Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

Abstract

channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1 (Ϫ/Ϫ) ], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 g·kg Ϫ1 ·min Ϫ1 ) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1(Ϫ/Ϫ) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 L-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicinmediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4 -6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1 (Ϫ/Ϫ) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channeldependent pathway that is corrupted in diabetes. transient receptor potential vanilloid 1 channels; capsaicin; coronary; cardiac metabolism; myocardial blood flow TYPE II DIABETES INCREASES the morbidity and mortality to many cardiovascular-related diseases, such as coronary artery disease (CAD) by as much as fourfold vs. nondiabetic patients (17,30). This is attributed in part, to a greater development of both micro-and macrovascular disease. Impaired coronary microvascular blood flow contributes to the increased cardiovascular events associated with diabetes through numerous mechanisms (27, 35). The proposed mechanism for the pathogenesis of diabetic cardiomyopathy likely reflects the multifactorial and highly complex nature of diabetes, but arterial dysfunction clearly appears to be a contributing factor.The transient receptor potential vanilloid 1 (TRPV1) channels are characteristically gated by chemical and physical stimuli including changes in pH, heat, ethanol, and endovanilloid compounds such as capsaicin (5). We and others (1,3,7,10,31,41,43) have revealed TRP channel expression in vascular smooth muscle cells (VSMC) and endothelial cells (EC) suggesting th...

Transgenic overexpression of transient receptor potential vanilloid subtype 1 attenuates isoproterenol-induced myocardial fibrosis in mice

“…TRP channels, as Ca 2+ -permeable channels, play a beneficial role in cardiovascular diseases. Moreover, the TRPV1 channel has been included in the activation of eNOS in several previous studies (40)(41)(42)(43). The present study demonstrated that TRPV1 overexpression increased the phosphorylation of eNOS in the myocardium from isoproterenol-treated mice.…”

Impaired capsaicin-induced relaxation in diabetic mesenteric arteries

“…Interestingly, previous vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was impaired in db/db mice compared with controls 13 . Several mechanisms that mediate CAP-induced vasodilation have been proposed.…”

“…ACCEPTED MANUSCRIPT 13 pretreated with L-NAME at CAP concentrations of 10 -7~1 0 -5 mol/L (P < 0.05, Fig. 3A),…”

Successful TRPV1 antagonist treatment for cardiac hypertrophy and heart failure in mice

“…18 This parallels mast cell induction of cardiac hypertrophy and cardiac fibrosis, 19 with mast cell knockout impacting repair responses in infarcted hearts. 20 From a neuronal and excitable tissue perspective the literature identifies TRPV1 as a molecular sensor to detect tissue ischemia, 21 as responsible for excitation of cardiac nocioceptors by bradykinin, 22 coupling myocardial blood flow to cardiac metabolism, 23 and regulating vascular tension. 24 TRPV1 is therefore putatively involved in both immunological and neuronal, and producing left ventricular hypertrophy by constriction of the aorta.…”