A new inbred Wistar-Kyoto rat substrain exhibiting  apparent salt sensitivity and borderline hypertension

Alemayehu, Adamu; Breen, Laura; Printz, Morton P.

doi:10.1152/ajpheart.00187.2002

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…24 We observed spontaneous BK current events in myocytes isolated from SD, WKY, and SHR arteries held at a membrane potential of Ϫ40 mV ( Figure 1A). Although the frequency of these events was comparable at approximately 4 Hz ( Figure 1B; PϾ0.05), BK current amplitudes were about 50% smaller in SHR than in SD myocytes (PϽ0.05, nϭ700 events from 5 myocytes).…”

Section: Bk Currents But Not Ca 2؉ Sparks Are Smaller In Borderlinementioning

confidence: 94%

“…The systolic blood pressure of SD and SHR rats used in this study was 117Ϯ3 and 195Ϯ5 mm Hg, respectively, as determined by tail-cuff plethysmography. We also examined a putative "borderline hypertensive" WKY rat substrain 24 to determine if there is a relationship between BK channel function and the severity of hypertension. The systolic blood pressure of our WKY rats was 135Ϯ3 mm Hg.…”

Section: Bk Currents But Not Ca 2؉ Sparks Are Smaller In Borderlinementioning

confidence: 99%

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Downregulation of the BK Channel β1 Subunit in Genetic Hypertension

Amberg

Santana

2003

Circulation Research

180

138

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Abstract-The molecular mechanisms underlying increased arterial tone during hypertension are unclear. In vascular smooth muscle, localized Ca 2ϩ release events through ryanodine-sensitive channels located in the sarcoplasmic reticulum (Ca 2ϩ sparks) activate large-conductance, Ca 2ϩ -sensitive K ϩ (BK) channels. Ca 2ϩ sparks and BK channels provide a negative feedback mechanism that hyperpolarizes smooth muscle and thereby opposes vasoconstriction. In this study, we examined Ca 2ϩ sparks and BK channel function in Wistar-Kyoto (WKY) rats with borderline hypertension and in spontaneously hypertensive rats (SHR), a widely used genetic model of severe hypertension. We found that the amplitude of spontaneous BK currents in WKY and SHR cells were smaller than in normotensive cells even though Ca 2ϩ sparks were of similar magnitude. BK channels in WKY and SHR cells were less sensitive to physiological changes in intracellular Ca 2ϩ than normotensive cells. Our data indicate that decreased expression of the BK channel ␤1 subunit underlies the lower Ca 2ϩ sensitivity of BK channels in SHR and WKY myocytes. We conclude that the lower expression of the ␤1 subunit during genetic borderline and severe hypertension reduced BK channel activity by decreasing the sensitivity of these channels to physiological changes in Ca 2ϩ . These results support the view that changes in the molecular composition of BK channels may be a fundamental event contributing to the development of vascular dysfunction during hypertension. Large-conductance, Ca 2ϩ -activated K ϩ (BK) channels are important regulators of vascular smooth muscle membrane potential. 4 BK channels are activated by spontaneous, local Ca 2ϩ release events (Ca 2ϩ sparks) through ryanodine-sensitive channels in the sarcoplasmic reticulum. 5 On activation by Ca 2ϩ sparks, BK channels produce large currents that hyperpolarize and relax vascular smooth muscle, which causes vasodilation. 5,6 Arterial smooth muscle BK channels are composed of pore-forming ␣ and accessory ␤1 subunits. 7,8 The ␤1 subunit, which is highly and uniquely expressed in smooth muscle, 9 enhances the sensitivity of BK channels to activation by physiological changes in Ca 2ϩ . 10,11 The functional significance of the ␤1 subunit has been demonstrated by the work of Brenner et al 9 and Plüger et al. 12 These authors found that genetically engineered mice lacking expression of the ␤1 subunit had vascular smooth muscle BK channels that were uncoupled from Ca 2ϩ sparks. These mice also had increased vascular tone and were hypertensive.Recently, we showed that a change in the molecular composition of BK channels contributes to vascular dysfunction in an angiotensin II infusion model of acquired, severe hypertension (systolic pressure Ͼ190 mm Hg). 13 We found that angiotensin II reduced the expression of the BK channel ␤1 subunit in arterial smooth muscle. The resultant BK channels had reduced Ca 2ϩ sensitivity, which significantly reduced their ability to respond to activating Ca 2ϩ sparks. Because of this, these B...

