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In dog pulmonary arterial and venous strips without endothelium under treatment with prazosin, nicotine induced relaxation that was abolished by N(G)-nitro-L-arginine, hexamethonium and methylene blue. L-Arginine antagonized the N(G)-nitro-L-arginine action. Neurogenic relaxations tended to be more evident in the vein. Nitric oxide (NO)-induced relaxations were greater in the veins than in the arteries. Concentrations of NO to induce the same magnitude of relaxation as that to nicotine were higher in the arteries. In conclusion, dog pulmonary arteries and veins are innervated by nitroxidergic (nitrergic) nerves, and NO is released by nerve stimulation with nicotine in a larger amount in the artery than the vein.

In cerebral arteries isolated from most of mammals, nerve stimulation produces relaxations in contrast to contractions in peripheral arteries. The relaxant mechanism is found to be non-adrenergic and non-cholinergic, but the neurotransmitter is not clarified until recently. Based on several functional and histological studies with isolated cerebral arteries, nitric oxide (NO) is now considered to be a neurotransmitter of the vasodilator nerve and the nerve has been called a nitroxidergic (nitrergic) nerve. Upon neural excitation, calcium influxed through N-type Ca2+ channels activates neuronal NO synthase, and then NO is produced by the enzyme from L-arginine. The released NO activates soluble guanylate cyclase in smooth muscle cells, resulting in relaxation with a cyclic GMP-dependent mechanism. The functional role and neuronal pathway have also been investigated in anesthetized dogs and Japanese monkeys. The nitroxidergic (nitrergic) nerves innervating the circulus arteriosus, including the anterior and middle cerebral and posterior communicating arteries, are found to be postganglionic nerves originated from the ipsilateral pterygopalatine ganglion and tonically dilate cerebral arteries in the resting condition. Our findings suggest that the nitroxidergic (nitrergic) nerve plays a physiologically important role to maintain a steady blood supply to the brain.

In isolated canine cerebral and cutaneous arteries and duodenum, effects of neosurugatoxin (NSTX) on the response to nicotine were compared. Nicotine-induced relaxations are mediated by nitric oxide (NO) from vasodilator nerves in cerebral arteries and by calcitonin gene-related peptide (CGRP) in cutaneous arteries treated with NO synthase inhibitors. Duodenal relaxation to nicotine is mediated by NO from inhibitory nerves. Cerebral arterial strips without endothelium responded to nicotine with relaxations that were inhibited by NSTX (3 x 10(-10) to 3 x 10(-9) M) concentration-dependently. Relaxations to nicotine of duodenal strips were attenuated by NSTX and abolished by tetrodotoxin, whereas those induced by K+ and electrical stimulation were not influenced. In cutaneous arteries treated with N(G)-nitro-L-arginine, nicotine-induced relaxations were attenuated by NSTX as low as 10(-10) M, but unaffected by tetrodotoxin. The inhibitory potency of NSTX was in the order of cutaneous artery > duodenum > cerebral artery. It is concluded that NSTX selectively antagonizes actions on nicotinic receptors in nitroxidergic nerves of cerebral arteries, CGRP-mediated sensory nerves of cutaneous artery and ganglionic cells of the duodenum, but the affinity of this toxin to nicotinic receptors in sensory nerves is the highest.

Functional roles of autonomic efferent nerves were compared in the isolated canine corpus cavernosum, penile artery and penile vein that participate in the penile erection by changing blood distribution. Nicotine produced moderate contraction in the arterial strips, but only a slight or no contraction in the corpus and venous strips. The contraction was suppressed or reversed to a relaxation by prazosin. Under alpha 1-adrenoceptor blockade, relaxations induced by nicotine were in the order of the corpus > artery > > vein. The response was abolished by NG-nitro-L-arginine (L-NA) and restored by L-arginine. The responses to nicotine and exogenous nitric oxide (NO) were abolished by oxyhemoglobin. The relaxant response to transmural electrical stimulation at 5 Hz was greater in the corpus than venous strips treated with prazosin, and it was abolished by L-NA. Contractions caused by nicotine under treatment with L-NA were greater in the artery than in the vein and corpus. Histochemical studies demonstrated nerve fibers containing NO synthase and tyrosine hydroxylase immunoreactivity in the corpus cavernosum, artery and vein. It is concluded that the canine corpus cavernosum, penile artery and penile vein are innervated by adrenergic, vasoconstrictor and nitroxidergic, vasodilator nerves; neurogenic vasodilatation is predominant in the corpus muscle, whereas neurogenic vasoconstriction predominates in the artery. Such a different functioning of the nerves may be responsible for the penile erection.

