Combination Therapy for the Cardiovascular Effects of
					Perinatal Lead Exposure in Young and Adult Rats

Gaspar, Andréia Fresneda; Cordellini, Sandra

doi:10.5935/abc.20140103

Andréia Fresneda Gaspar

Departamento de Farmacologia, Instituto de Biociências - Universidade Estadual Paulista (UNESP), Botucatu, SP - Brazil

Faculdade da Alta Paulista (FAP), Tupã, SP - Brazil

Sandra Cordellini Mailing Address: Sandra Cordellini, Rua João Carmelo 145, Jardim Paraíso. CEP 18610-290, Botucatu, SP - Brazil. Email: cordelli@ibb.unesp.br

Departamento de Farmacologia, Instituto de Biociências - Universidade Estadual Paulista (UNESP), Botucatu, SP - Brazil

Mailing Address: Sandra Cordellini, Rua João Carmelo 145, Jardim Paraíso. CEP 18610-290, Botucatu, SP - Brazil. Email: cordelli@ibb.unesp.br

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Figures (3)
Tables (4)

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Figure 1
Experimental design

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Figure 2
Arterial blood pressure in 52-day-old rats who were or were not exposed to Pb in the perinatal period (during pregnancy and lactation) and were treated or not treated with DMSA, L-arginine, enalapril, or combination therapy. Treatment: a group of 22-day-old offspring received DMSA, L-arginine, enalapril, or a combination of these compounds for 30 additional days. DMSA was orally administered at 60 mg/kg by gastric gavage two times a day (30 mg/kg per dose) for 5 days a week. L-arginine (1.0%) was administered through drinking water ad libitum. Enalapril was administered through drinking water at a dosage of 5 mg/rat/day. Age-matched controls received tap water. Values are expressed as means ± standard errors. *p < 0.05 compared with controls; #p < 0.05 compared with Pb/water. (n) = animal number per group.

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Figure 3
Arterial blood pressure in 100-day-old rats who were or were not exposed to Pb in the perinatal period (during pregnancy and lactation) and were treated or not treated with DMSA, L-arginine, enalapril, or combination therapy. Treatment: a group of 100-day-old offspring received DMSA, L-arginine, enalapril, or a combination of these compounds for 30 additional days. DMSA was orally administered at 60 mg/kg by gastric gavage two times a day (30 mg/kg per dose) for 5 days a week. L-arginine (1.0%) was administered through drinking water ad libitum. Enalapril was administered through drinking water at a dosage of 5 mg/rat/day. Age-matched controls received tap water. Values are expressed as means ± standard errors. *p < 0.05 compared with controls; #p < 0.05 compared with Pb/water; (n) = animal number per group.

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Table 1
Body weights of females exposed or not exposed to Pb during pregnancy and lactation and their male offspring who were treated or not treated with DMSA, L-arginine, enalapril, or combination therapy

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Table 2
Blood Pb levels in females who were or were not exposed to Pb during pregnancy and lactation and their male offspring who were or were not treated with DMSA, L-arginine, enalapril, or combination therapy

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Table 3
Maximal responses and EC50 values for the response to noradrenaline obtained in aortas with and without endothelium that were isolated from rats who were or were not exposed to Pb in the perinatal period (during pregnancy and lactation) and were or were not treated with L-arginine or enalapril

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Table 4
Maximal responses and EC₅₀ values for the response to noradrenaline In aortas with and without endothelium that were isolated from rats who were or were not exposed to Pb during pregnancy and lactation and were or were not treated with DMSA or combination therapy

		Body weight (g)
Rats	Groups		Pregnancy	Lactation		Post-weaning age
		0 day	21 days	1 day	21 days	52 days	70 days	100 days
Dams	Control (n = 20)	272.2 ± 6.2	378.8 ± 9.0	304.6 ± 7.0	276.9 ± 5.6	-	-	-
	Pb (n = 20)	269.0 ± 4.9	360.3 ± 8.1	293.1 ± 5.0	275.44 ± 5.3	-	-	-
Male offspring	Control (n = 20)	-	-	6.2 ± 0.2	39.1 ± 0.5	208.3 ± 0.2	323.1 ± 5.3	357.0 ± 2.7
	Pb (n = 20)	-	-	5.8 ± 1.7	40.0 ± 1.2	198.6 ± 4.1	327.9 ± 8.6	357.1 ± 3.2
	Pb/DMSA (n = 20)	-	-	-	41.2 ± 2.2	195.0 ± 2.2	326.8 ± 6.1	365.7 ± 1.7
	Pb/L-arginine (n = 15)	-	-	-	43.0 ± 2.3	205.5 ± 2.3	325.4 ± 2.5	369.9 ± 2.2
	Pb/enalapril (n = 15)	-	-	-	42.4 ± 1.8	194.8 ± 4.2	301.7 ± 2.4	351.1 ± 1.8
	Combination therapy (n = 20)	-	-	-	43.0 ± 5.5	206.0 ± 8.5	314.7 ± 2.6	360.6 ± 1.2