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Section: Bk Currents But Not Ca 2؉ Sparks Are Smaller In Borderlinementioning

confidence: 94%

Section: Bk Currents But Not Ca 2؉ Sparks Are Smaller In Borderlinementioning

confidence: 99%

Downregulation of the BK Channel β1 Subunit in Genetic Hypertension

Amberg

Santana

2003

Circulation Research

180

138

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“…The susceptibility of different substrains to dietary sodium manipulation may be tied to differences in the expression of receptors, such as the tachykinins, in brain regions that mediate the psychomotor stimulant and reinforcing properties of amphetamine and sodium solutions (27,32). These results add to the literature identifying strain differences in salt intake, responses to stress, and psychomotor stimulant sensitivity (2,5,35,43,54).…”

Section: Discussionmentioning

confidence: 67%

Dietary sodium manipulation during critical periods in development sensitize adult offspring to amphetamines

McBride

Culver²,

Flynn³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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McBride SM, Culver B, Flynn FW. Dietary sodium manipulation during critical periods in development sensitize adult offspring to amphetamines. Am J Physiol Regul Integr Comp Physiol 295: R899 -R905, 2008. First published July 9, 2008 doi:10.1152/ajpregu.00186.2008This study examined critical periods in development to determine when offspring were most susceptible to dietary sodium manipulation leading to amphetamine sensitization. Wistar dams (n ϭ 6 -8/group) were fed chow containing low (0.12% NaCl; LN), normal (1% NaCl; NN), or high sodium (4% NaCl; HN) during the prenatal or early postnatal period (birth to 5 wk). Offspring were fed normal chow thereafter until testing at 6 mo. Body weight (BW), blood pressure (BP), fluid intake, salt preference, response to amphetamine, open field behavior, plasma adrenocorticotropin hormone (ACTH), plasma corticosterone (Cort), and adrenal gland weight were measured. BW was similar for all offspring. Offspring from the prenatal and postnatal HN group had increased BP, NaCl intake, and salt preference and decreased water intake relative to NN offspring. Prenatal HN offspring had greater BP than postnatal HN offspring. In response to amphetamine, both prenatal and postnatal LN and HN offspring had increased locomotor behavior compared with NN offspring. In a novel open field environment, locomotion was also increased in prenatal and postnatal LN and HN offspring compared with NN offspring. ACTH and Cort levels 30 min after restraint stress and adrenal gland weight measurement were greater in LN and HN offspring compared with NN offspring. These results indicate that early life experience with low-and high-sodium diets, during the prenatal or early postnatal period, is a stress that produces long-term changes in responsiveness to amphetamines and to subsequent stressors. behavioral sensitization; psychomotor stimulant; salt appetite DRUGS OF ABUSE and natural motivators or stimuli, such as sodium deprivation or stress, activate similar neural circuits involved in mediating reward and drive-related responses (12,18,28). One of the main systems believed to be involved in triggering these behaviors is the mesocorticolimbic dopamine system, with dopaminergic projections traveling from the midbrain ventral tegmental area to the nucleus accumbens and other limbic and cortical areas (38, 44). With repeated exposure to both amphetamines and sodium deprivation, behavioral sensitization develops (38, 48). Sensitization can be described as an increased and enduring response to the same stimuli with repeated exposures (38). With amphetamines, sensitization manifests itself as increased locomotor behavior (21, 53). Repeated amphetamine treatment leading to sensitization is associated with morphological changes in nucleus accumbens neurons, including increased spine density, dendritic length, and dendritic branching (46). Repeated sodium deprivation can lead to an enduring daily increase in the ingestion of hypertonic NaCl in otherwise sodium-replete rats (48), and a history of sodium deple...

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“…In this vein, it is not clear why the authors chose SD rats over other strains of WKY that have been shown to be normotensive and salt resistant, such as WKY/ lj-cr, having a similar SBP (Ϸ118 mm Hg) to SD themselves. 9 small cumulative effect on BP.…”

Section: Ion Channel Dysfunction In Genetic Hypertensionmentioning

confidence: 98%

“…Recent studies suggest that WKY, because of random breeding with certain suppliers, exist as different genetic strains, with some having borderline hypertension and high salt sensitivity (WKY/lj-tf). 9 SHR develop hypertension within 6 weeks of age and is fully established by 12 to 16 weeks. Using these SHR models, numerous patch-clamp studies have reported increased amplitude of currents through VDCCs in several vascular beds, including the cerebral circulation, resulting from both upregulation of the channel and membrane depolarization (see Reference 3).…”

Section: Ion Channel Dysfunction In Genetic Hypertensionmentioning

confidence: 99%

The BK Channel

Jabr

2003

Circulation Research

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A new inbred Wistar-Kyoto rat substrain exhibiting apparent salt sensitivity and borderline hypertension

Cited by 8 publications

References 25 publications

Downregulation of the BK Channel β1 Subunit in Genetic Hypertension

Downregulation of the BK Channel β1 Subunit in Genetic Hypertension

Dietary sodium manipulation during critical periods in development sensitize adult offspring to amphetamines

The BK Channel

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