Cerebral artery sarcoplasmic reticulum Ca²⁺stores and contractility: changes with development

Abstract

To test the hypothesis that sarcoplasmic reticulum (SR) Ca(2+) stores play a key role in norepinephrine (NE)-induced contraction of fetal and adult cerebral arteries and that Ca(2+) stores change with development, we performed the following study. In main branch middle cerebral arteries (MCA) from near-term fetal ( approximately 140 days) and nonpregnant adult sheep, we measured NE-induced contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) in the absence and presence of different blockers. In adult MCA, after thapsigargin (10(-6) M), the NE-induced responses of tension and [Ca(2+)](i) were 37 +/- 5 and 47 +/- 7%, respectively, of control values (P < 0.01 for each). In the fetal artery, in contrast, this treatment resulted in no significant changes from control. When this was repeated in the absence of extracellular Ca(2+), adult MCA increases in tension and [Ca(2+)](i) were 32 +/- 5 and 13 +/- 3%, respectively, of control. Fetal cerebral arteries, however, showed essentially no response. Ryanodine (RYN, 3 x 10(-6) to 10(-5) M) resulted in increases in tension and [Ca(2+)](i) in both fetal and adult MCA similar to that seen with NE. For both adult and fetal MCA, the increased tension and [Ca(2+)](i) responses to RYN were essentially eliminated in the presence of zero extracellular Ca(2+). These findings provide evidence that in fetal MCA, in contrast to those in the adult, SR Ca(2+) stores are of less importance in NE-induced contraction, with such contraction being almost wholly dependent on Ca(2+) flux via plasma membrane L-type Ca(2+) channels. In addition, they suggest that in both adult and fetal MCA, the RYN receptor is coupled to the plasma membrane Ca(2+)-activated K(+) channel and/or L-type Ca(2+) channel.

Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries

“…These data indicate that the pressure-induced arterial wall [Ca 2ϩ ] i elevation and constriction is not due to, but instead opposed by, SR Ca 2ϩ release. Consistent with this notion is evidence that in ovine fetal cerebral arteries norepinephrineinduced contractions occur primarily due to Ca 2ϩ influx, whereas in adults Ca 2ϩ released from intracellular stores also contributes (35). Whether, in addition to depolarization, mechanosensitive elements directly signal pressure-induced voltagedependent Ca 2ϩ channel activation in the newborn cerebrovasculature cannot be concluded from our study (21,36).…”

“…Disorders of the newborn cerebral circulation, in particular, are a predominant cause of mortality and can result in life-long disabilities in survivors. Recent studies have indicated that the newborn and adult vasculature show important physiological differences, including those relating to resting membrane potential (14), voltage-dependent Ca 2ϩ channels (7), intracellular Ca 2ϩ dynamics (35), localized intracellular Ca 2ϩ release events (17), and cGMP sensitivity (37). A functional myogenic response is known to be present at the newborn stage of development and appears to involve the activation of voltagedependent Ca 2ϩ channels (17).…”

Fetal cerebrovascular acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease?

“…For many vessels, including cerebral arteries (51,55), calcium entry through L-type Ca 2ϩ channels constitutes the main fraction of contractile calcium, owing to sparse or poorly developed sarcoplasmic reticulum. This is particularly true for immature cerebral arteries, which are essentially totally dependent on Ca 2ϩ influx through L-type Ca 2ϩ channels for contraction (1,41,44).…”

Carbon monoxide activates KCachannels in newborn arteriole smooth muscle cells by increasing apparent Ca2+sensitivity of α-subunits

“…Recent studies have indicated that physiological regulation of the newborn vasculature is very different when compared with that of the adult. When considering the physiological functions of vascular smooth muscle, several age-related differences have been described, including those relating to resting membrane potential (8), voltage-dependent Ca 2ϩ channels (2), intracellular Ca 2ϩ dynamics (29), localized intracellular Ca 2ϩ release events (14), and sensitivity to cGMP (33). Thus signal transduction mechanisms characterized in the adult circulation may not extrapolate to the newborn.…”