Functional study of the [Ca2+]i signaling pathway in aortas of L-NAME-hypertensive rats.
A variety of mechanisms has been proposed to suggest that nitric oxide participates in the regulation of smooth muscle free [Ca(2+)](c) (the primary determinant of contractile tone), including inhibition of Ca(2+) influx across the plasma membrane and inhibition of intracellular Ca(2+) release. In view of such considerations, the aim of this study was to investigate the possible alterations in contractile responses induced by drugs that mobilize Ca(2+) from different sources in aortae from N(G)-nitro-L-arginine methyl ester (L-NAME) hypertensive rats (LHR). Treatment with L-NAME did not alter the contractile response induced by phenylephrine; however, indomethacin increased the contraction to phenylephrine only in LHR aortae (1.36 +/- 0.08 g, n = 6, vs. 1.97 +/- 0.09 g, n = 7). Both phenylephrine and caffeine evoked rapid and phasic contractions in intact or denuded aortic rings in Ca(2+)-free solution containing EGTA. Phenylephrine-elicited phasic contractions were lower in normotensive rats (NR; 0.41 +/- 0.05 g, n = 9) than in LHR (0.57 +/- 0.06 g, n = 6) and were increased by endothelium removal only in the NR group (0.64 +/- 0.05 g, n = 6). Conversely, neither with treatment with L-NAME nor endothelium removal altered the phasic contractile responses induced by caffeine. The Ca(2+) influx stimulated with phenylephrine was greater in NR (1.95 +/- 0.08 g; pD(2) 6.06 +/- 0.69; n = 8) than in the LHR denuded aorta (1.63 +/- 0.11 g; pD(2) 3.52 +/- 0.06; n = 6). Similarly, contractions stimulated with phorbol ester in denuded arteries were greater in NR (1.76 +/- 0.08 g, n = 7) than in LHR (1.11 +/- 0.11 g, n = 7). In the same manner, indomethacin failed to alter the contraction stimulated with phorbol ester in NR arteries (2.01 +/- 0.21 g, n = 7), although it completely blocked the inhibitory effect of chronic treatment with L-NAME on this contractile response (1.94 +/- 0.24 g; n = 9). Indomethacin did not change the contractile responses stimulated by increasing concentrations of extracellular Ca(2+) in either NR aortas (1.44 +/- 0.26 g; pD(2) 4.74 +/- 0.79; n = 6) or LHR aorta (1.99 +/- 0.19 g; pD(2) 4.10 +/- 0.47; n = 8). However, in the presence of indomethacin, the Ca(2+) influx was similar in NR and LHR aortae. Taken together, these results suggest that, in this model of hypertension, the increase in agonist-induced release of Ca(2+) from intracellular stores may be partly compensated by inhibition of Ca(2+) influx and that this effect is due to the increased production of the relaxant prostanoid in vascular smooth muscle cells.
de Campos Grifoni
Samira
S
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Bendhack
Lusiane Maria
LM
D015121:6-Ketoprostaglandin F1 alpha; D000109:Acetylcholine; D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D006973:Hypertension / Q000139:chemically induced*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000378:metabolism / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis; D011493:Protein Kinase C / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects
D010703:Phorbol Esters; D011453:Prostaglandins; D010656:Phenylephrine; D009569:Nitric Oxide; D015240:Phorbol 12,13-Dibutyrate; D002110:Caffeine; D015121:6-Ketoprostaglandin F1 alpha; D011493:Protein Kinase C; D000109:Acetylcholine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; D007213:Indomethacin