Isoprenaline is known to produce vascular relaxation through activation of β-adrenoceptors. In recent years, β-adrenoceptor-activated vascular relaxation has been the focus of pharmacological study in terms of both the receptor subtypes and the intracellular signaling mechanisms which trigger smooth muscle mechanical functions. In addition, the possible contribution of the endothelium to β-adrenoceptor-activated relaxation of vascular beds has provoked considerable discussion, with consensus still to be established. In the present study, we examined the effects of isoprenaline on isolated mouse aortic smooth muscles to determine whether the presence of the endothelium plays a substantial role in the relaxation it produces. A possible role for nitric oxide (NO) as a primary endothelium-derived factor released in response to isoprenaline was also elucidated pharmaco-mechanically. In isolated thoracic and abdominal aortae pre-contracted with phenylephrine (3 × 10^-7-10^-6 M), isoprenaline elicited relaxation in a concentration-dependent fashion (10^-9-10^-5 M). In endothelium-denuded preparations, isoprenaline-elicited relaxation was reduced to 40~50% of the response obtained in endothelium-intact preparations. In the preparations treated with N^G-nitro-L-arginine methyl ester (L-NAME, 3 × 10^-4 M; an NO synthase inhibitor) or 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ, 10^-5 M; a soluble guanylyl cyclase inhibitor), isoprenaline-elicited relaxation was attenuated almost to the same degree as the response in endothelium-denuded preparations. The degree of endothelium-dependency in isoprenaline-elicited relaxation was largely diminished when treated with propranolol (3 × 10^-6 M). The present findings indicate that isoprenaline substantially relaxes the mouse aorta with both endothelium-dependent and -independent mechanisms. The endothelium-dependent component seems to correspond to about 50% of the isoprenaline-elicited relaxation, and is almost entirely due to endothelium-derived NO. Activation of propranolol (3 × 10^-6 M)-inhibitable β-adrenoceptors seems to be primarily responsible for the NO-mediated endothelium-dependent pathway in isoprenaline-elicited relaxant response of mouse aorta.

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To investigate the mechanism underlying increased endothelin-1 (ET-1) release in diabetic rats, we administered L-arginine chronically to streptozotocin (STZ)-induced diabetic rats. The plasma concentrations of glucose, ET-1 and NOx (NO₂^- + NO₃^-) were all significantly raised at 10 weeks after the STZ injection. Chronic administration of L-arginine resulted in a significantly higher plasma NOx concentration and a significantly lower plasma ET-1 level at 10 weeks compared with the untreated diabetic group. ET-1 induced a biphasic vasodilator/vasoconstrictor response in the perfused isolated mesenteric arterial beds from all groups. The vasodilatation was significantly greater in diabetic rats than in age-matched controls. Chronic oral L-arginine administration had no significant effect on the enhanced ET-1-induced vasodilatation seen in the untreated diabetic rats. The vasoconstrictions induced by ET-1 and methoxamine were significantly attenuated in STZ-diabetic rats. The attenuated vasoconstrictor response to ET-1, but not that to methoxamine, was further attenuated by chronic treatment with L-arginine. We conclude that since chronic L-arginine administration not only reduced the increase in plasma ET-1 levels but also further attenuated the ET-1-induced vasoconstriction without affecting the change in vasodilatation, chronic L-arginine administration could be valuable for the treatment of the symptoms of diabetic mellitus related to ET-1.

