Functional and pharmacological consequences of the distribution of voltage‐gated calcium channels inthe renal blood vessels

Abstract

Calcium channel blockers are widely used to treat hypertension because they inhibit voltage-gated calcium channels that mediate transmembrane calcium influx in, for example, vascular smooth muscle and cardiomyocytes. The calcium channel family consists of several subfamilies, of which the L-type is usually associated with vascular contractility. However, the L-, T- and P-/Q-types of calcium channels are present in the renal vasculature and are differentially involved in controlling vascular contractility, thereby contributing to regulation of kidney function and blood pressure. In the preglomerular vascular bed, all the three channel families are present. However, the T-type channel is the only channel in cortical efferent arterioles which is in contrast to the juxtamedullary efferent arteriole, and that leads to diverse functional effects of L- and T-type channel inhibition. Furthermore, by different mechanisms, T-type channels may contribute to both constriction and dilation of the arterioles. Finally, P-/Q-type channels are involved in the regulation of human intrarenal arterial contractility. The calcium blockers used in the clinic affect not only L-type but also P-/Q- and T-type channels. Therefore, the distinct effect obtained by inhibiting a given subtype or set of channels under experimental settings should be considered when choosing a calcium blocker for treatment. T-type channels seem to be crucial for regulating the GFR and the filtration fraction. Use of blockers is expected to lead to preferential efferent vasodilation, reduction of glomerular pressure and proteinuria. Therefore, renovascular T-type channels might provide novel therapeutic targets, and may have superior renoprotective effects compared to conventional calcium blockers.

Differential effect of T-type voltage-gated Ca2+ channel disruption on renal plasma flow and glomerular filtration rate in vivo

“…However, in the present study, K ϩ -induced contractility responses of afferent and efferent arterioles of Ca v 3.1 Ϫ/Ϫ mice were not significantly different compared with WT mice. This is in disagreement with previous pharmacological studies (15,22) showing an effect of a T-type blocker on arteriolar contractility.…”

“…L-type Ca 2ϩ channels. Combined T-and L-type blockers have been suggested to have a therapeutic advantage over selective L-type blockers by providing renoprotection due to differential expression of Ca 2ϩ channels, with only T-type Ca 2ϩ channels (Ca v 3.1 and Ca v 3.2) expressed in efferent arterioles (15,22,42). Clinical data support a renoprotective effect of combined T-and L-type blockers as it was concluded that treatment with a combined L-and T-type antagonist yields greater efficacy that a L-type antagonist in reducing blood pressure and proteinuria (32,33,38).…”

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

“…The rise in plasma Pi and/or the fall in plasma calcium may be (in)direct triggers affecting factors controlling glomerular filtration, such as vascular tone of afferent and/or efferent arterioles, where calcium channels play an important role. 39 PTH is also required for the downregulation of renal Pi transporters after 4 hours, because this response was also blunted in PTX rats. Thus, our results show that PTH is required for the early response to high Pi intake.…”

Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system: news from the world of knockout mice

“…However, not all of the antagonists are selective for the L-subtype. The calcium channel antagonists differ in their selectivity for the various calcium channel subtypes (25,26,32,82). Despite the existence of several Ca v subtypes, the physiological importance of these various calcium channels subtypes is unknown.…”

“…Several studies have suggested that T-type channel blockers have superior renoprotective effects compared with conventional calcium blockers. T-type blockers could be an additional tool for treating hypertensive proteinuric kidney disease (32). The T-type antagonist efonidipine slows the progression of proteinuric kidney disease in a manner similar to angiotensin-converting enzyme inhibitors (39), and proteinuria treatment with a combination of L-and T-type antagonists yields greater efficacy than the L-type antagonist alone (76,77,89).…”