Potential Role of Bradykinin in Forearm Muscle Metabolism in Humans

Abstract

Using the euglycemic-hyperinsulinemic glucose clamp and the human forearm technique, we have demonstrated that the improved glucose disposal rate observed after the administration of an angiotensin-converting enzyme (ACE) inhibitor such as captopril may be primarily due to increased muscle glucose uptake (MGU). These results are not surprising because ACE, which is identical to the bradykinin (BK)-degrading kininase II, is abundantly present in muscle tissue, and its inhibition has been observed to elicit the observed metabolic actions via elevated tissue concentrations of BK and through a BK B2 receptor site in muscle and/or endothelial tissue. These findings are supported by several previous studies. Exogenous BK applied into the brachial artery of the human forearm not only augmented muscle blood flow (MBF) but also enhanced the rate of MGU. In another investigation, during rhythmic voluntary contraction, both MBF and MGU increased in response to the higher energy expenditure, and the release of BK rose in the blood vessel, draining the working muscle tissue. Inhibition of the activity of the BK-generating protease in muscle tissue (kallikrein) with aprotinin significantly diminished these functional responses during contraction. Applying the same kallikrein inhibitor during the infusion of insulin into the brachial artery significantly reduced the effect of insulin on glucose uptake into forearm muscle. This is of interest, because in recent studies insulin has been suggested to elicit its actions on MBF and MGU via the accelerated release of endothelium-derived nitric oxide, the generation of which is also stimulated by BK in a concentration-dependent manner. This new evidence obtained from in vitro and in vivo studies sheds new light on the discussion of whether BK may play a role in energy metabolism of skeletal muscle tissue.

Temporal profiling of the transcriptional basis for the development of corticosteroid-induced insulin resistance in rat muscle

“…However, it has been reported that skeletal muscle membranes also contain this enzyme (Dragovic et al 1996). Regardless of the origin of this transcript, inhibitors of this enzyme have been shown to improve glucose uptake into skeletal muscles (Bottermann & Classen 1991, Dietze et al 1996. Thus the enhanced expression of kininase II would contribute to insulin resistance.…”

Cardioprotective properties of bradykinin: role of the B2 receptor

“…35 Another property of the kallikrein-kinin system contributing to its tissue-protective actions is its capacity to enhance the insulin-dependent glucose transport and metabolism, 36,37 which has been shown in both animal and human experiments. 37,38 Indeed, the well-recognized effect of ACE inhibition to improve insulin sensitivity is in part attributed to bradykinin, 39 whereas kininogen-deficient rats were found to be resistant to insulin. 40 This effect of ACE inhibition is also mediated by the B 2 R, because it is reversed by selective B 2 R antagonists; 19,20 but, unlike the vasodilatory effects of bradykinin, which are exerted via B 2 R-mediated activation of the prostaglandin-NO cascade (which can also be stimulated by the B 1 R, albeit via different mechanism), 41 this metabolic activity appears to be a direct effect of the B 2 R. 20,42,43 Indeed, B 2 R gene knockout mice show severe insulin resistance, despite compensatory upregulation of the B 1 R. 42 Cardiovascular complications of hypertension and atherosclerosis are associated with elevation in plasma levels of biochemical markers of inflammation, such as the proinflammatory cytokines interleukin-6 and tumor necrosis factor-a (TNF-a), as well as the resulting stimulation of C-reactive protein.…”

Review: Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis

“…79 Kinins are involved in the effects of contraction and insulin on vasodilation and glucose transport, respectively, primarily in muscles containing predominantly red fibres. 47,49,[80][81][82][83] Inhibiting kinin generation attenuates their actions, 48,50 whereas blocking their degradation has the opposite effect. [84][85][86][87][88] The provision of kinins accelerates GLUT4 translocation to the sarcolemma and increases glucose transport activity by an insulin-, protein kinase C-, and phosphatidyl-inositol-3-kinase-independent pathway.…”

“…[62][63][64][65][66] Moreover, they increase glucose utilisation in SMT similar to a contraction stimulus. [48][49][50] Thus, both adenosine and kinins may contribute to the multifactorial metabolic control of the physiological responses of SMT during endurance exercise. 58 However, with regard to their physiological role in this multifactorial regulation, kinins appear to fit better into the inherent mechanisms which optimally control muscle bioenergetics and thus maintain BP and glucose homeostasis during endurance exercise, as will be discussed in the following section.…”