In this study, we aimed to elucidate whether the daily hypertensive dose of long-term N(G)-nitro-l-arginine methyl ester (l-NAME) treatment, could make a difference between endothelial and smooth muscle functions in rat thoracic aorta. We test the hypothesis that high-dose, long-term l-NAME treatment has a depressive effect on vascular smooth muscle contractile activity which is not related with nitric oxide (NO) synthesis inhibition. After 14 days of treatment, isometric tension and (45)Ca(2+) influx were measured in aortic tissues isolated from l-NAME(10) and l-NAME(100) hypertensive (10 and 100 mg/kg/day, systolic blood pressures 167 +/- 7 and 172 +/- 10 mmHg, respectively) and control normotensive rats (132 +/- 7 mmHg). In l-NAME(10)- and l-NAME(100)-treated rats, acetylcholine-induced relaxation in aortic rings was suppressed with no significant difference between the treatments. l-NAME(100) (but not l-NAME(10)) treatment, significantly inhibited contractile responses to phenylephrine, angiotensin II, and K(+) (80 mm) in endothelium-intact tissues. The effect of l-NAME(100) on phenylephrine-induced contractile responses was not observed after 3 days of treatment. In endothelium-denuded aortic tissues of l-NAME(100) (but not l-NAME(10))-treated rats, phenylephrine (1 x 10(-6) m)- and K(+) (80 mm)-induced contractions and (45)Ca(2+) influxes were significantly reduced. In Ca(2+)-free medium (0.1 mm EDTA), on the contrary, the transient contractions obtained by either phenylephrine (1 x 10(-6) m) or caffeine (1 x 10(-2) m), or the sustained contractions induced by 12-o-tetradecanoylphorbol-13-acetate (1 x 10(-6) m; a protein kinase C activator) in endothelium-denuded aortic rings, were not modified by both l-NAME treatments. These results indicate that in aortic rings from l-NAME hypertensive rats, low and high doses, long-term l-NAME administration may be associated with equivalent inhibition in NO-dependent vasodilator tone (corresponding to equivalent hypertension values); whereas only high-dose, long-term l-NAME administration produces an endothelium-independent decrease in vasocontrictor activity, at least partly explained by a reduction in extracellular Ca(2+) influx.
In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.
The objective of this study was to re-examine whether the effect of the nitric oxide synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), on blood pressure depends on peripheral vascular tone. The effects of L-NAME (10 mg/kg, i.v.) on diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP) and heart rate (HR) were studied in pithed rats. Sal-pithed rats received 0.9% NaCl, 10 microl/kg/min. Vascular tone was step-wise increased with 3, 10 and 30 microg/kg/min intravenous phenylephrine infusion (LPhe-pithed, MPhe-pithed and HPhe-pithed rats respectively). L-NAME elicited vasopressor responses in all the animals studied. L-NAME increases in SBP and DBP in Sal-pithed rats were significantly smaller than the ones obtained in phenylephrine infused rats. The increases in DBP elicited by L-NAME were greater in LPhe-pithed rats compared with those of MPhe-pithed and HPhe-pithed rats (i.e. the step-wise rises in DBP obtained with phenylephrine were inversely related to the increases in DBP produced by L-NAME); however, the increases in SBP were similar between these experimental groups. The PP increased during L-NAME-induced pressor responses in phenylephrine-infused rats. l-NAME increases in PP showed the following order: Sal-pithed < LPhe-pithed < MPhe-pithed < or = HPhe-pithed rats. HR was not modified by L-NAME. In conclusion, the vasopressor responses produced by L-NAME in pithed rats are influenced by the pre-existing vasomotor tone in complex form. We did not find a simple positive correlation between the vascular tone or level of arterial pressure, and the magnitude of the diastolic and systolic pressor responses elicited by L-NAME. Interestingly, the increase in PP induced by l-NAME was greater in accordance with the increasing value of baseline arterial pressure. NO synthesis inhibition in the arterial endothelium may possibly explain the increase in PP caused by L-NAME, as resulting from the reduction in proximal conduit artery compliance.
We examined the contractile responsiveness of rat thoracic aortas under pressure
overload after long-term suprarenal abdominal aortic coarctation (lt-Srac).
Endothelium-dependent angiotensin II (ANG II) type 2 receptor
(AT2R)-mediated depression of contractions to ANG II has been reported in
short-term (1 week) pressure-overloaded rat aortas. Contractility was evaluated in
the aortic rings of rats subjected to lt-Srac or sham surgery (Sham) for 8 weeks. ANG
I and II levels and AT2R protein expression in the aortas of lt-Srac and
Sham rats were also evaluated. lt-Srac attenuated the contractions of ANG II and
phenylephrine in the aortas in an endothelium-independent manner. However, lt-Srac
did not influence the transient contractions induced in endothelium-denuded aortic
rings by ANG II, phenylephrine, or caffeine in Ca2+-free medium or the
subsequent tonic constrictions induced by the addition of Ca2+ in the
absence of agonists. Thus, the contractions induced by Ca2+ release from
intracellular stores and Ca2+ influx through stored-operated channels were
not inhibited in the aortas of lt-Srac rats. Potassium-elicited contractions in
endothelium-denuded aortic rings of lt-Srac rats remained unaltered compared with
control tissues. Consequently, the contractile depression observed in aortic tissues
of lt-Srac rats cannot be explained by direct inhibition of voltage-operated
Ca2+ channels. Interestingly,
12-O-tetradecanoylphorbol-13-acetate-induced contractions in
endothelium-denuded aortic rings of lt-Srac rats were depressed in the presence but
not in the absence of extracellular Ca2+. Neither levels of angiotensins
nor of AT2R were modified in the aortas after lt-Srac. The results suggest
that, in rat thoracic aortas, lt-Srac selectively inhibited protein kinase C-mediated
activation of contraction that is dependent on extracellular Ca2+
entry.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.