Analysis of the vasorelaxant action of angiotensin II in the isolated rat renal artery.

Taking into consideration that mechanisms involved in the vasodilatator actions of angiotensin II have not yet been completely elucidated, the present study was undertaken in order to examine the mechanisms underlying the angiotensin II-induced relaxation of rat renal artery (RRA). Angiotensin II produced concentration-dependent and endothelium-independent relaxation of isolated RRA. Angiotensin II-induced relaxation was partially reduced by inhibitors of nitric oxide synthase and guanylyl cyclase. The remaining dilatation was inhibited by a potassium channel blocker, charybdotoxin. Precontraction of RRA with high concentration of K(+) partially reduced angiotensin II-evoked relaxation, while indomethacin, glibenclamide, apamin and barium did not alter the angiotensin II concentration-response curve. Losartan had no effect on angiotensin II effect. Oppositely, HOE 140 and PD123319, separately or in combination, partially antagonized vasorelaxation induced by angiotensin II. Complete blockade of RRA response was obtained after simultaneous incubation of all three receptor antagonists HOE-140, PD123319, and losartan; L-NOARG plus HOE-140; or PD123319 plus charybdotoxin. These results indicate that angiotensin II produces endothelium-independent relaxation of RRA, which is most probably mediated by the interaction of the NO-cGMP pathway and K(+) channels. Moreover, we can assume that AT(1), AT(2), and B(2) receptors are involved in the vasorelaxant effect of angiotensin II.

[Endothelial dysfunction: mechanisms of development and therapeutic options].

INTRODUCTION: Vascular endothelial cells play a key role in cardiovascular regulation by producing a number of potent vasoactive agents, including the vasodilator molecule nitric oxide (NO) and the vasoconstrictor peptide endothelin (ET). ENDOTHELIAL DYSFUNCTION: Endothelial dysfunction is recognized as the initial step in the atherosclerotic process. Impairment of NO synthesis, or increased inactivation of NO by superoxide radicals, may account for the increased periferal vascular tone, as well as contribute to the clinical consequences of different pathophysiological conditions which include vascular hypertrophy, increased platelet and monocyte adhesion to the endothelium, atherosclerosis, myocardial infarction and stroke. To date, most interventions attempting to improve endothelial dysfunction have targeted one or more of the numerous risk factors that can cause endothelial damage: hypertension (ACE inhibitors and calcium antagonists), hypercholesterolemia (lipid-lowering agents), cigarette smoking (cessation), sedentary lifestyle (increased physical activity), menopause (estrogen replacement therapy), and diabetes mellitus (control of metabolic abnormalities). Several pharmacologic agents have been suggested to achieve vascular protection through mechanisms that go beyond their primary therapeutic actions (ACE-and HMG-CoA reductase inhibitors). Beneficial changes to the endothelium might result from promotion of vasorelaxation, inhibition of vasoconstriction, reduction in the production of free radicals, or other mechanisms that protect the endothelium from injury. CONCLUSION: This study deals with the results of many experimental and clinical investigations. The possibility of using different classes of drugs was also established, including ACE inhibitors, Ca-antagonists, AT and endothelin receptor antagonists, direct activator of adenyl cyclase, statins, antioxidants, L-arginine, phosphodiesterase inhibitors, beta-blockers and organic nitrates.

Isolated rat inferior mesenteric artery response to adenosine: possible participation of Na+/K+-ATPase and potassium channels.

Adenosine (10(-7)-3 x 10(-4) M) produced concentration-dependent and endothelium-independent relaxation of isolated rat inferior mesenteric artery. Application of indomethacin (10(-5) M) or N(G)-nitro-L-arginine (10(-5) M) did did not alter adenosine-elicited relaxation. Conversely, in the presence of high concentration of K+ (100 mM), ouabain (10(-4)) or combination of tetraethylammonium (5 x 10(-4) M) and glibenclamide (10(-6) M), adenosine-evoked relaxant effect was significantly reduced. In K+-free solution, 1-3 mM potassium induced relaxation, which was partially reversed by ouabain (10(-4) M). 1,3-Dipropyl-8-cyclopentylxanthine (10(-9) M), an A1-receptor antagonist, did not affect adenosine-evoked relaxation. Oppositely, 8-(3-chlorostyryl)-caffeine (3 x 10(-7)-10(-6) M), a selective A2A receptor antagonist, significantly inhibited adenosine-induced relaxation in a concentration-dependent manner (pA2 = 6.74). These results indicate that in the isolated rat inferior mesenteric artery, adenosine produces endothelium-independent relaxation, which is partly induced by activation of smooth muscle adenosine A2A receptors, and further mediated by the activation of smooth muscle Na+/K+-ATPase and opening of mixed population of K+ channels.

Effect of the vascular endothelium on contractions induced by noradrenaline and phenylephrine in perforating branch of the human internal mammary artery.

The effects of noradrenaline (Nor) and phenylephrine (Phe) on the isolated, non-precontracted perforating branch of the human internal mammary artery (HIMA) were investigated. Nor and Phe induced concentration-dependent contractions of intact and endothelium-denuded arterial rings with no statistically significant differences between the pEC(30) and maximal response values. The pretreatment of arterial rings with indomethacin had no effect on Nor- and Phe-induced contractions of both, intact and endothelium-denuded preparations. The pre-addition of L-NMMA did not affect contractions of perforating branch of the HIMA evoked by Nor, but provoked significant potentiation of Phe-induced contractions of perforating branch of the HIMA both intact and denuded of endothelium only at Phe concentration higher than 3 x 10(-6)M. The effects of selective alpha1-adrenoceptor antagonist, prazosin and selective alpha2-adrenoceptor antagonist, rauwolscine were concentration-dependent, and they induced a significant shift to the right (for both studied antagonists) of the concentration-response curves for Nor in both preparations with or without endothelium. The effects of prazosin and rauwolscine on the concentration-response curves for Phe were similar. In conclusion, this study has shown that Nor and Phe induce concentration-dependent contractions of the perforating branch of the HIMA. Removal of the endothelium did not modify this effect. Products of cyclooxygenase pathway had no influence on Nor and Phe action. Endothelium derived nitric oxide (NO) had no modulatory effect of Nor-induced contractions, but inhibition of NO synthesis provoked potentiation of Phe-induced contractions either in intact or endothelium-denuded preparations. The mechanism of this effect remains still unclear. On the basis of differential affinity of the antagonists and affinities of Nor and Phe themselves, we suggest that alpha1-adrenoceptor subtype is probably involved in the Nor- and Phe-induced contraction of the perforating branch of the HIMA both intact or denuded of endothelium.