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EFFECT OF NIFEDIPINE AND VERAPAMIL ON URINARY PH, VOLUME AND ELECTROLYTES IN RATS
H L Dhar*, K Farzan**
*Director, Medical Research Centre, Bombay Hospital, Mumbai - 400 020;
**Dept of Pharmacology, LTM Medical College, Mumbai.
Nifedipine 100 mg/kg (IP) does not alter the urine volume at 5 and 24 hrs but higher dose 500 mg/kg reduces the volume of urine in 5 hrs which comes back to normal at 24 hrs without significant change in pH and electrolytes, but none of the values are altered on prolonged treatment (3 weeks). Increased urinary output by hydrochlorothiazide (2.5 mg/kg) remains unaltered with prior treatment with nifedipine (100 mg/kg) remains unaltered with prior treatment with nifedipine (100 mg/kg) both after acute and chronic treatment.
Verapamil 100 mg and 1000 mg/kg under similar conditions did not have any effect either on single dose treatment or for a period of 3 weeks. Effect of verapamil on hydrochlorothiazide (2.5 mg/kg) was similar to nifedipine.INTRODUCTION
Acute effect of nifedipine on water and electrolyte balance in the dog has been reported earlier. [1] Now we are reporting the chronic effect in the rats.
A number of clinically distinct calcium channel blockers including verapamil and diltiazem and selected dihydropyridines have produced saluretic action in rats. [2] On the otherhand, calcium channel blockers as a class are known vasodilators and vasodilators cause urine and electrolyte retention, [3] however, calcium channel blockers used in the therapy of hypertension do not generally provoke fluid retention, [4] and diuresis and natriuresis are not always accompanied by kaliuresis. [5] In view of the conflicting reports it was decided to study the effects of nifedipine and verapamil on urinary volume, pH and electrolytes i.e. Na+, K+, Cl-, Ca++ and HCO-3 in rats. Attempt has been made to find out whether prior administration of nifedipine and verapamil alter the effect of hydrochlorothiazide on urine volume, pH and electrolytes.MATERIAL AND METHODS
Albino rats (both sexes) weighing between 120-200 g obtained from Haffkin’s Institute Bombay were observed for a week, kept on peas with water ad libitum. Five groups of animals (6 in each group) were treated as follows: gr. 1 received saline (IP) served as control, gr. 2 and 3 received nifedipine (Cadila) (IP) 100 mg and 500 mg/kg respectively for one day, and gr. 4 and 5 received nifedipine 100 mg/kg and 500 mg/kg respectively daily for 3 weeks. Animals were kept in metabolic cases and urine was collected for 5 and 24 hrs after administration of single dose of nifedipine and volume measured, pH detected and electrolytes were estimated by methods as follows: sodium and potassium, [6] chloride, [7] calcium, [8] and bicarbonate. [9]
Another five groups of similar animals were treated as follows: gr. 1 received hydrochlorothiazide (2.5 mg/kg) orally served as control, gr. 2 and 3 received nifedipine (100 mg and 500 mg/kg) alongwith hydrochlorothiazide (2.5 mg/kg) and gr. 4 and gr. 5 received nifedipine (both doses), as well as hydrochorothiazide (same dose) for 3 weeks. Urine was collected for 5 and 24 hrs and processed accordingly.
Similar groups of rats were treated with verapamil (Boehringer) (100 mg/kg 1000 mg/kg) as nifedipine and volume of urine measured, pH detected and electrolytes estimated accordingly.
Statistical analysis was done by applying student’s ‘t’ test.RESULTS
Nifedipine 100 mg/kg single dose did not have any effect either on pH or electolytes at 5 and 24 hr. However, higher dose of nifedipine (500 mg/kg) reduced the urine volume after 5 hr from 3.53 + 0.86 to 0.83 + 0.25 ml which was restored to normal after 24 hr without any change in pH and electrolytes. Prolonged treatment with nifedipine at either dose for 3 weeks did not alter the volume of urine, pH and any of the electrolytes at 5 hrs as well as at 24 hrs (Table 1).
