Effect of long-term streptozotocin-induced diabetes on coronary vasoconstriction in isolated perfused rat heart

Abstract

The primary goal of this study was to investigate the effect of long-term (9 months) streptozotocin (STZ)-induced diabetes on the coronary vasoconstrictor responses to vasoactive agents such as high K(+), acetylcholine (ACh), endothelin-1 (ET-1), and the calcium-channel activator Bay K 8644. For this, we used isolated rat hearts perfused at constant flow rate. Each of the four agents caused dose-dependent increases in perfusion pressure in isolated hearts from age-matched control and STZ-induced diabetic rats. The dose-response curves for high K(+), ACh, and ET-1 were shifted to the left, so that at some lower doses of these agents the increased perfusion pressure was greater in coronary arteries obtained from diabetic rats than in those from control rats. On the other hand, the maximum contractile response induced by each of these agents was lower in the diabetic perfused heart. The Bay K 8644-induced contractile response was significantly greater in the coronary arteries of diabetic rats than in those of control rats. A threshold-constrictor concentration of Bay K 8644 (1 nM) potentiated the ACh-induced vasoconstriction in coronary arteries from both groups, and the potentiated responses were greater in diabetic rats than in controls at lower concentrations of ACh (100 nM and 1 microM). These findings suggest that the coronary artery contractile responses to lower concentrations of ACh or ET-1 are exaggerated in long-term STZ-induced diabetic hearts. These changes may be due to alterations in the activity of voltage-gated Ca(2+) channels.

Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia

“…At this later time point, both HFD and DM ϩ HFD swine showed an increased responsiveness to exogenous ET-1. These results are in agreement with rat models of long-term type 1 DM showing exaggerated coronary ET-1 responsiveness combined with increased ET-1 plasma levels, although the presence of CAD was not verified (29,31).…”

“…For example, the ET-1 system is activated in diabetes, resulting in increased ET-1 plasma levels (5,23), which correlates well with diabetic microangiopathy (2). However, conflicting data have been reported regarding ET-1 reactivity, with reduced responsiveness to exogenous ET-1 in the peripheral circulation of obese (74) and type 2 DM (15,44,59) patients and increased ET-1 vasoconstriction in animal models of DM (31,67,73). Although this discrepancy is not readily explained, the present study, in conjunction with our previous observations (71), demonstrates that disease progression might be one explanation.…”

Impaired Ca2+ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

“…Thus, the increased reactivity to ␣ 1 -adrenoceptor stimulation was found to be largely dependent on the increase in cytosolic [Ca 2ϩ ] i in arteries from type 1 diabetic humans (16) and rats (1,2). Furthermore, enhanced extracellular Ca 2ϩ influx through voltage-gated Ca 2ϩ channels has been suggested to contribute to the enhanced contraction to norepinephrine in type 1 diabetic arteries (21,36,42), although an apparent increased release of intracellular Ca 2ϩ was also reported (1,2). In contrast to the latter studies, enhanced contractile responses to norepinephrine were shown to be largely independent of changes in [Ca 2ϩ ] i but rather due to the enhanced sensitivity of the contractile proteins to Ca 2ϩ in mesenteric arteries from streptozotocin-induced diabetic rats (12).…”

Diabetes enhances the intrahepatic vascular response to endothelin‐1 in cirrhotic rats: association with the ETA receptor and pERK up‐regulation

“…ET‐1 plays an important role in the vascular derangements associated with diabetes. Coronary artery contractile response to ET‐1 has been found to be enhanced in isolated perfused hearts of long‐term diabetic rats . Furthermore, after 12 weeks of hyperglycaemia, ET‐1 gene transcription was found to be increased by 2.1‐fold in diabetic vs control rat kidneys .…”