, 10, 100 μΜ) or 5-hydroxydecanoate (100 μΜ).

Results

The presence of diazoxide throughout hypoxia improved recovery of contractility during reoxygenation, allowed for significant response to norepinephrine at the end of reoxygenation, prevented “ischemic contracture” development, and reduced release of troponin I to tissue bath during hypoxia. Adding diazoxide 10 minutes before hypoxia conferred significantly weaker protective effects in all the above respects. We failed to show a protective effect of diazoxide used as a preconditioning signal or during reoxygenation. Neither 5-hydroxydecanoate nor glibenclamide significantly influenced protective effects of diazoxide added during hypoxia.

Conclusions

Administration of diazoxide throughout hypoxia provided maximal protective effect, suggesting that diazoxide may be an important adjunct to cardioplegic solution. The protection offered by diazoxide used during hypoxia appears independent of its influence on KATP channels.

Section snippets

Material and Methods

The experiments were performed on right atrial trabeculae obtained from patients undergoing elective coronary artery surgery (Table 1). Specimens acquired from diabetic patients were excluded. The Local Bioethics Committee approval for the use of human tissue was obtained and individual patient consent was waived.

The tissue was transferred in ice-cold Krebs-Henseleit solution to the laboratory. The single trabecula less than 1 mm in diameter was mounted in the organ chamber (Schuler Organbath;

Results

The recovery of contraction force at 10 minutes of reoxygenation after 90-minute hypoxia was on average 30% ± 2.7% in control. It was significantly enhanced by adding 100 μΜ diazoxide to the tissue bath. When diazoxide was present throughout hypoxia, the 10-minute recovery was 65% ± 4.3% (p < 0.001); and when it was added 10 minutes before and present throughout hypoxia, it reached 82% ± 10.5% (p < 0.001). Diazoxide pretreatment also conferred some protective effect with the contraction force

Comment

The important findings of our study are as follows: (1) diazoxide presence in tissue bath during hypoxia allows for significantly stronger myocardial protection than its use as a “pharmacologic preconditioning” signal as assessed by both functional recovery and troponin I release; (2) diazoxide presence in the tissue bath throughout hypoxia prevents development of ischemic contracture; (3) the functional recovery correlates significantly with the degree of ischemic contracture at the end of

References (19)

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    In the present study, the addition of 5HD (mitochondrial KATP-channel blocker) or HMR 1098 (sarcolemmal KATP-channel blocker) did not reverse the beneficial effect observed by diazoxide after metabolic inhibition. These findings are consistent with our previous work in which HMR 1098 did not inhibit the beneficial effects of diazoxide or pinacidil in animal and human myocytes [2; unpublished data] and the work of others who have found that 5HD does not inhibit the protective effects of diazoxide [18]. However, these results are not consistent with other reports documenting a reversal or a partial reversal of diazoxide’s cardioprotection with the use of 5HD [14, 17, 19, 20].

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