Blood Pb levels (μg/dL)
Groups	Females	Male offspring
		23 days	52 days	70 days	100 days
Control (n = 5)	< 5.0	< 5.0	< 5.0	< 5.0	< 5.0
Pb (n = 6)	53.39 ± 5.88^* * p < 0.05 compared with the respective control group;	35.61 ± 7.43^* * p < 0.05 compared with the respective control group;	-	-	-
Pb/water (n = 6)	-	-	19.98 ± 6.31^* * p < 0.05 compared with the respective control group;	13.15 ± 0.97^* * p < 0.05 compared with the respective control group; ⁺ + p < 0.05 compared with Pb-exposed, 23-day-old rats;	11.17 ± 2.11^* * p < 0.05 compared with the respective control group; ⁺ + p < 0.05 compared with Pb-exposed, 23-day-old rats;
Pb/DMSA (n = 5)	-	-	< 5.0^$ $ p < 0.05 compared with the respective Pb/water group;	-	< 5.0^$ $ p < 0.05 compared with the respective Pb/water group;
Pb/L-arginine (n = 6)	-	-	10.65 ± 2.12^* * p < 0.05 compared with the respective control group;	-	6.55 ± 3.29^* * p < 0.05 compared with the respective control group;
Pb/enalapril (n = 5)	-	-	< 5.0^$ $ p < 0.05 compared with the respective Pb/water group;	-	< 5.0^$ $ p < 0.05 compared with the respective Pb/water group;
Combination therapy (n = 5)	-	-	< 5.0^$ $ p < 0.05 compared with the respective Pb/water group;	-	< 5.0^$ $ p < 0.05 compared with the respective Pb/water group;

Male offspring		Aorta With Endothelium			Aorta Without Endothelium
Male offspring		¹ 1 Values represent means ± standard errors. Maximum response (g of tension)	² 2 EC50: levels producing half-maximum responses; values represent means with 95% confidence intervals. EC₅₀ (×10^-8 M)	³ 3 N = number of animals. N	¹ 1 Values represent means ± standard errors. Maximum response (g of tension)	² 2 EC50: levels producing half-maximum responses; values represent means with 95% confidence intervals. EC₅₀ (x 10^-9 M)	³ 3 N = number of animals. N
Not treated
23-day-old	Control	1.8 ± 0.1	1.3 (0.5 - 3.4)	6	2.6 ± 0.2⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.4⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.3 - 6.4)	8
	Pb	2.1 ± 0.2	1.5 (0.4 - 4.9)	6	3.0 ± 0.1⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.1⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 7.5)	8
52-day-old	Control	2.4 ± 0.3	2.0 (0.4 - 10.8)	7	4.1 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.0⁺ + p < 0.05 compared with the respective aorta with endothelium. (2.8 - 6.4)	8
	Pb	3.4 ± 0.2^* * p < 0.05 compared with the respective control group;	11.0 (6.0 - 20.3)	6	4.5 ± 0.2⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.0⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.3 - 4.2)	8
70-day-old	Control	3.4 ± 0.1	16.0 (7.1 - 35.4)	5	5.2 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	5.0⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.7 - 36.0)	7
	Pb	4.3 ± 0.2^* * p < 0.05 compared with the respective control group;	4.8 (1.7 - 13.3)	6	5.0 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.3⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.4 - 4.2)	8
100-day-old	Control	3.2 ± 0.2	8.5 (4.6 - 15.6)	6	5.3 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	5.6⁺ + p < 0.05 compared with the respective aorta with endothelium. (1.4 - 21.9)	8
	Pb	4.2 ± 0.2^* * p < 0.05 compared with the respective control group;	4.3 (0.9 - 20.7)	6	5.2 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	3.8⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.7 - 19.7)	8
L-arginine treatment
52-day-old	Control	2.8 ± 0.1	3.3 (1.5 - 7.3)	5	4.5 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.6⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 29.0)	8
	Pb	2.7 ± 0.1	10.0 (4.1 - 37.3)	6	4.3 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	8.5⁺ + p < 0.05 compared with the respective aorta with endothelium. (1.0 - 27.5)	8
100-day-old	Control	3.3 ± 0.2	8.9 (5.5 -14.5)	8	4.8 ± 0.2⁺ + p < 0.05 compared with the respective aorta with endothelium.	9.2⁺ + p < 0.05 compared with the respective aorta with endothelium. (3.2 - 26.3)	8
	Pb	3.2 ± 0.4	8.6 (2.3 - 31.4)	12	4.9 ± 0.5⁺ + p < 0.05 compared with the respective aorta with endothelium.	0.9⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.2 - 7.3)	14
Enalapril treatment
52-day-old	Control	2.7 ± 0.4	3.0 (0.4 - 23.4)	12	4.2 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	0.4⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 8.7)	12
	Pb	2.7 ± 0.2	6.15 (1.31 - 28.91)	7	4.2 ± 0.2⁺ + p < 0.05 compared with the respective aorta with endothelium.	6.2 ⁺ + p < 0.05 compared with the respective aorta with endothelium. (1.0 - 38.0)	8
100-day-old	Control	3.1 ± 0.2	5.4 (1.0 -27.5)	8	5.0 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	4.1⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.6 - 25.9)	11
	Pb	3.2 ± 0.1	9.4 (3.0 - 30.1)	5	5.6 ± 0.6⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.2⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.2 - 19.3)	14

