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Calcium channel blockade in rats with cyclosporine-induced vasoconstriction
J S Abraham1, F R Bentley, R N Garrison
1Department of Surgery, University of Louisville School of Medicine, Louisville 40292.
Abstract:
Calcium channel blockade has been found to attenuate nephrotoxicity of cyclosporine. However, it is not known whether intrarenal vasoconstriction caused by cyclosporine is totally mediated by vascular smooth muscle calcium influx. To study the protective effects of two calcium blockers on cyclosporine-induced intrarenal vasoconstriction and renal microvascular blood flow, hydronephrotic rat kidneys were suspended in an environmentally controlled tissue bath. Renal microvessel diameters and microvascular blood flow were determined by in vivo videomicroscopy and Doppler velocimetry. Calcium channel blockade was achieved by adding verapamil hydrochloride (5.6 x 10(-5) M) or diltiazem hydrochloride (2.8 x 10(-5) M) to the tissue bath, which respectively resulted in a 15 +/- 2% and 16 +/- 3% interlobular arteriolar dilation, a 13 +/- 3% and 12 +/- 2% afferent arteriolar dilation, and a 60 +/- 8% and 46 +/- 14% increase in interlobular blood flow. When cyclosporine (1.7 x 10(-3) M) was added to the tissue bath, there was a constriction of the interlobular arterioles to 4 +/- 3% below baseline in rats receiving verapamil and 9 +/- 3% below baseline in rats receiving diltiazem. Microvascular blood flow was reduced by the addition of cyclosporine to 3 +/- 4% above original baseline values in the verapamil group and 22 +/- 6% below baseline in the diltiazem group. Afferent arterioles were similarly constricted by cyclosporine. The results indicate that calcium blockade causes preglomerular vasodilation and protects the microvascular blood flow induced by cyclosporine. Since verapamil or diltiazem did not prevent arteriolar constriction as observed when cyclosporine was added, it was concluded that the mechanism of acute cyclosporine-induced vasoconstriction is not solely mediated by vascular smooth muscle calcium influx through potential dependent channels.
Insights
Calcium channel blockers like verapamil and diltiazem protect kidney blood flow from cyclosporine. However, cyclosporine-induced vasoconstriction is not solely due to calcium influx in vascular smooth muscle.
Area of Science:
- Nephrology
- Pharmacology
- Physiology
Background:
- Cyclosporine (CsA) can cause kidney damage (nephrotoxicity).
- Calcium channel blockers (CCBs) may reduce CsA nephrotoxicity.
- The exact mechanism of CsA-induced intrarenal vasoconstriction is unclear.
Purpose of the Study:
- To investigate the protective effects of verapamil and diltiazem on CsA-induced intrarenal vasoconstriction.
- To assess the impact of CCBs on renal microvascular blood flow during CsA administration.
- To determine if CsA-induced vasoconstriction is entirely mediated by calcium influx.
Main Methods:
- Hydronephrotic rat kidneys were studied in vitro.
- Renal microvessel diameters and blood flow were measured using videomicroscopy and Doppler velocimetry.
- Effects of verapamil and diltiazem on CsA-induced changes were analyzed.
Main Results:
- Both verapamil and diltiazem caused arteriolar dilation and increased renal blood flow.
- CsA induced arteriolar constriction and reduced microvascular blood flow, though CCBs offered some protection.
- Verapamil and diltiazem did not fully prevent CsA-induced vasoconstriction.
Conclusions:
- Calcium channel blockade promotes preglomerular vasodilation and preserves microvascular blood flow against CsA effects.
- Acute CsA-induced vasoconstriction is not exclusively mediated by calcium influx via voltage-dependent channels.
- Further research is needed to elucidate the complete mechanism of CsA nephrotoxicity and vasoconstriction.