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We examined the relaxant effects of natriuretic peptide family on the isolated guinea-pig aorta to determine the receptor subtype which primarily mediates this vascular relaxation, with particular attention to the apparent contribution of voltage-dependent and Ca ²⁺-activated K⁺ (BK_Ca) channels to the response. Three endogenous natriuretic peptide ligands (natriuretic peptide, ANP; brain natriuretic peptide, BNP; C-type natriuretic peptide, CNP) produced a concentration-dependent relaxation in de-endothelialized guinea-pig aorta pre-contracted by noradrenaline (NA), with a potency order of ANP ≥ BNP >> CNP. Although the relaxations elicited by these three natriuretic peptide ligands were significantly diminished by iberiotoxin (IbTx, 10^-7 M), a selective BK_Ca channel blocker, the inhibitory effect of IbTx was most pronounced for the CNP-induced relaxation; when estimated at 10^-7 M of each peptide, the apparent extent of BK_Ca channel contribution to the total relaxant response was ≈ 60% for CNP > ≈ 20% for either ANP or BNP. Supporting the substantial role of BK_Ca channels in the vascular responses, high-KCl (80 mM) potently suppressed the relaxations induced by these natriuretic peptide ligands. The relaxant response to 8-Bromo-cyclic GMP, a membrane permeable cyclic GMP analogue, was also diminished by IbTx (10^-7 M) and high-KCl (80 mM), which indicates the key role of cyclic GMP in the BK_Ca channel-mediated, natriuretic peptide-elicited vascular relaxation. These results indicate that the A-type receptor (NPR-A, which is more selective for ANP and BNP) rather than the B-type receptor (NPR-B, which is more selective for CNP) predominates in the guinea-pig aorta as the natriuretic peptide receptor which mediates this vascular smooth muscle relaxation. Although activation of BK_Ca channels substantially contributes to both NPR-A-and NPR-B-activated relaxations, particularly in the NPR-B-activated relaxation, this K⁺ channel may function as a primary relaxant mediator in this conduit artery.

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To evaluate whether the elevated blood pressure induced by chronic treatment with Nω-nitro-L-arginine methyl ester (L-NAME) contributes to an impairment of endothelium-dependent relaxation (EDR), the effects of chronic treatment of Wistar rats with L-NAME on systolic blood pressure, pulmonary arterial blood pressure and EDR of the pulmonary arteries were studied and compared with those of stroke-prone spontaneously hypertensive rats (SHRSP). While the systolic blood pressure (SBP) of Wistar rats was increased above that of controls by chronic treatment with L-NAME, it was still significantly lower than that of SHRSP. Chronic treatment with L-NAME did not affect pulmonary arterial blood pressure. On the other hand, the pulmonary arterial blood pressure of SHRSP was slightly but significantly higher than that of the control normotensive Wistar Kyoto rats (WKY). EDR in response to acetylcholine in the pulmonary artery of L-NAME-treated rats was significantly smaller than that in control Wistar rats. The EDR markedly increased in the presence of L-arginine and completely disappeared in the presence of N^ω-nitro-L-arginine. Indomethacin hardly affected EDR. In preparations from SHRSP, the EDR was not different from that in those from WKY. Relaxation induced by sodium nitroprusside was identical in all preparations. Elevation of SBP and the impairment of EDR observed in L-NAME-treated rats recovered two weeks following cessation of treatment. These results suggest that the impaired EDR in the pulmonary artery of L-NAME-treated rats is not due to an L-NAME-induced increase in blood pressure but due to the inhibition of nitric oxide synthase by the drug remaining in the endothelium.

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Fenoterol, a β₂-adrenoceptor selective agonist, belongs to the arylethanolamine class. To understand the receptor subtypes responsible for β-adrenoceptor-mediated relaxation of guinea pig taenia caecum, we investigated the effect of fenoterol. Fenoterol caused concentration-dependent relaxation of the guinea pig taenia caecum. Propranolol, bupranolol and butoxamine produced shifts of the concentration-response curve for fenoterol. Schild regression analyses carried out for propranolol, butoxamine and bupranolol against fenoterol gave pA₂ values of 8.41, 6.33 and 8.44, respectively. However, in the presence of 3 × 10 ^-4 M atenolol, 10^-4 M butoxamine and 10^-6 M phentolamine to block the β₁-, β₂- and α-adrenoceptor effects, respectively, Schild regression analysis carried out for bupranolol against fenoterol gave pA₂ values of 5.80. These results suggest that the relaxant response to fenoterol in the guinea pig taenia caecum is mediated by both the β₂- and the β₃-adrenoceptors.

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