Hydrochlorothiazide (2.5 mg/kg) raised the volume of urine (from 3.53 + 0.86 to 11.29 + 1.95) as well as potassium level (from 22.36 + 4.09 to 60.40 + 4.84) at 5 hr but not at 24 hr (Table 2). Chloride level was raised both at 5 (from 50.00 + 10.28 to 147.00 + 5.82) and 24 (from 54.80 + 10.45 to 139.60 + 14.67) hr, however rise in sodium and bicarbonate was not statistically significant. None of these parameters were altered significantly with either dose of nifedipine (100 mg and 500 mg/kg) both after acute treatment or on prolonged administration (Table 2).
Verapamil (100 mg/kg) as well as (1000 mg/kg) under similar conditions did not alter any parameters both on acute treatment and for 3 weeks (Table 3) and also did not alter the values of hydrochlorothiazide (Table 4).
Table 1 Effect of nifedipine at 5 and 24 hr on urine volume pH and electrolytes in rats
(N=6 animals in each gr.)Urine
Dose
Time (hr)Control Nifedipine single mg/kg dose Nifedipine mg/kg daily for 3 weeks 100 500 100 500 5 24 5 24 5 24 5 24 5 24 Vol 3.53 10.80 2.20 12.14 *0.83 11.10 2.70 14.70 3.58 15.50 + 0.86 + 3.08 + 0.24 + 2.45 + 0.25 + 0.95 + 0.34 + 2.39 + 0.50 + 2.13 PH 7.09 7.20 7.12 7.52 7.28 7.56 7.18 7.54 7.31 7.58 + 1.57 + 1.58 + 1.58 + 1.67 + 1.61 + 1.68 + 1.59 + 1.67 + 1.62 + 1.67 Na+ 167.32 177.60 171.60 178.40 173.08 182.60 175.70 181.60 176.00 186.20 + 31.20 + 25.00 + 31.90 + 29.30 + 31.96 + 34.20 + 34.50 + 34.60 + 35.20 + 31.11 K+ 22.36 29.38 24.20 30.80 24.54 30.40 25.00 30.65 24.39 29.60 + 4.09 + 3.33 + 4.43 + 3.47 + 4.46 + 2.75 + 4.99 + 2.53 + 4.83 + 3.51 Cl- 50.00 54.80 54.80 60.60 55.46 61.80 56.87 61.40 57.00 63.70 + 10.28 + 10.45 + 10.95 + 12.34 + 11.00 + 12.38 + 11.52 + 13.10 + 12.65 + 13.00 Ca++ 115.64 123.00 118.30 129.70 121.08 130.80 120.22 131.40 125.22 141.80 + 24.76 + 24.88 + 24.50 + 27.50 + 26.46 + 28.21 + 26.00 + 28.45 + 27.28 + 30.68 HCO3- 85.92 84.80 89.70 90.46 90.98 91.70 90.30 92.00 92.21 93.80 + 18.95 + 17.61 + 19.34 + 18.86 + 19.78 + 10.78 + 19.98 + 19.87 + 20.17 + 20.26 Na+ and K+; mEq/L; Cl- and HCO3- : mmol/L; Ca++ : mg/L *p < 0.05 Values are mean + SEM)
DISCUSSION
Nifedipine does not significantly alter the electrolyte balance in the dog. Present work shows nifedipine (100 mg/kg IP) does not have any effect on volume pH or electrolytes as a single dose as well as for 3 weeks but higher dose (500 mg/kg) reduces the volume of urine at the initial stage (5 hrs.) which comes back to normal at 24 hrs. However effect of long term administration of either dose is without any effect on urine volume, pH and electrolytes (Table 1). There are isolated references regarding fluid retention [2, 3] and infrequent loss of potassium [4] induced by nifedipine. In a recent study it has been commented without experimental data that calcium channel antagonists used in therapy of hypertension do not generally provoke fluid retention. [5] Still recently it has been reported that Ca channel antagonists can cause sodium and water retention although antihypertensive effect prevail in sodium depleted patients. [10]
