Kyoko Matsuda

Endothelium-dependent relaxation by α2-adrenoceptor agonists in spontaneously hypertensive rat aorta

Differences in alpha(2)-adrenoceptor-induced relaxation of the aorta between stroke-prone spontaneously hypertensive rats (SHRSP) and control normotensive Wistar Kyoto rats (WKY) were studied. Changes in the tension of ring preparations of the aortas were measured isometrically. Relaxation was observed in the preparations precontracted in the presence of ONO-11113, a thromboxane A(2) analogue. The alpha(2)-agonist clonidine and UK-14304 induced dose-dependent relaxation in both the WKY and SHRSP preparations. The relaxation was impaired in the SHRSP preparation. A modified sandwich experiment showed that the relaxing substance from the SHRSP endothelium was decreased. Acetylcholine (ACh) also induced dose-dependent relaxation, and the relaxation was impaired in the SHRSP preparations. alpha(2)-Agonists induced a greater degree of impairment in the relaxation than did ACh. The relaxation induced by alpha(2)-agonists and by ACh was blocked by N G-nitro-L-arginine (L-NNA). Indomethacin improved the relaxation induced by ACh but not that induced by alpha(2)-agonists in the SHRSP aortas. These results suggest that the impairment of relaxation by alpha(2)-agonists in SHRSP is not caused by the increase in the release of endothelium-derived contracting factor (EDCF) but by the reduction in the release of nitric oxide (NO). Alteration of the alpha(2)-adrenoceptors and/or the intracellular mechanism through which NO is synthesized by stimulation of the alpha(2)-adrenoceptors may be the cause of the reduction in relaxation.

Attenuation of intrinsic active tone by endothelium-derived nitric oxide in aortae of spontaneously hypertensive rats with different levels of blood pressure

The influences of endothelium on the basal tone of aortae from various strains of spontaneously hypertensive rats with different blood pressure (SHR, SHRSP, M-SHRSP) were studied. Endothelium-intact preparations of aortae from spontaneously hypertensive rats exhibited spontaneous active tone, which was greater in the order of SHR < SHRSP < M-SHRSP. The active tone of the M-SHRSP preparations was about 40% of high-K(+)-induced contraction, while that of normotensive WKY was less than 5%. The active tone was enhanced by the removal of endothelium. The active tone was sensitive to extracellular Ca2+ and abolished by verapamil. The application of N(G)-monomethyl-L-arginine caused the increase in the active tone which was counteracted by L-arginine. These results indicate that the active tone of smooth muscle increases as the blood pressure of the rat increases, and that endothelium attenuates the active tone by releasing nitric oxide (NO) spontaneously. It was also demonstrated that the attenuating action of endothelium was impaired depending on the blood pressure level.

SPONTANEOUS AND AGONIST‐INDUCED CONTRACTIONS AND ENDOTHELIUM‐DEPENDENT RELAXATION IN AORTAE FROM SHRSP AND WKY RATS UNDER VARIOUS LEVELS OF PASSIVE FORCE

1. The influence of the passive force on the contraction and endothelium‐dependent relaxation in aortae of normotensive Wistar Kyoto (WKY) rats and stroke‐prone spontaneously hypertensive rats (SHRSP) were compared.

Membrane potential of mesenteric artery from carvedilol-treated spontaneously hypertensive rats

