Inhibition Of L-type Calcium Channel By Nifedipine Differentially Regulate The Function Of Cerebral Artery In Simulated Microgravity Rats

It has been regarded that postspaceflight orthostatic intolerance is one of the mostimportant adverse effects after exposure to space microgravity and there are still noeffective countermeasures until now. Human studies from space flight have revealed thataltered autoregulation of cerebral vasculature and the inability to adequately elevateperipheral vascular resistance may be the fundamental causes in the occurrence oforthostatic intolerance after space flight. In addition, ground-based animal studies withtail-suspended hindlimb unweighting (HU) rat model have demonstrated that simulatedmicrogravity induced hypertrophic adaptations and enhanced contractile responsiveness inthe cerebral arteries, whereas simulated microgravity induced atrophic adaptations and decreased contractile responsiveness in small mesenteric arteries. These findings suggestthat differential adaptations of cerebrovasculature and small mesenteric arteries could beone of critical factors in postspaceflight orthostatic intolerance, but the cellularmechanisms remain unknown and there are no therapeutic targets for the preventionduring long term microgravity exposure.An increase in intracellular Ca2+of vascular smooth muscle cells (VSMCs) has beenconsidered as one of the important determinants for vasoconstriction (by triggeringvascular contraction) and vascular hypertrophic remodeling (by stimulating VSMCsmigration and proliferation). Ca2+influx from long-lasting voltage-dependent Ca2+(L-type,CaL) channel in plasma membrane is likely to play the central role in controllingintracellular Ca2+. It is well-known that the increased intraluminal pressure depolarizesVSMCs and then promotes the extracellular Ca2+influx by opening CaLchannels. Theincreased intracellular Ca2+subsequently activates ryanodine receptors (RyRs) and theninduces the transient local Ca2+release (Ca2+sparks) from sarcoplasmic reticulum (SR),which in turn activates nearby Ca2+-activated K+(KCa) channels in plasma membrane,leading to membrane hyperpolarization and then reducing the Ca2+influx by inhibition ofCaLchannels. Therefore, CaLchannels in plasma membrane are important mediators tocontrol arterial function and subsequent structural remodeling by handling intracellularCa2+. It has been demonstrated that hypertension, atherosclerosis, and diabetic vascularimpairments are all associated with the abnormal function of CaLchannels. The crucialrole of CaLchannels has made them as major therapeutic targets for the treatment ofcardiovascular disease.Our previous work reported that28-day simulated microgravity upregulated thefunction of CaLchannels by increasing current densities and1C-subunit expression incerebral arteries of rats. In addition,3-day recovery after removal of suspension could restore the function of CaLchannel to their control levels in cerebral arteries of simulatedmicrogravity rats. However, standing (STD) for1h/day, which was used to provide-G(x)as a countermeasure for simulated microgravity, neither decreased the upregulation of CaLchannels nor prevented the augmented myogenic tone and increased vasoreactivity incerebral arteries. All these findings suggested that CaLchannels might be a potential targetin the prevention of vascular remodeling during simulated or real microgravity. In thepresent study, the simulated microgravity rats were administrated with nifedipine, theinhibitor of CaLchannel. Firstly, we want to assess the function of cerebral artery/smallmesenteric artery after administration of nifedipine by comparing myogenic tone andvasoconstrictor responsiveness in control and simulated microgravity rats. Secondly, wewant to investigate the inhibitory effect of nifedipine on the function of CaLchannels invivo by comparing whole-cell current densities and protein expressions of1C-subunit incerebral arteries/mesenteric small artery isolated from control and simulated microgravityrats.The main results of our study are listed as bellow:(1) Inhibition of L-type calcium channel by nifedipine restored the function ofcerebral arteries in simulated microgravity ratsThe cerebral vascular function (myogenic tone and vasoconstriction to KCl and5-HT)increased in SUS group as compared with the CON group. However, nifedipinesignificantly decreased the MT and vasocontriction to KCl and5-HT in cerebral arteries ascompared with that of SUS rats, Western blot and patch clamp results suggest thatnifedipine also significantly decreased both the protein expression and whole-cell currentdensity of of CaLchannel in cerebral VSMCs as compared with that of SUS rats(2) Nifedipine did not affect the vascular function and L-type calcium channel insmall mesenteric arteries of rats. Simulated microgravity decreased the function of small mesenteric arteries of rats.However, there were no significant differences in the small mesenteric vascular function(myogenic tone and vasoconstriction to KCl and5-HT) between SUS and SUS+nifedipinegroup. Western blot and Patch clamp results also indicated that nifedipined did not changethe protein expression and whole-cell current density of CaLchannel in small mesentericarteries of SUS rats.Taken together, the present study provided initial evidences that inhibition of CaLchannels in cerebral VSMCs restored the function of cerebral artery in simulatedmicrogravity rats, which may provide a novel countermeasure in the prevention forcerebral arterial remodeling during exposure to microgravity.