Dose
Time
(hr)
chlorothiazide
mg/kg
single dose
for 3 weeks2.5 100 500 100 500 5 24 5 24 5 24 5 24 5 24 Vol 11.29 14.70 8.18 14.60 8.10 14.90 8.41 16.60 8.71 18.90 +
1.95+
2.58+
1.07+ 2.80 + 1.07 + 2.06 + 0.61 + 2.64 + 1.77 + 3.04 PH 7.45 7.86 7.54 7.88 7.55 7.90 7.57 7.20 7.60 7.92 +
1.65+
1.74+ 1.67 + 1.75 + 1.68 + 1.75 + 1.68 + 1.75 + 1.68 + 1.75 Na+ 228.43 195.80 231.56 198.20 233.35 201.20 232.60 199.60 237.16 204.80 + 46.50 + 36.50 + 40.43 + 28.79 + 40.83 + 32.54 + 39.82 + 38.80 + 42.70 + 40.00 K+ 60.40 41.00 61.43 48.96 59.62 46.70 59.25 47.60 61.78 48.28 + 4.84 + 7.41 + 5.02 + 7.17 + 5.02 + 7.17 + 6.74 + 5.39 + 3.37 + 7.43 Cl- 147.00 139.60 148.56 142.60 149.60 140.40 150.66 141.20 159.56 140.56 +
5.82+ 14.67 + 30.70 + 28.00 + 31.48 + 28.60 + 29.00 + 30.50 + 34.20 + 30.52 Ca++ 136.96 142.40 138.12 143.40 141.18 151.20 139.45 145.40 143.67 147.60 + 29.62 + 31.64 + 29.66 + 30.75 + 29.66 + 30.75 + 30.24 + 31.63 + 31.28 + 32.03 HCO3- 117.68 118.40 120.00 121.00 121.52 122.80 121.93 123.00 122.40 124.10 + 26.00 + 25.75 + 26.40 + 25.82 + 26.81 + 26.67 + 27.15 + 27.32 + 27.11 + 26.50 Na and K+ : mEq/L; Cl- and HCO3- : mmol/L; Ca++ : mg/L
Table 3 Effect of Verapamil mg/kg at 5 and 24 hr on urine volume, pH and electrolytes
(N=6 in each group)Urine
Dose
Time (hr)Control Verapamil single dose Verapamil for 3 weeks 100 1000 100 1000 5 24 5 24 5 24 5 24 5 24 Vol 3.53 10.80 2.47 13.60 2.06 15.40 2.66 15.20 2.83 15.20 + 0.86 + 3.08 + 0.32 + 2.67 + 0.99 + 2.98 + 0.20 + 3.05 + 0.11 + 2.26 PH 7.09 7.20 7.08 7.46 7.13 7.54 7.11 7.50 7.15 7.52 + 1.57 + 1.58 + 1.57 + 1.66 + 1.58 + 1.67 + 1.58 + 1.65 + 1.54 + 1.67 Na+ 167.32 177.60 69.50 176.40 192.96 177.80 171.15 176.80 174.40 178.00 + 31.20 + 25.00 + 32.34 + 31.30 + 33.14 + 30.48 + 36.36 + 25.97 + 32.80 + 29.00 K+ 22.36 29.38 24.80 29.54 24.20 30.90 24.40 29.62 23.60 28.90 + 4.09 + 3.33 + 3.86 + 3.31 + 4.69 + 3.04 + 4.13 + 2.69 + 5.00 + 3.05 Cl- 50.00 54.80 53.82 59.00 54.40 59.60 54.98 61.10 56.00 64.00 + 10.28 + 10.45 + 8.64 + 11.99 + 10.50 + 11.82 + 11.54 + 13.20 + 11.21 + 12.62 Ca++ 115.64 123.00 116.48 126.80 118.86 128.20 118.00 131.60 119.94 134.00 + 24.76 + 24.88 + 25.07 + 27.01 + 26.06 + 27.52 + 26.10 + 28.08 + 26.89 + 27.66 HCO3- 85.92 84.80 87.40 86.30 88.21 87.60 88.45 87.50 91.40 92.40 + 18.95 + 17.61 + 19.14 + 18.43 + 19.58 + 19.26 + 19.65 + 18.72 + 19.57 + 19.48 Na+ and K+ : mEq/L; Cl- and HCO3- : mmol/L; Ca++ : mg/LVery recently benedipine has been shown to produce diuresis in rats by inhibition of water and Na reabsorption at both the proximal and distal tubule. It has been demonstrated that benedipine, but not amlodipine can dilate glomerular efferentas well as afferent arterioles in spontaneously hypertensive rats. [11]
