Regional variation in arterial myogenic responsiveness: Links to potassium channel diversity/function

Abstract

Regional variation in small artery myogenic responsiveness is associated with differences in relationships amongst intraluminal pressure, smooth muscle cell (SMC) membrane potential (Em) and vessel diameter. For example, under in vitro conditions, small arteries from cremaster muscle show a steeper relationship between Em and myogenic contraction compared with cerebral arteries. To explain this difference, we hypothesized that the function/regulation of the large conductance, Ca 2+-activated, K + channel (BK Ca) differs between these vascular beds. This was based on previous observations by Nelson and colleagues that BK Ca, activated by sarcoplasmic reticulum (SR)-generated Ca 2+ sparks, exerts a hyperpolarizing infl uence that opposes myogenic constriction. To test this, studies were performed using Ca 2+ imaging, vessel myography, isolated cell electrophysiology and molecular biology techniques on small resistance arteries from the cerebral and cremaster muscle vasculatures. While BK Cain SMCs of both small arteries showed a similar conductance and voltage sensitivity, Ca 2+ sensitivity was 2-3-fold greater in cerebral SMCs. Single channel open times were greater in cerebral SMCs compared with those of cremaster SMCs. Conversely, closed times were signifi cantly shorter in cerebral SMCs. In addition to variation in biophysical characteristics, β 1 -BK Casubunit expression was decreased in cremaster SMCs. Further, siRNA-induced knockdown of the β1subunit of the BK Caholo-channel shifted gating behavior of cerebral BK Cachannels to resemble that observed in cremaster SMCs. Collectively, the data indicate that while BK Cais present in both vascular preparations expression levels and modes of regulation differ. In particular, BK Cain small cerebral arteries is confi gured to show a higher Ca 2+ sensitivity resulting in greater opening at physiological levels of membrane potential. Heterogeneity in SMC ion channel function is not limited to BK Caas vascular bed differences are also apparent for other K + channels including the voltage-gated Kv and Kv7 families of channels. With respect to the latter, Kv7 channels appear to play a greater role in cerebral vasculature compared to the coronary circulation. From a physiological perspective it is suggested that differences in local ion channel function allow for regional differences in the regulation of myogenic tone and hence the control of tissue hemodynamics.