Calcium-channel blockers and the progression of renal disease

Abstract

Effective blood pressure (BP) reduction is now generally recognized as a clinically proven strategy to retard the seemingly inexorable downhill progression of patients with diabetic and nondiabetic chronic renal disease. Although calcium-channel blockers (CCBs) are effective antihypertensive agents, the available experimental and clinical data are quite contradictory as to whether BP reduction achieved with CCBs provides the expected renoprotection. Blockade of the "L" type, voltage-gated Ca channels that mediate the BP reduction also concurrently impairs renal autoregulatory responses of the preglomerular vasculature. Because these renal autoregulatory resistance changes provide the primary protection against the transmission of systemic hypertension to the renal microvasculature, the adverse effects of CCBs on renal autoregulation counteract the beneficial effects on BP reduction. The degree of renoprotection achieved, therefore, depends on the balance between these two opposing effects. The data also indicate that there are probably important and clinically relevant differences between the classes of CCBs, with the dihydropyridine (DHP) CCBs most likely to have consistent deleterious effects on renal autoregulation. However, the available data also indicate that the adverse effects of DHP CCBs are not likely to be observed if BP is lowered well into the normotensive range, possibly through the use of combination therapies. Even when used as adjunctive therapy, close monitoring may be advisable to ensure BP normalization and the absence of any untoward effects on proteinuria and renal function.

A gap junction inhibitor, carbenoxolone, induces spatiotemporal dispersion of renal cortical perfusion and impairs autoregulation

“…Our results show that this provides smoothing in space and time that minimizes the cumulative error in regulation of downstream blood flow and glomerular capillary pressure. Given the importance of autoregulation in protecting the renal vasculature from hypertensive injury (20,21,34,70), synchronization of autoregulation is becoming an increasingly important aspect of RBF control. Certainly there is experimental evidence for frequency-and amplitude-modulation of MR by TGF (29,30,48,50,53,62,63) at levels from neighboring nephrons to whole kidney blood flow.…”

Improving Antihypertensive Agent Selection to Promote Nephroprotection

“…By contrast, renal plasma flow is somewhat decreased by diuretics and beta-blockers. One concern expressed for calcium channel blockers (CCBs) is whether blood pressure reduction achieved with CCBs provides the expected renoprotection [3]. Blockade of the "L" type, voltage-gated Ca channels that mediate the BP reduction has been shown to concurrently impair renal autoregulatory responses of the preglomerular vasculature [4].…”

“…A large percentage of end-stage renal disease cases are directly attributable to the consequences of diabetes. Some authors [3,4] have suggested that the common use of calcium channel blockers has been responsible for higher rates of renal disease despite improved blood pressure control. Other authors [5] have pointed to thiazide diuretics as being permissive of nephrotoxicity through a failure to inhibit angiotensin II (Ang II) and indeed raising renin levels that induce Ang II production, as well as through mechanisms that increase serum uric acid levels.…”