Upregulation of L-Type Ca ²⁺ Channels in Mesenteric and Skeletal Arteries of SHR

Abstract

Abstract-An increased Ca2ϩ influx attributed to dihydropyridine-sensitive L-type Ca 2ϩ channels has been demonstrated in mesenteric vascular smooth muscle cells of spontaneously hypertensive rats (SHR). This study examined whether an upregulation of the pore-forming ␣ 1C subunit of the L-type Ca 2ϩ channel underlies this ionic defect. With the use of mesenteric arcade arteries from 12-to 16-week-old SHR and normotensive Wistar Kyoto (WKY) rats, reverse transcriptase-polymerase chain reaction demonstrated an increased level of amplified cDNA corresponding to the ␣ 1C subunit mRNA in the SHR arteries. Western blots confirmed that the increased mRNA expression was associated with a 3.4-fold increase in the immunoreactive signal of the ␣ 1C subunit protein in SHR compared with WKY mesenteric arteries, and immunocytochemistry confirmed this abnormality at the single-cell level. Finally, isolated mesenteric arteries from SHR were highly reactive to Bay K8644 and developed anomalous Ca 2ϩ -dependent tone, suggesting a functional role for ␣ 1C subunit upregulation in vascular hyperreactivity. To determine if these Ca 2ϩ channel abnormalities extended to the SHR skeletal muscle bed, we repeated a similar series of studies in WKY and SHR hind limb arteries. Skeletal muscle arteries from SHR also expressed higher levels of [1][2][3] Similarly, the arterioles of the mesenteric and skeletal muscle beds of SHR develop an abnormal Ca 2ϩ -dependent vascular tone and show increased myogenic responsiveness. 4 -6 Isolated mesenteric and femoral arteries of SHR also develop abnormal Ca 2ϩ -dependent tone, whereas similar arteries from WKY rats are quiescent. 7,8 In view of its central role in generating vascular tone, it is surprising that the mechanism of the elevated Ca 2ϩ influx in SHR VSMCs remains unclear. Some evidence suggests that VSMC membranes are depolarized in hypertension, resulting in the activation of L-type Ca 2ϩ channels. 9 Alternatively, excitatory stimuli including neurotransmitters and intracellular mediators may preferentially activate vascular L-type Ca 2ϩ channels during hypertension. 10,11 Recently, however, studies using mesenteric arteries as a model have shown that VSMCs of SHR, studied in patchclamp conditions that tightly control cell membrane potential and environment, still exhibit an enhanced voltage-gated Ca 2ϩ influx compared with WKY cells. Ohya et al 12 demonstrated a higher membrane density of L-type Ca 2ϩ current in mesenteric VSMC of 5-to 6-week-old SHR compared with agematched WKY rats, although density was normalized in SHR by 16 to 18 weeks of age. No differences in L-type Ca 2ϩ channel properties were detected between these preparations. In detailed studies, Cox and Lozinskaya 13,14 detected a higher density of L-type Ca 2ϩ current in mesenteric VSMC from 6-, 12-, and 20-week-old SHR and observed normal voltagedependent activation of the SHR Ca 2ϩ channel. Finally, single-channel analysis by Ohya and colleagues 15 in cell-

Hypertension attenuates cell-to-cell communication in hamster retractor muscle feed arteries

“…2) One could suggest that the hypertensioninduced reduction in cell-to-cell communication reflects a loss of signal regeneration due to altered ion channel activity. Although past studies showed that chronic hypertension can influence the activity of K ϩ and Ca 2ϩ channels (1,24,38), such changes typically coincide with alterations in arterial reactivity to vasoactive stimuli (24,38). Interestingly, no substantive change in feed artery responsiveness to myogenic tone or to global application of phenylephrine, U-46619, or acetylcholine was observed in this investigation.…”

Modulation of the molecular composition of large conductance, Ca2+ activated K+ channels in vascular smooth muscle during hypertension

“…The resulting increase in Ca 2+ influx raises global [Ca 2+ ] i , which causes vasoconstriction and hence contributes to increased arterial pressure. It is important to note that expression of L-type Ca 2+ channels is reportedly higher in vascular smooth muscle cells of HT than in NT animals (33)(34)(35) This is the first study to examine the role of RyR-BK channel communication and the subunit composition of BK channels in HT vascular smooth muscle. However, the Ca 2+ sensitivity of single BK channels in smooth muscle of cerebral arteries and the aorta from spontaneously hypertensive rats (SHR), a genetic model of hypertension, has been previously investigated (32,36).…”

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

“…Several attempts have been made to explain these unique features. In hypertension, there is an increase of reactivity to vasoconstrictors, which is not only due to a higher number of L-type Ca 2+ channels (Godfraind, 2005;Pesic et al, 2004;Pratt et al, 2002), but also to depolarization of the resting potential of hypertensive VSMCs (Morel & Godfraind, 1994;Pesic et al, 2004). Depolarization leads to an increased proportion L-type Ca 2+ channels in the inactivated state, which according to the "modulated receptor theory" may have higher affinity to CaBs than channels in the resting state (Bean et al, 1986;Godfraind, 2005;Morel & Godfraind, 1987).…”