RESUMO
Previous studies from our own laboratory have shown that abdominal aorta rings from two kidney - two clip hypertensive rats (HT) develop hypersensitivity to serotonin (SER) which is related to a decreased nitric oxide (NO) availability and enhanced thromboxane A2 production. In the present study we investigated whether calcium and prostanoid-NO interactions are involved in these findings. To this purpose, the aortic responses to SER were analyzed in calcium-free medium and in calcium-depleted aorta placed in normal medium. Moreover, effects of ridogrel (RID, an antagonist of TxA 2/PGH2 receptors and inhibitor of thromboxane synthetase) were analysed by cumulative dose-response curves to SER in the presence and in the absence of the NO synthase inhibitor N(omega)-nitro-L-arginine (NOLA). Vascular responses to SER in vessels from HT rats were associated with increased intracellular calcium mobilization. In addition, hypersensitivity to SER in HT group respect to sham group (SH) disappeared in the presence of RID, NOLA and RID plus NOLA. RID decreases the maximum tension to SER and this effect was prevented by NOLA. This inhibition was of a greater magnitude in rings from sham rats (SH): 34 +/- 6% than in HT rats: 15 +/- 6% (p < 0.05). Besides, RID decreased the sensibility to SER in the presence of NOLA only in the HT group. In conclusion, the present study suggests that SER hypersensitivity observed in HT rats is related to a facilitated intracellular calcium mobilization and enhanced TxA2-endoperoxide response. Changes in membrane SER-gated calcium channels opening are observed only during the early hypertensive period. Besides, the lower depressor effect of RID on the maximal tension to SER in aorta rings from HT rats are related with a decreased NO availability in this model of renovascular hypertension.
Assuntos
Aorta/efeitos dos fármacos , Cálcio/farmacologia , Rim/metabolismo , Serotonina/farmacologia , 6-Cetoprostaglandina F1 alfa/biossíntese , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Hipertensão/tratamento farmacológico , Masculino , Contração Muscular/efeitos dos fármacos , Nitroarginina/farmacologia , Ácidos Pentanoicos/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Tromboxano B2/biossíntese , Fatores de TempoRESUMO
Nitric oxide (NO) has been identified as an effective vascular relaxant. This study analyses the contribution of the precursor L-arginine (L-arg) by oral administration in two kidney-two clip hypertension in the rat (2K-2C). Two groups were studied: sham (SH, n=21) and hypertensive (HT, n=15). After 4 weeks of surgery, a group of rats remained as controls (SHc and HTc, respectively), while others were supplemented with L-arg (1.25 g/L) in drinking water (SHa and HTa) for 3 weeks. Blood pressure was significantly increased in 2K-2C rats but remained unchanged after L-arg treatment. Plasma nitrite/nitrate concentrations were not different among groups. The contractile response of aorta to KCl, serotonin and the protein kinase C (PKC) stimulant, phorbol 12,13-dibutyrate (PDBu) was also evaluated. Higher contractile responses to PDBu (p<0.001) and lower relaxation to acetylcholine (Ach 10(-6) M, p<0.05 and 10(-5)M, p<0.02) were observed in aortic rings of HTc vs SHc; L-arg supplementation significantly diminished tension development to all agonists (p<0.05) but failed to modify the lower relaxation to Ach in HTa. Thromboxane (TxA(2)) - synthesis in rings of HTc was higher than in SHc under basal conditions (p<0.05). In the groups with supplement of L-arg, PDBu significantly stimulated prostacyclin (PGI(2)) synthesis more in HTa rats than in SHa ones (p<0.05). To conclude: 1) L-arg fails to modify hypertension development in 2K-2C rats; and 2) L-arg exerts a beneficial effect on the vascular wall, by reducing contractility in rings from HTa rats; it also improved PGI(2) synthesis under PDBu stimulation. 3) greater PKC activation and TxA(2) production rather than lower NO availability might result in systemic hypertension in 2K-2C rats.
Assuntos
Administração Oral , Arginina/farmacologia , Rim/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Arginina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Epoprostenol/biossíntese , Epoprostenol/metabolismo , Hipertensão/tratamento farmacológico , Soluções Isotônicas/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Nitratos/sangue , Nitritos/sangue , Tamanho do Órgão/efeitos dos fármacos , Dibutirato de 12,13-Forbol/farmacologia , Cloreto de Potássio/farmacologia , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia , Tromboxano B2/biossíntese , Fatores de TempoRESUMO
A fructose-enriched diet promotes hypertension in rats. We thought that an enhancement of the glycolytic and/or lipid disorder (s) that raise blood pressure could be the cause. Therefore, we studied 4 groups of Sprague-Dawley rats (+/-200 g): (1) control rats received a standard diet and tap water; (2) the glycerol group of rats received a standard diet and 0.54 mol/L glycerol in tap water; (3) the fructose group was given a fructose-enhanced diet (chow had 55% fructose instead of dextrin) and tap water; and (4) the fructose-glycerol group was given the fructose-enhanced diet and 0. 54 mol/L glycerol in drinking water. At the end of the second week, the findings were as follows. Blood pressure was 149+/-2 mm Hg in the fructose-glycerol group versus 129+/-2 (P<0.001), 131+/-2 (P<0. 001), and 140+/-3 (P<0.005) mm Hg in the control, glycerol, and fructose groups, respectively. Insulinemia was higher in the fructose-glycerol group than the control (P<0.001), glycerol (P<0. 001), and fructose groups (P<0.001); triglyceridemia was higher in the fructose-glycerol (P<0.02), fructose (P<0.05), and glycerol groups (P<0.02) than the control group. Thoracic aorta rings showed a lower ED(50) to 12,13-phorbol dibutyrate in the fructose-glycerol group than in the control (P<0.001), glycerol (P<0.002), and fructose groups (P<0.001). In conclusion, glycerol-fructose administration resulted in hypertriglyceridemia, hyperinsulinemia, and increased vascular sensitivity to 12,13-phorbol dibutyrate (with respect to the control group), and significantly greater expression of protein kinase C alpha and betaII (with respect to the glycerol group).