Streptozotocin diabetes protects against arrhythmias in rat isolated hearts: role of hypothyroidism
Introduction
Ischaemic heart disease is an important cause of death in diabetic patients Kannel et al., 1974, Schernthaner, 1996, Pickup and Williams, 1997. Whether or not the diabetic heart is more susceptible to ischaemia–reperfusion arrhythmias is uncertain (Feuvray and Lopaschuk, 1997) and results obtained from experimental diabetes are conflicting. Diabetic animals were reported to have more spontaneous arrhythmias Navaratnam and Khatter, 1989, Hekimian et al., 1985. Other studies showed the diabetic heart to be either more vulnerable Hekimian et al., 1985, Bhimji et al., 1986, Bakth et al., 1986, Beatch and McNeill, 1988, Tosaki et al., 1996 or more resistant to ischaemia–reperfusion arrhythmias Kusama et al., 1992, Suzuki et al., 1993. Most of these studies have used streptozotocin- or alloxan-induced diabetes, which are models widely used to study all aspects of the disease. Hypothyroidism is associated with both models of diabetes Sochor et al., 1987, Sundaresan et al., 1984, Rodgers et al., 1991, Rondeel et al., 1992, Schroder-Van Der Elst and Van Der Heide, 1992, Katovitch et al., 1993. As thyroid hormones are important in maintaining cardiac function, hypothyroidism could contribute to the cardiac dysfunction in diabetes. Indeed, hypothyroidism was shown to contribute significantly to the reduced cardiac contractility seen in the diabetic, renovascular hypertensive rat (Rodgers et al., 1991). However, other studies showed no effect of thyroid hormone treatment on diabetes-induced cardiac dysfunction Barbee et al., 1988, Sato et al., 1989, Beenen et al., 1996. Moreover, cardiac dysfunction was also observed in spontaneous diabetic BB rats, in the absence of hypothyroidism (Ramanadham et al., 1989). Most of these studies have concentrated on measurement of cardiac contractility, and there is no information about the contribution of hypothyroidism to altered susceptibility to ischaemia–reperfusion arrhythmias in diabetes. Apart from its negative cardiac inotropic and chronotropic effects, hypothyroidism is profoundly antiarrhythmic in dog Venkatesh et al., 1991, Liu et al., 1996 and rat hearts (Chess-Williams and Coker, 1989) in vivo. Preliminary observations Zhang et al., 1999a, Zhang et al., 1999b indicated that streptozotocin-induced diabetes protected the ex vivo heart against ischaemia–reperfusion induced arrhythmias. This effect of diabetes may conceivably be secondary to hypothyroidism. Activation of protein kinase C has been implicated in the protective effect on the heart of ischaemic preconditioning (Downey and Cohen, 1997), although there is little work on the role of protein kinase C in the protective effect of preconditioning against arrhythmias. Increases in protein kinase C activity and expression have been found in the diabetic heart Giles et al., 1998, Inoguchi et al., 1992, Xiang and McNeill, 1992. Therefore, we determined the effect of diabetes on ventricular levels of protein kinase C isoforms to see if these changes could be related to the effects on the heart.
Section snippets
Experimental diabetes
Diabetes was induced in male Sprague–Dawley rats (200–220 g) by a single streptozotocin injection (60 mg/kg, i.p.). Age- and weight-matched control rats received the same volume of vehicle. Animals were housed in pairs for 2–8 weeks with free access to normal laboratory diet and water. Diabetes was confirmed by glycosuria with reagent strips for urinalysis (Bayer, Berks) and serum glucose was assayed at the end of experiments (Beckman Glucose Analyzer). Any streptozotocin-injected rat not
Effects of streptozotocin diabetes on body weight, heart weight, Q–T interval, ex vivo heart rate, rectal temperature and serum concentrations of glucose and thyroid hormones
Two weeks after induction of diabetes, the serum glucose concentration of diabetic rats was significantly increased and serum free thyroxine concentration was significantly decreased, compared to age-matched control rats (Table 1). There was a significant negative correlation between serum free thyroxine and glucose concentrations (r=−0.76, n=10, P<0.05). The weight gain was significantly lower in the diabetic rats. There was no significant difference in the rectal temperature, ex vivo heart
Diabetes-induced hypothyroidism
The present study confirmed that streptozotocin diabetes in the rat produces hypothyroidism Sundaresan et al., 1984, Rodgers et al., 1991, Rondeel et al., 1992, Schroder-Van Der Elst and Van Der Heide, 1992, Katovitch et al., 1993 as evidenced by the reduction of serum concentrations of thyroid hormone concentrations. The reduction in free thyroxine and free triiodothyronine concentrations, together with clinical signs of hypothyroidism (decreased heart rate, prolonged Q–T interval and
Acknowledgements
LQZ was supported by an ORS award. We are grateful to the Henry Lester Trust and Great Britain-China Education Trust for financial support (LQZ) and to G. Walker, G. Watt and C. Whitehouse for their excellent technical support.
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