T‐type and L‐type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats

Wagner, Charlotte; Krämer, Bernhard K.; Hinder, Markus; Kieninger, Martin; Kurtz, Armin

doi:10.1038/sj.bjp.0701861

Cited by 36 publications

(29 citation statements)

References 33 publications

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“…In intact dogs, both nifedipine and mibefradil increased renal blood flow, whereas only nifedipine affected glomerular filtration rate. Mibefradil has also been reported to decrease renin secretion in rats with renal artery clips, but had no effect on renin secretion from isolated juxtaglomerular cells (423). In conclusion, these studies suggest that T-type channels on afferent and efferent glomerular arterioles may be an important therapeutic target (89).…”

Section: Kidneymentioning

confidence: 82%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Section: Kidneymentioning

confidence: 82%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

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“…T-type CCBs inhibit renin secretion and renin gene expression in vivo, whereas L-type CCBs function as stimulators of the renin system. 34,35 T-type CCBs have a dual effect on plasma renin activity and renin messenger RNA expression in vivo, with low concentrations stimulating and high concentrations inhibiting the renin system. 36 However, in this study, plasma renin activity did not change significantly; therefore, the change in aldosterone may not have been due to the effect of renin but rather to a direct inhibition of aldosterone secretion.…”

Section: Discussionmentioning

confidence: 99%

Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria

et al. 2010

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Benidipine inhibits both L-and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with mild-tomoderate stage chronic kidney disease (CKD). Patients with BPX130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30-90 ml min À1 per 1.73 m 2 , and with albuminuria430 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (n¼52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10 mg per day (n¼52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction.

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“…18 Previously, a T-and L-type CCB, mibefradil, has been shown to suppress renin mRNA levels and PRA in normal rats, but an L-type CCB amlodipine did not have this effect. 9 In two-kidney, one-clip renal hypertensive rats, a model that is known to show increased PRA levels, mibefradil, significantly reduced PRA; in contrast, amlodipine increased these levels. 9 In high salt-loaded DS rats, PRA is known to be suppressed, 18 and it was also significantly lowered in the placebo-treated group in our study.…”

Section: Discussionmentioning

confidence: 99%

“…9 In two-kidney, one-clip renal hypertensive rats, a model that is known to show increased PRA levels, mibefradil, significantly reduced PRA; in contrast, amlodipine increased these levels. 9 In high salt-loaded DS rats, PRA is known to be suppressed, 18 and it was also significantly lowered in the placebo-treated group in our study. However, PRA tended to be higher in the irbesartan-treated group than in the placebo-treated group, although the difference was not significant (P¼0.054).…”

Section: Discussionmentioning

confidence: 99%

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Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

2010

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Angiotensin receptor blockers (ARBs) or T-and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg À1 ), efonidipine (30 mg kg À1 ), irbesartan (60 mg kg À1 )+efonidipine (30 mg kg À1 ), amlodipine (3 mg kg À1 ), or irbesartan (60 mg kg À1 )+amlodipine (3 mg kg À1 ) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine-and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22 phox , transforming growth factor-b, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T-and L-type CCB might produce a powerful renal protective effect. INTRODUCTIONKidneys have an important role not only in the homeostasis of water and electrolyte balance but also in the regulation of blood pressure. Angiotensin II is a crucial peptide for regulating blood pressure by slow and rapid pressor responses. The main functions of slow response are augmentation of sodium reabsorption in the proximal tubules and release of aldosterone from the adrenal cortex, whereas the main functions of rapid response are direct contractile response in peripheral resistance arteries and enhancement of peripheral noradrenergic neurotransmission. Therefore, blockade of angiotensin II is a useful antihypertensive strategy. In addition, angiotensin II directly increases mesangial matrix formation by stimulating transforming growth factor (TGF)-b expression. 1 Inhibition of angiotensin II function induces dilation of efferent arterioles, and this mechanism contributes to amelioration of glomerular hypertension, resulting in a decrease in mesangial matrix formation. 2 Therefore, blockade of angiotensin II is also useful for preventing glomerular injury.Calcium channel blockers (CCBs), such as angi...

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T‐type and L‐type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats

Cited by 36 publications

References 33 publications

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

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