Rationale In the working heart coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels, which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox sensitive. Objective To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. Methods and Results In mice (wild type [WT], Kv1.5 null [Kv1.5−/−], and Kv1.5−/− and WT with inducible, smooth muscle specific expression of Kv1.5 channels) we measured mean arterial pressure (MAP), myocardial blood flow (MBF), myocardial tissue pO2, and ejection fraction (EF) before and after inducing cardiac stress with norepinephrine (NE). Cardiac work (CW) was estimated as the product of MAP and heart rate. Isolated arteries were studied to establish if genetic alterations modified vascular reactivity. Despite higher levels of CW in the Kv1.5−/− (versus WT at baseline and all doses of NE), MBF was lower in Kv1.5−/− than in WT. At high levels of CW, tissue pO2 dropped significantly along with EF. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5−/− mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared to WT. Conclusions Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow resulting in cardiac pump dysfunction and tissue hypoxia.

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...

Objective The connection between metabolism and flow in the heart, metabolic dilation, is essential for cardiac function. We recently found redox-sensitive Kv1.5 channels play a role in coronary metabolic dilation; however, more than one ion channel likely plays a role in this process since animals null for these channels still showed limited coronary metabolic dilation. Accordingly, we examined the role of another Kv1 family channel, the energetically-linked Kv1.3 channel, in coronary metabolic dilation. Methods We measured myocardial blood flow (contrast echocardiography) during norepinephrine-induced increases in cardiac work (heart rate × mean arterial pressure) in wild type mice (WT), WT mice given correolide (preferential Kv1.3 antagonist), and Kv1.3 null mice (Kv1.3−/−). We also measured relaxation of isolated small arteries mounted in a myograph. Results During increased cardiac work, myocardial blood flow was attenuated in Kv1.3−/− and in correolide-treated mice. In isolated vessels from Kv1.3−/− mice, relaxation to H2O2 was impaired (vs WT), but responses to adenosine and acetylcholine were equivalent to WT. Correolide reduced dilation to adenosine and acetylcholine in WT and Kv1.3−/−, but had no effect on H2O2-dependent dilation in vessels from Kv1.3−/− mice. Conclusion Kv1.3 channels participate in the connection between myocardial blood flow and cardiac metabolism.

Transient receptor potential channels, TRPA1 and TRPV1 are known to play a major role in pain and inflammatory pathways. Recent evidences have shown that general anesthetics can either directly or indirectly sensitize these channels. Similarly studies have also implicated cross‐talk between these channels which plays an immense role in regulating these channels. Propofol, an intravenous anesthetic, causes hypotension when administered to patients during surgery. Our main objective was to determine the role of these channels in the regulation of vascular reactivity while further demonstrating Propofol mediates vasodilation through TRPA1/TRPV1 signaling. Using high‐fidelity microtip transducer catheter, changes in mean arterial pressure were recorded in C57BL6 and TRPA1(−/−) mice. Propofol induced a dose‐dependent depressor response which was blunted in TRPA1(−/−) mice and was further attenuated in TRPA1(−/−) mice in the presence of a specific TRPV1 antagonist SB366791. Isometric‐tension studies in endothelium intact and denuded aortic rings from TRPA1(−/−)mice in presence/absence of SB366791 illustrated a role for TRPA1/TRPV1. Furthermore propofol elicited robust relaxation in isolated coronary microvessel from controls which was blunted in the presence of SB366791 and in vessels from TRPA1(−/−)mice. In conclusion, Propofol mediated regulation of vascular reactivity occurs in part via combined TRPA1/TRPV1 mediated signaling.