Role of PKC in autocrine regulation of rat ventricular K⁺currents by angiotensin and endothelin

Abstract

Shimoni, Yakhin, and Xiu-Fang Liu. Role of PKC in autocrine regulation of rat ventricular K ϩ currents by angiotensin and endothelin. Am J Physiol Heart Circ Physiol 284: H1168-H1181, 2003 10.1152 10. /ajpheart.00748.2002 and sustained K ϩ currents were measured in isolated rat ventricular myocytes obtained from control, steptozotocin-induced (Type 1) diabetic, and hypothyroid rats. Both currents, attenuated by the endocrine abnormalities, were significantly augmented by in vitro incubation (Ͼ6 h) with the angiotensin-converting enzyme inhibitor quinapril or the angiotensin II (ANG II) receptor blocker saralasin. Western blots indicated a parallel increase in Kv4.2 and Kv1.2, channel proteins that underlie the transient and (part of the) sustained currents. Under diabetic and hypothyroid conditions, both currents were also augmented by an endothelin receptor blocker (PD142893) or by an endothelin-converting enzyme inhibitor. Kv4.2 density was also enhanced by PD142893. Incubation (Ͼ5 h) with the PKC inhibitor bisindolylmaleimide augmented both currents, whereas the PKC activator dioctanoyl-rac-glycerol (DiC8) prevented the augmentation of currents by quinapril. DiC8 also prevented the augmentation of Kv4.2 density by quinapril. Specific peptides that activate PKC translocation indicated that PKC-⑀ and not PKC-␦ is involved in ANG II action on these currents. In control myocytes, quinapril and PD142893 augmented the sustained late current but had no effect on peak current. It is concluded that an autocrine release of angiotensin and endothelin in diabetic and hypothyroid conditions attenuates K ϩ currents by suppressing the synthesis of some K ϩ channel proteins, with the effects mediated at least partially by PKC-⑀. diabetes; protein kinase C WE HAVE RECENTLY ESTABLISHED that an autocrine release of angiotensin II (ANG II) plays a central role in attenuating a transient and a sustained K ϩ current in single myocytes isolated from (Type 1) diabetic rats (45). The in vitro blockade of ANG II action or formation (for Ͼ5 h) augments both currents. This effect is blocked by cycloheximide, suggesting that new protein synthesis mediates current augmentation after removal of ANG II-related current inhibition.

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

“…The down-regulation of I to might be, at least in part, responsible for the arrhythmogenic potential of angiotensin II. Experiments with isolated cardiomyocytes demonstrated that angiotensin II inhibits I to in rat and canine myocytes (15,16). As with other G q -coupled receptors (e.g.…”

“…In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18).…”

Ca2+ Controls Functional Expression of the Cardiac K+ Transient Outward Current via the Calcineurin Pathway

“…Interestingly, these modulators regulate both Kv4 channel current densities and mRNA levels. For example, angiotensin II has been implicated in the modulation of I to (35). An autocrine/paracrine release of ET-1 modulates Kv4.2 and Kv1.2 (35).…”

“…For example, angiotensin II has been implicated in the modulation of I to (35). An autocrine/paracrine release of ET-1 modulates Kv4.2 and Kv1.2 (35). Thyroid status also regulated I to density and Kv4.2 mRNA levels (36).…”

Neurohumoral Control of Heart Rate

“…Several lines of evidence suggest that Ang II may exert a direct modulation on cardiac ionic channels. Experiments have shown that stimulation of AT 1 receptor result in the inhibition of transient outward potassium channel in myocytes from rat or canine ventricle (Shimoni and Liu, 2003;Yu et al, 2000). Ang II also increases cardiac L-type Ca 2+ current (ICaL) in isolated cat myocytes (Aiello and Cingolani, 2001).…”