Aging and muscle fiber type alter K⁺ channel contributions to the myogenic response in skeletal muscle arterioles

Abstract

Kang LS, Kim SJ, Dominguez JM 2nd, Sindler AL, Dick GM, Muller-Delp JM. Aging and muscle fiber type alter K ϩ channel contributions to the myogenic response in skeletal muscle arterioles. J Appl Physiol 107: 389 -398, 2009. First published April 30, 2009 doi:10.1152/japplphysiol.91245.2008.-Aging diminishes myogenic tone in arterioles from skeletal muscle. Recent evidence indicates that both large-conductance Ca 2ϩ -activated (BKCa) and voltage-dependent (K V) K ϩ channels mediate negative feedback control of the myogenic response. Thus we tested the hypothesis that aging increases the contributions of K V and BKCa channels to myogenic regulation of vascular tone. Because myogenic responsiveness differs between oxidative and glycolytic muscles, we predicted that K V and BK Ca channel contributions to myogenic responsiveness vary with fiber type. Myogenic responses of first-order arterioles from the gastrocnemius and soleus muscles of 4-and 24-mo-old Fischer 344 rats were evaluated in the presence and absence of 4-aminopyridine (5 mM) or iberiotoxin (30 nM), inhibitors of K V and BKCa, respectively. 4-Aminopyridine enhanced myogenic tone with aging and normalized age-related differences in both muscle types. By contrast, iberiotoxin eliminated age-related differences in soleus arterioles and had no effect in gastrocnemius vessels. KV1.5 is an integral component of KV channels in vascular smooth muscle; therefore, we determined the relative protein expression of KV1.5, as well as BKCa, in soleus and gastrocnemius arterioles. Immunoblot analysis revealed no differences in KV1.5 protein with aging or between variant fiber types, whereas BKCa protein levels declined with age in arterioles from both muscle groups. Collectively, these results suggest that the contribution of BKCa to myogenic regulation of vascular tone changes with age in soleus muscle arterioles, whereas increased KV channel expression and negative feedback regulation of myogenic tone increases with advancing age in arterioles from both oxidative and glycolytic muscles. delayed rectifier potassium channel; calcium-activated potassium channel; iberiotoxin; 4-aminopyridine; KV1.5 THE MYOGENIC RESPONSE IS ESSENTIAL in regulating peripheral vascular resistance as well as tissue-specific blood flow. This autoregulatory mechanism, in which vessels contract or dilate in response to changes in transmural pressure, may be impaired with advancing age. The magnitude of myogenic tone development declines with aging in both mesenteric (19) and skeletal muscle arterioles (32), and age-induced modifications of vascular smooth muscle contractile mechanisms may contribute to this reduced myogenic reactivity (32). Myogenic tone development depends on an increase in intracellular Ca2ϩ and subsequent initiation of contractile activity, which is mediated by voltage-gated Ca 2ϩ channels (VGCC). In the presence of steady Ca 2ϩ influx from VGCC, an opposing, hyperpolarizing force is likely required to prevent regenerative Ca 2ϩ entry and tonic contraction (13,21,35). Severa...

Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice

“…6B) suggest that BK Ca channels do not play a key role in functional maladaptation of aged cerebral arteries to high pressure. Previous studies reported that with advanced age the activity of K V channels may increase in skeletal muscle arteries (32) and that disruption of K V channel function may contribute to the adaptation of young rat cerebral arteries to hypertension (4). Yet data obtained with inhibitors of K V channels (Fig.…”

“…Role of BK Ca channels in regulation of pressure-induced SMC calcium signaling and myogenic constriction in MCAs. Regulation of large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channel activity represents an important mechanism modulating the magnitude of pressure-induced myogenic constriction (32,52). To assess the role of BK Ca channels in functional maladaptation of cerebral arteries to hypertension in aging, we tested the effect of iberiotoxin on myogenic constriction (Fig.…”

“…In addition to activation of TRP channels, regulation of BK Ca channel activity represents another important mechanism modulating the magnitude of pressure-induced myogenic constriction (32,52). Importantly, previous studies demonstrate that high pressure is associated with significant activation of BK Ca channels leading to forced dilation of cerebral arteries (autoregulatory breakthrough) (52).…”

The Vascular Conducted Response in Cerebral Blood Flow Regulation

“…Aging is associated with a reduction in BK Ca channel expression and function in rat coronary and skeletal muscle arteries, 63,64 and this might alter conducted vasomotor responses in arterioles from aged individuals. In hypertensive animals, cerebral artery BK Ca channels are upregulated, 65 whereas in diabetic mice and rats the b 1 -subunit of the BK Ca channel is downregulated, leading to impaired function of the channel.…”

Genistein and tyrphostin AG556 decrease ultra‐rapidly activating delayed rectifier K+ current of human atria by inhibiting EGF receptor tyrosine kinase

“…Abnormal Src kinase phosphorylation of hK v 1.5 channels is implicated in familial atrial fibrillation (Yang et al, 2010). In addition, K v 1.5 current plays a role in the maintenance of the cell membrane potential in a wide variety of cells/tissues, such as pancreatic beta cells (MacDonald and Wheeler, 2003), brain tissue (Tipparaju et al, 2012), macrophages (Vicente et al, 2006) and skeletal muscle (Kang et al, 2009), as well as smooth muscles in vessels (Overturf et al, 1994) and airways (Adda et al, 1996). Therefore, tyrosine phosphorylation of hK v 1.5 channels could also be important in maintaining normal cellular function of these types of cells.…”