Cardiac kinin level in experimental diabetes mellitus: role of kininases

Abstract

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n ϭ 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinindegrading enzymes.bradykinin; kininase; myocardial ischemia AN INCREASE IN CARDIAC KININS might be a mechanism for protecting the heart during hypertension, cardiac failure, or acute myocardial infarction (MI). Several authors have reported increased endogenous levels of kallikrein (KLK), kininogen, and bradykinin (BK) and an upregulation of B 1 and B 2 receptors in response to cardiac ischemia (1,12,15,18,25,34,35). Direct application of BK in perfusion medium improves cardiac left ventricular (LV) function, coronary flow, and myocardial metabolism and reduces the infarct size of isolated working rat hearts during and after induction of myocardial ischemia via activation of the prostaglandin and nitric oxide (NO) axis (36). Likewise, the inhibition of kinin breakdown by kininase inhibitors has been shown to exert cardioprotective effects in in vivo models of MI (11,42).Several changes of the cardiac kallikrein-kinin system (KKS) have been found under diabetic conditions that may contribute to the profoundly altered myocardial and vascular integrity during the development of diabetic cardiopathy (30,31,38). Reduced effectiveness of exogenously applied BK on vascular dilation has been reported in diabetic subjects with endothelial dysfunction (14, 39). Moreover, we and others (30, 31, 38) have described reduced endogenous cardiac kininogen and KLK levels and/or alterations in the activation of cardiac tissue KLK in diabetic animals. Thus a reduction in the BK precursor content and in the activity of the BK-forming enzyme KLK may indicate a decreased capacity for generating cardiac BK and may be among the mechanisms involved in the development of coronary...

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

“…n=4-6 per group. Asterisks p<0.05 vs SD, section marks p< 0.05 vs STZ + atorvastatin after STZ-injection, as indicated by impaired systolic and diastolic function [33], a finding which is in agreement with others [34][35][36][37]. Atorvastatin treatment in diabetic rats led to a significant improvement of systolic contraction and relaxation compared with untreated diabetic animals (dP/dt max +95%, dP/dt min +64%; p<0.05), whereas atorvastatin did not affect LV function in non-diabetic animals.…”

The role of the renal kallikrein–kinin system in diabetic nephropathy

“…Although the mechanisms have not been well understood, the interaction of the KKS and RAS is further supported by our findings, showing that the renal expression of ACE in transgenic rats expressing the human KLK1 gene is reduced, whereas it is increased in kidneys of kininogen-deficient rats (Fig. 1) [45]. The clinical relevance of the newly elucidated mechanisms of ACE inhibitor inducing a cross-talk between ACE and B2 receptors, the role of ANG-(1-7)-dependent bradykinin-accumulation and the importance of AT2 receptor-dependent KKS stimulation during AT1 antagonism still remain to be determined, however.…”

“…ACE binding was reduced in TGR(KLK1) compared with controls and BN-K rats. TGR(KLK1) rats are characterized by increased basal bradykinin levels [45]. Kininogen deficiency led to a significant increase in renal ACE binding, suggesting an interaction between the renal kallikrein-kinin system and the renin-angiotensin system.…”

Improvement of defective sarcoplasmic reticulum Ca2+transport in diabetic heart of transgenic rats expressing the human kallikrein‐1 gene

“…Coronary BK outflow was determined in Langendorff mode buffer-perfused isolated hearts of WT and TGR(hKLK1) (n=7 each) as recently described (14). Briefly, hearts were perfused via the aorta at a constant perfusion pressure of 60 mmHg using a modified Krebs-Henseleit solution.…”