Table 4 Effect of Verapamil (acute and chronic treatment) on hydrochlorothiazide induced
urine volume, pH and lelectrolytesUrine
Dose
Time (hr)Control Verapamil single dose Verapamil daily for 3 weeks mg/kg 100 1000 100 1000 5 24 5 24 5 24 5 24 5 24 Vol 11.29 14.70 9.97 19.60 8.10 13.60 8.22 18.60 8.86 16.40 + 1.95 + 2.58 + 1.80 + 3.58 + 1.96 + 2.67 + 0.52 + 3.11 + 0.42 + 2.13 PH 7.45 7.82 7.52 7.84 7.53 7.84 7.11 7.50 7.46 7.88 + 1.65 + 1.74 + 1.62 + 1.74 + 1.68 + 1.74 + 1.58 + 1.65 + 1.66 + 1.60 Na+ 228.43 195.81 229.10 196.20 231.74 200.20 232.80 198.60 234.00 200.50 + 46.50 + 36.50 + 47.30 + 38.47 + 44.34 + 32.50 + 48.00 + 36.00 + 36.30 + 38.40 K+ 60.40 41.00 57.38 45.00 58.24 46.60 57.60 66.72 59.30 46.80 + 4.34 + 7.41 + 3.86 + 6.85 + 3.62 + 3.89 + 6.91 + 7.82 + 12.34 + 4.81 Cl- 147.20 139.60 147.00 139.20 148.30 138.60 146.98 139.40 150.24 138.98 + 5.82 + 41.67 + 30.94 + 28.66 + 31.13 + 30.59 + 31.28 + 29.49 + 31.00 + 29.20 Ca++ 136.96 142.40 136.74 142.80 138.69 143.00 137.64 143.60 138.21 145.20 + 29.62 + 31.64 + 29.89 + 30.61 + 30.39 + 30.38 + 30.08 + 29.75 + 30.18 + 30.99 HCO3- 117.68 118.40 118.54 119.80 120.90 121.60 119.98 121.00 121.69 122.80 + 26.00 + 27.75 + 26.27 + 26.45 + 26.52 + 26.45 + 26.48 + 26.00 + 27.13 + 26.85 Na+ and K+ : mEq/L; Cl- and HCO3- : mmol/L; Ca++ : mg/L
Present result shows that nifedipine does not cause fluid retention except in the initial phase (5 hr) that too at a higher dose (500 mg/kg) and verapamil does not cause fluid retention even at the initial phase. None of them alters pH and electrolytes even on prolonged treatment for 3 weeks.
Hydrochlorothiazide which increased the volume of urine as well as excretion of potassium and chloride, dose not influence the acute as well as prolonged effect of nifedipine upto 500 mg/kg (Table 2) and verapamil upto a dose of 1000 mg/kg (Table 4). It has been shown that effect of furosemide also are not effected by prior administration of nifedipine and verapamil [12] which is an advantage when diuretics are used with these drugs. Vasodilators cause urine and electrolyte retention [3] as such absence of potassium loss alongwith vasodilator effect of nifedipine is a distinct advantage on prolonged administration.
Present result shows that neither nifedipine nor verapamil cause retention of water and electrolytes even on prolonged administration, which may be comparable with benedipine. However, further studies will be required particularly the effect on creatinine and hippuric acid clearance to substantiate this claim.REFERENCES
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