dihydropyridines and Hydronephrosis

Cilnidipine is a dihydropyridine calcium channel blocker that acts on both L-type and N-type calcium channels. The effects of cilnidipine given intravenously at doses of 2.5, 5.0, and 10 microg/kg were studied using an ex vivo hydronephrosis model in spontaneously hypertensive rats. The effects of nifedipine at a dose of 10 microg/kg were also studied using the same model as a reference. Cilnidipine caused dose-dependent blood pressure reduction and dilatation of the glomerular afferent arterioles; the arteriolar diameter after cilnidipine infusion at 2.5, 5.0, and 10 microg/kg was 101% +/- 3%, 112% +/- 4%, and 123% +/- 6% relative to baseline, respectively. With cilnidipine, dilatation of the efferent arterioles was also observed; it was maximal after 5 to 10 minutes. Five minutes after administration of 2.5, 5.0, and 10 microg/kg of cilnidipine, the efferent arteriolar diameter was 103% +/- 2%, 109% +/- 4%, and 119% +/- 4% of baseline, respectively. This efferent arteriolar dilating action of cilnidipine was abolished after pretreatment with omega-conotoxin, a selective N-type calcium channel blocker. A dose-dependent increase of glomerular blood flow volume was also observed after cilnidipine infusion. Nifedipine, an L-type calcium channel blocker, at a dose of 10 microg/kg reduced systolic blood pressure to a similar extent as cilnidipine at a dose of 10 microg/kg, but only dilated the afferent arterioles and had no significant effect on efferent arterioles. Cilnidipine dilated both the afferent and efferent glomerular arterioles. The efferent arteriolar dilating effect of cilnidipine may be attributed to its inhibition of the N-type calcium channel.

Topics: Animals; Arterioles; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Female; Hydronephrosis; Kidney Glomerulus; Nifedipine; omega-Conotoxins; Rats; Rats, Inbred SHR; Vasodilator Agents

Although calcium antagonists elicit predominant dilation of afferent arterioles that might be associated with glomerular hypertension, there have been reported diverse observations demonstrating the effect of calcium antagonists on the progression of renal injury. The present study examined the effect of pranidipine (CAS 99522-79-9) on the renal microvascular tone in the isolated perfused hydronephrotic rat kidney, and the progression of renal insufficiency in subtotally nephrectomized spontaneously hypertensive rats. In the hydronephrotic kidney, angiotensin II caused marked constriction of both afferent and efferent arterioles. The subsequent addition of pranidipine (10 nmol/l, 100 nmol/l, 1 mumol/l) elicited dose-dependent afferent arteriolar dilation, with 97 +/- 3% reversal at 1 mumol/l. In contrast, efferent arterioles were resistant to pranidipine, with only 20 +/- 4% reversal at 1 mumol/l. In subtotally nephrectomized rats, 10-week treatment with pranidipine (3.0 mg/kg/day) markedly decreased blood pressure (from 270 +/- 6 to 158 +/- 8 mmHg) and improved renal histopathological changes, including glomerular and arteriolar sclerosis. Proteinuria was also less than than in the control rats (233 +/- 5 vs. 305 +/- 26 mg/day). Thus, although glomerular hypertension might develop as a consequence of preferential afferent arteriolar dilation, pranidipine actually improved the renal injury in subtotally nephrectomized SHR. These ostensibly discrepant observations could be attributed to the simultaneous reduction in blood pressure and the salutary actions of this agent mediated by non-hemodynamic mechanisms.

Topics: Animals; Arterioles; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hydronephrosis; In Vitro Techniques; Kidney; Microcirculation; Nephrectomy; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation

The objective of this study was to investigate the effects of a dihydropyridine calcium antagonist, manidipine HCl, and an angiotensin II receptor antagonist, CV-11974, on renal microvasculature in hypertensive rats. Hydronephrosis was induced by ligation of the left ureter in 8-week-old stroke-prone spontaneously hypertensive rats. Two months after the operation, the hydronephrotic kidney was split longitudinally and spread out as a thin sheet, and the renal microvasculature was observed directly under a light microscope. Administration of manidipine HCl (20 micrograms/kg) caused a gradual fall in blood pressure (-34 mmHg). The afferent arterioles were dilated, and maintained the same level of dilatation until 30 min (+20%). The efferent arterioles were also dilated (+8%). Glomerular blood flow was significantly increased (+38%). Administration of CV-11974 (100 micrograms/kg) caused a sharp fall in blood pressure at 2 min (-24 mmHg), with a continuous fall in blood pressure until 60 min (-46 mmHg). The afferent arterioles were gradually dilated (+15%). The efferent arteriole was also dilated until 60 min, but to a lesser extent than the afferent arteriole. Glomerular blood flow was immediately increased (+35%). We conclude that both manidipine HCl and CV-11974 dilated both the afferent and efferent arterioles and increased glomerular blood flow.

Topics: Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Arterioles; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Hydronephrosis; Hypertension; Kidney; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Artery; Tetrazoles

We have recently proposed that the actions of endothelin (ET) are in part mediated by opening of chloride channels (K. Iijima, L. Lin, A. Nasjletti, and M. S. Goligorsky. Am. J. Physiol. 260 (Cell Physiol. 29: C982-C992, 1991). In the present study the ability of a chloride channel inhibitor, an indanyloxyacetic acid (IAA-94), to block ET-induced effects was examined in cultured vascular smooth muscle cells (VSMC) by spectrofluorometry and direct videomicroscopic visualization of the renal microcirculation in isolated perfused hydronephrotic kidneys (IPHK). A fluorescein isothiocyanate (FITC)-labeled IAA-94 analogue showed specific binding to VSMC. IAA-94 (30 microM) neither affected basal cytosolic calcium concentration ([Ca2+]i) in VSMC nor peak response to ET, but it significantly curtailed sustained elevation of [Ca2+]i (half-time recovery was 147 +/- 23 vs. 248 +/- 33 s in control, P less than 0.05). IAA-94 blunted ET-induced membrane depolarization from 24.5 +/- 3.3 to 8.0 +/- 1.8 mV. In IPHK, ET constricted afferent arterioles (AA) by 29 +/- 2% (18.7 +/- 0.8 to 13.2 +/- 0.6 microns, P less than 0.001). Isradipine reversed this ET-induced vasoconstriction. Pretreatment with IAA-94 did not alter AA diameter, but markedly attenuated ET-induced AA constriction (reduction of AA diameters by only 9 +/- 2%, P less than 0.001). The subsequent addition of isradipine (0.1-1 microM) did not further dilate AA. Our data indicate that IAA-94 markedly attenuates AA vasoconstriction elicited by ET and suggest that ET-induced opening of chloride channels, membrane depolarization, and subsequent activation of voltage-dependent calcium channels contribute to the vasoconstrictor mechanisms of this peptide.

Topics: Animals; Antihypertensive Agents; Arterioles; Calcium; Cells, Cultured; Chloride Channels; Dihydropyridines; Electrophysiology; Endothelins; Glycolates; Hydronephrosis; In Vitro Techniques; Isradipine; Membrane Proteins; Muscle, Smooth, Vascular; Potassium Chloride; Rats; Renal Circulation; Vasoconstriction