Male offspring		Aorta With Endothelium			Aorta Without Endothelium
Male offspring		¹ 1 Values represent means ± standard errors. Maximum response (g of tension)	² 2 EC50: levels producing half-maximum responses; values represent means with 95% confidence intervals. EC₅₀ (x 10^-8 M)	³ 3 N = number of animals. N	¹ 1 Values represent means ± standard errors. Maximum response (g of tension)	² 2 EC50: levels producing half-maximum responses; values represent means with 95% confidence intervals. EC₅₀ (x 10^-9 M)	³ 3 N = number of animals. N
Not treated
52-day-old	Control	2.8 ± 0.4	9.0 (3.6 - 22.9)	8	4.1 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	12.8⁺ + p < 0.05 compared with the respective aorta with endothelium. (1.3 - 93.3)	8
	Pb	4.0 ± 0.4^* * p < 0.05 compared with the respective control group;	11.5 (5.3 - 25.1)	8	4.8 ± 0.2⁺ + p < 0.05 compared with the respective aorta with endothelium.	2.7⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.4 - 20.2)	6
100-day-old	Control	2.7 ± 0.3	7.9 (2.2 - 28.0)	5	5.1 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	10.5⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.3 - 49.1)	7
	Pb	4.1 ± 0.2^* * p < 0.05 compared with the respective control group;	15.4 (2.8 - 31.5)	5	5.4 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	15.2⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.4 - 69.6)	12
DMSA treatment
52-day-old	Control	2.8 ± 0.3	13.7 (5.7 - 32.7)	6	4.5 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	13.9⁺ + p < 0.05 compared with the respective aorta with endothelium. (2.4 - 81.0)	7
	Pb	2.7 ± 0.3	9.1 (3.8 - 21.8)	6	4.3 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	1.7⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 67.1)	12
100-day-old	Control	2.3 ± 0.2	18.1 (4.4 - 43.8)	6	4.6 ± 0.4⁺ + p < 0.05 compared with the respective aorta with endothelium.	35.1⁺ + p < 0.05 compared with the respective aorta with endothelium. (3.6 - 141.2)	7
	Pb	2.8 ± 0.2	27.6 (11.6 - 55.6)	6	4.3 ± 0.5⁺ + p < 0.05 compared with the respective aorta with endothelium.	11.8⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 151.7)	14
Combination therapy
52-day-old	Control	3.1 ± 0.2	7.1 (3.7 - 13.5)	5	4.9 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	0.3⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 17.8)	6
	Pb	2.4 ± 0.3	5.0 (2.8 - 9.1)	6	3.9 ± 0.6⁺ + p < 0.05 compared with the respective aorta with endothelium.	10.1⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1- 23.3)	14
100-day-old	Control	3.2 ± 0.3	7.0 (2.2 -22.5)	7	4.8 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	4.7⁺ + p < 0.05 compared with the respective aorta with endothelium. (1.2 - 18.0)	6
	Pb	2.8 ± 0.2	9.7 (1.6 - 30.3)	6	4.4 ± 0.3⁺ + p < 0.05 compared with the respective aorta with endothelium.	6.2⁺ + p < 0.05 compared with the respective aorta with endothelium. (0.1 - 39.7)	8

[1] Mailing Address: Sandra Cordellini, Rua João Carmelo 145, Jardim Paraíso. CEP 18610-290, Botucatu, SP - Brazil. Email: cordelli@ibb.unesp.br

Brasil

Brasil

Combination Therapy for the Cardiovascular Effects of Perinatal Lead Exposure in Young and Adult Rats

Background:

Objective:

Methods:

Results:

Conclusions: