Aging, ion channel expression, and vascular function

Toro, Ligia; Marijic, Jure; Nishimaru, Kazuhide; Tanaka, Yoshio; Song, Min; Stefani, Enrico

doi:10.1016/s0306-3623(02)00128-3

Cited by 70 publications

(44 citation statements)

References 29 publications

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“…24 In contrast in rat coronary smooth muscle, there is downregulation of the transcripts for both the a-and the b-subunits correlating with a decrease in the activity of the channels seen with patch clamping. 24,[28][29][30] This suggests that therapies addressing age-related changes in the activity of MaxiK may need to be tailored to a particular organ.…”

Section: Discussionmentioning

confidence: 99%

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

et al. 2007

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The MaxiK channel plays a critical role in the regulation of corporal smooth muscle tone and thereby erectile function. Given that ageing results in a decline in erectile function, we determined changes in the expression of MaxiK, which might impact erectile function. Quantitative-polymerase chain reaction demonstrated that although there is no significant change in transcription of the a-and b-subunits that comprise the MaxiK channel, there are significant changes in the expression of transcripts encoding different splice variants. One transcript, SV1, is 13-fold increased in expression in the ageing rat corpora. SV1 has previously been reported to trap other isoforms of the MaxiK channel in the cytoplasm. Correlating with increased expression of SV1, we observed in older rats there is approximately a 13-fold decrease in MaxiK protein in the corpora cell membrane and a greater proportion is retained in the cytoplasm (approximately threefold). These experiments demonstrate that ageing of the corpora is accompanied by changes in alternative splicing and cellular localization of the MaxiK channel.

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Section: Discussionmentioning

confidence: 99%

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

et al. 2007

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“…These results indicate that, in a situation of compromised or diminished BK Ca channel function, the CCSM cannot be kept in a relaxed state, and consequently the penis in an erect state, even in the presence of the potent ED drug sildenafil. BK Ca channel expression has been shown to decrease with age in coronary arteries (38), and, if this occurs in the CCSM, it may diminish the efficacy of a PDE5 inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In vascular smooth muscle of aged rats (20,29) as well as of humans (38), the BK Ca channel ␣-and ␤ 1 -subunit expression is decreased. Correlated with this downregulation are increased risks of cardiovascular diseases such as coronary artery vasospasm, myocardial ischemia, and infarct (20,38).…”

Section: Perspectives and Significancementioning

confidence: 99%

“…Correlated with this downregulation are increased risks of cardiovascular diseases such as coronary artery vasospasm, myocardial ischemia, and infarct (20,38). Recently, gene therapy using the gene for the pore-forming BK Ca ␣-subunit (Kcnma or Slo1) has been shown to restore age-related erectile function in vivo in rats (23,25).…”

Section: Perspectives and Significancementioning

confidence: 99%

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Hypercontractility and impaired sildenafil relaxations in the BK_Cachannel deletion model of erectile dysfunction

Werner

Meredith

Aldrich³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Werner ME, Meredith AL, Aldrich RW, Nelson MT. Hypercontractility and impaired sildenafil relaxations in the BK Ca channel deletion model of erectile dysfunction. Am J Physiol Regul Integr Comp Physiol 295: R181-R188, 2008. First published May 14, 2008 doi:10.1152/ajpregu.00173.2008.-Erectile dysfunction (ED) can be elicited by a variety of pathogenic factors, particularly impaired formation of and responsiveness to nitric oxide (NO) and the downstream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large-conductance, Ca 2ϩ -activated potassium (BKCa) channel. In our previous report (42), we demonstrated that deletion of the BK Ca channel in mice induced force oscillations and led to reduced nerve-evoked relaxations and ED. In the current study, we used this ED model to explore the role of the BK Ca channel in the NO/sGC/PKGI pathway. Electrical field stimulation (EFS)-induced contractions of corpus cavernosum smooth muscle strips were significantly enhanced in the absence of BK Ca channel function. In strips precontracted with phenylephrine, EFS-induced relaxations were converted to contractions by inhibition of sGC, and this was further enhanced by loss of BK channel function. Sildenafil-induced relaxations were decreased to a similar extent by inhibition of sGC or BK Ca channels. At concentrations Ͼ1 M, sildenafil caused relaxations independent of inhibition of sGC or BK Ca channels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of BK Ca channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent Ca 2ϩ channels (VDCCs). These results suggest that therapeutically relevant concentrations of sildenafil act through cGMP and BK Ca channels, and loss of BKCa channel function leads to hypercontractility, which depends on VDCCs and cannot be modified by the cGMP pathway. smooth muscle; calcium-activated potassium channel; mouse ERECTILE DYSFUNCTION (ED) is described as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance (44). It affects 30 million men in the United States (5), and its prevalence increases with age and diseases like diabetes and hypertension (4,24,31). Erectile function and a proper penile erection occurs in response to nerve stimulation and the release of nitric oxide (NO) from parasympathetic nonadrenergic-noncholinergic (NANC) nerves as well as from the vascular endothelium (2,13,16,27). In mice, the NO-producing enzyme NO synthase has been found in the dorsal penile nerve and its branches in the mouse penis (9) as well as in intrinsic nerves of the erectile tissue (14). The majority of NO effects are mediated through the soluble guanylate cyclase (sGC) and its product, cGMP (2,8,16,33). cGMP acts as a modifying agent on ion channels, phosphodiesterases, and protein kinases (19). One of the protein kinases, the cGMP-dependent protein kinase I (PKGI), phosphorylat...

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“…El envejecimiento puede estar asociado con una menor disponibilidad de NO, lo cual puede conducir a una reducción marcada de la capacidad vasodilatadora (disfunción endotelial), asociada a la disminución de la producción de otros agentes vasodilatadores o al aumento de factores vasoconstrictores, tales como los relacionados con los receptores α-adrenérgicos 22 .…”

Section: N V E S T I G a C I ó Nunclassified

Influencia del sistema nitridérgico en la respuesta contráctil a fenilefrina de anillos de vasos usados en revascularización coronaria

et al. 2007

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Aging, ion channel expression, and vascular function

Cited by 70 publications

References 29 publications

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

Hypercontractility and impaired sildenafil relaxations in the BK_Cachannel deletion model of erectile dysfunction

Influencia del sistema nitridérgico en la respuesta contráctil a fenilefrina de anillos de vasos usados en revascularización coronaria

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Aging, ion channel expression, and vascular function

Cited by 70 publications

References 29 publications

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

Ageing causes cytoplasmic retention of MaxiK channels in rat corporal smooth muscle cells

Hypercontractility and impaired sildenafil relaxations in the BKCachannel deletion model of erectile dysfunction

Influencia del sistema nitridérgico en la respuesta contráctil a fenilefrina de anillos de vasos usados en revascularización coronaria

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Hypercontractility and impaired sildenafil relaxations in the BK_Cachannel deletion model of erectile dysfunction