The effects of chronic treatment of stroke-prone spontaneously hypertensive rats (SHRSP) with carvedilol, an antihypertensive agent which has both alpha- and beta-adrenoceptor-blocking actions, on membrane potential and relaxation of mesenteric resistant artery were studied. Five-week old SHRSP were treated with carvedilol for three months. At 16 weeks, the resting membrane potential of arteries from carvedilol-treated SHRSP was more negative than that of arteries from untreated SHRSP. The magnitude of acetylcholine-induced hyperpolarization in arteries from carvedilol-treated SHRSP was not different from that of arteries from untreated SHRSP. In the presence of noradrenaline, the membrane potential of arteries from carvedilol-treated SHRSP was more negative than that of arteries from untreated SHRSP. The membrane potential of arteries from carvedilol-treated SHRSP in the presence of noradrenaline and acetylcholine was more negative than that of arteries from untreated SHRSP. The acetylcholine-induced relaxation in noradrenaline-precontracted preparations from carvedilol-treated SHRSP was greater than that in preparations from untreated SHRSP and was smaller than that in preparations from Wistar Kyoto rats. Scanning electronmicroscopy showed that carvedilol-treatment decreased the structural abnormalities of the endothelium of arteries from SHRSP. These results indicate that chronic carvedilol treatment made the membrane potential of smooth muscle more negative and improved endothelial function in the mesenteric artery of SHRSP, which may contribute to the antihypertensive effect of carvedilol.

Role of nitric oxide in the contraction of circular muscle in the rat portal vein

Abstract. The role of nitric oxide in the electrical and mechanical activities of the rat portal vein was examined in circular muscle preparations with intact endothelium that were isolated from the longitudinal muscle layer. In contrast to the longitudinal muscle preparation, the circular muscle preparation did not show spontaneous phasic contraction. Inhibition of nitric oxide synthesis by Nω-nitro-l-arginine (L-NNA) induced a tonic contraction. The contraction was inhibited by l-arginine, sodium nitroprusside or nifedipine. L-NNA did not induce contraction in endothelium-damaged preparations. The membrane potential of smooth muscle cells recorded in endothelium-intact preparations showed sporadic action potentials. L-NNA increased the frequency of action potentials without changing the resting membrane potential. The action potentials were inhibited by nifedipine. In the presence of L-NNA, sodium nitroprusside decreased the frequency of the action potentials without changing the resting membrane potential. These results indicated that contraction of rat portal vein circular muscles is inhibited tonically by nitric oxide, at least partly through inhibition of electrical activity.

ALTERATION IN THE RELEASE OF ENDOTHELIUM‐DERIVED RELAXING FACTORS BY α‐ADRENOCEPTOR STIMULATION IN THE AORTA OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. Endothelium‐dependent relaxation by a‐adrenoceptor agonists was examined in the thoracic aorta from normoten‐sive Wistar‐Kyoto (WKY) rats and stroke‐prone spontaneously hypertensive rats (SHRSP).

Unaltered endothelium-dependent modulation of contraction in the pulmonary artery of hypertensive rats

Involvement of endothelium-derived nitric oxide (EDNO) in alpha-adrenoceptor agonist-induced contractile responses was studied in isolated pulmonary arteries from Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). In the presence of propranolol, noradrenaline-induced contraction was potentiated by endothelium removal or by N(G)-nitro-L-arginine (L-NOARG). The magnitude of the potentiation was independent of the noradrenaline concentration. L-NOARG also shifted the concentration-response curves for phenylephrine and methoxamine to the left and upward. Contractile responses to 2-amino-5,6,7,8, -tetrahydro-6-ethyl-4H-oxazolo-(5,4-d)-azepine-dihydrochloride (BHT-933) and 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK-14304) were augmented by L-NOARG in a concentration-dependent manner. There were no differences in the effects of L-NOARG on the contractile responses to alpha-adrenoceptor agonists between the preparations from WKY and SHRSP. Endothelium-dependent relaxation in response to acetylcholine was not impaired in the preparations from SHRSP when compared with those from WKY. These observations suggest that the contractile responses to the alpha(1)-adrenoceptor agonists were depressed mainly by basally released EDNO, while the responses to the alpha(2)-adrenoceptor agonists were depressed mainly by EDNO released in response to alpha(2)-adrenoceptor stimulation. The comparable influence of the endothelium on the alpha-adrenoceptor agonist-induced contractions in the pulmonary arteries from WKY and SHRSP, which were markedly different from other arteries, could be explained by the unaltered endothelium-dependent relaxation in the preparations from SHRSP.