The underlying vascular smooth muscle is activated by the release of a specific arachidonic acid metabolite called epoxyeicosatrienoic acid (EET), which is produced by endothelial cells in response to various stimuli. EET activates a transient receptor channel known as TRPV4 in the sarcolemma of smooth muscle, resulting in the influx of Ca++. This influx of Ca++ then opens RYR channels in the SR, leading to the occurrence of Ca++ sparks. Ca++ sparks, in turn, activate a large-conductance K+ channel called BKCa in the sarcolemma, causing the smooth muscle cell to become hyperpolarized. Hyperpolarization decreases the basal influx of Ca++ through voltage-gated Ca++ channels in the smooth muscle, thereby reducing intracellular [Ca++] levels and promoting smooth muscle relaxation. Additionally, the SR contains the Ca++-gated Ca++ channel known as RYR, which can be activated during periods of Ca++ influx through the sarcolemma. Short-lived spontaneous opening of RYR leads to localized elevations in myoplasmic [Ca++] referred to as Ca++ sparks. In smooth muscle, an increase in cAMP has been linked to an increase in the frequency of Ca++ sparks, particularly in situations where the SR is close to the sarcolemma. The increased frequency of these sparks results in hyperpolarization of vascular smooth muscle through the activation of a large-conductance Ca++-gated K+ channel in the sarcolemma, leading to overall relaxation.
Fig.14.11 ).Specifically,EDHFappearstobeanarachidonicacidmetabolite(e.g.,epoxyeicosatrienoic acid [EET])thatisproducedbyendothelialcellsinresponsetovariousstimuliandthenreleasedtotheunderlyingvascularsmoothmuscle.EEThasbeenshowntoactivateatransient receptor channel (e.g.,TRPV4)inthesarcolemmaofsmoothmusclethatleadstotheinfluxofCa++ ,whichthenopensRYRchannelsintheSRandresultsinCa++ sparks.TheCa++ sparksinturnactivatealarge-conductanceK+ channelinthesarcolemma(BKCa),andthesmoothmusclecellbecomeshyperpolarized.HyperpolarizationinturndecreasesbasalCa++ influxthroughvoltage-gatedCa++ channelsinthesmoothmuscle,therebydecreasingintracellular[Ca++]andhencerelaxingthesmoothmuscle,asdescribedearlier.
In addition to the InsP3 receptor, the SR also contains the Ca++-gated Ca++ channel, also called the RYR, which may be activated during periods of Ca++ influx through the sarcolemma. Short-lived spontaneous opening of the RYR 11,12 EET COOH •Fig. 14.11 Anarachidonicacidmetabolite(11,12-epoxyeicosatrienoicacid[11,12EET])releasedfromendothelialcellscanopenthetransientreceptorchannelTRPV4intheunderlyingsmoothmuscletopermittheinfluxofCa++ ,whichinturninitiatesbriefopeningsoftheSRryanodinereceptor(Ca++ sparks)localizednearthesarcolemma.OpeningofCa++-activatedK+ channelsinthesarcolemmabycalciumsparksresultsinhyperpolarizationofthesmoothmuscleandhencevasodilation.BKCa,largeconductanceCa++-activatedpotassiumchannel.(FromEarleySetal.Circ Res 2005;97:1270-1279.) resulting in localized elevations in myoplasmic [Ca++] occurs in many cells, including smooth muscle. When observed with Ca++-sensitive fluorescent dyes, these spontaneous localized elevations in myoplasmic [Ca++] produce brief light flashes and as a result are named Ca++ sparks. In smooth muscle an increase in cAMP has been associated with an increase in the frequency of Ca++ sparks, particularly in situations in which the SR is in close proximity to the sarcolemma (i.e., junctional SR, perhaps near caveolae). An increase in the frequency of these sparks hyperpolarizes vascular smooth muscle by activation of a large-conductance Ca++-gated K+ channel in the sarcolemma. This hyperpolarization then decreases overall myoplasmic [Ca++], and relaxation occurs.