The purpose of this investigation was to determine if neurally induced vasodilatation is mediated by nitric oxide (NO) in monkey mesenteric veins. Helical strips of the monkey mesenteric vein were exposed to the bathing media for isometric tension recording, and perivascular nerves were stimulated by nicotine. Nicotine produced a contraction, which was potentiated by treatment with NG-nitro-L-arginine, a NO synthase inhibitor, the effect being reversed by L-arginine. The nicotine-induced contraction was reversed to a relaxation by prazosin. The relaxation was abolished by the NO synthase inhibitor, and it was restored by L-arginine. D-Enantiomers were without effect. The response was not influenced by timolol and indomethacin, but was abolished by hexamethonium and oxyhemoglobin. There were perivascular nerve fibers containing NO synthase immunoreactivity in the monkey vein. Neurally induced venous relaxations appear to be mediated by NO from perivascular nerves, as seen in dog and monkey mesenteric arteries. It is concluded that monkey mesenteric veins are innervated by nitroxidergic and adrenergic nerves, which may balance the vascular tone.

Nitroxidergic nerves and their functional role were determined in a variety of monkey arteries. Nitric oxide synthase-immunoreactive nerve fibers innervating the monkey arterial wall were histochemically determined by the use of nitric oxide synthase antiserum. Thin nitric oxide synthase-immunoreactive fibers were consistently found in the outer media of monkey cerebral, mesenteric and temporal arteries, in addition to many thicker fibers and nerve bundles in the adventitia. In the monkey pterygopalatine ganglion, the immunoreactivity was clearly seen in nerve cells, bundles and fibers. Helical strips of monkey arteries were exposed to the bathing media for tension recordings and were stimulated by electrical square pulses. In helical strips of the cerebral artery denuded of the endothelium, transmural electrical stimulation produced relaxations that were abolished by tetrodotoxin or NG-nitro-L-arginine, a nitric oxide synthase inhibitor. In the monkey mesenteric and temporal arterial strips treated with alpha-adrenoceptor antagonists, the relaxation caused by electrical stimulation was also abolished by the nitric oxide synthase inhibitor, and it was restored by L-arginine. Nitroxidergic perivascular nerves, histologically demonstrated, appear to play an important role in dilating the monkey cerebral artery and in counteracting a vasoconstriction associated with noradrenergic nerve activation in the mesenteric and temporal arteries.

Biochemical and pharmacological properties of KRI-1314, a newly synthesized, low molecular weight (M.W.: 690) renin inhibitor, were investigated in vitro and in vivo. The novel amino acid norstatine, which is shorter in chain length than the well-known statine, was incorporated into KRI-1314 as a tetrahedral transition-state analogue for the Leul0-Val11 scissile peptide in the renin substrate. KRI-1314 more strongly inhibited plasma renins from primates than those from dogs, rabbits, guinea pigs and rats. KRI-1314 competitively inhibited highly-purified human renin with a Ki value of 9.9 × 10-10 M. KRI-1314 strongly inhibited the tissue renin-like activities of various organs from Japanese monkeys, with IC50 values on the order of 10-8 M. KRI-1314 was also very stable in various tissue homogenates from Japanese monkeys. Both intravenous (from 0.25 to 3 mg/kg) and oral (10 and 30 mg/kg) administration of KRI-1314 to anesthetized and conscious sodium-depleted Japanese monkeys, respectively, significantly lowered the blood pressure and plasma renin activity without affecting the heart rate. In Japanese monkeys, KRI-1314 was continuously detected in the plasma up to at least 7 hr after oral administration of 10 and 30 mg/kg. These results demonstrate that KRI-1314 is a highly potent, primate-selective and long-lasting oral renin inhibitor with a blood pressure lowering effect.

Halothane (0.75 to 2.25%) dose-dependently relaxed the vascular smooth muscle of endothelium-denuded rat aortae previously contracted with KCl, and the relaxing effect was not significantly affected by indomethacin nor dexamethasone, but partly inhibited by methylene blue. The cyclic GMP levels were increased by treatment with halothane (2.25%). It was suggested that halothane-induced relaxation of vascular smooth muscle is partly mediated by cyclic GMP formation.

In coronary, renal and femoral arteries and mesenteric veins isolated from Japanese monkeys, tachyphylaxis to angiotensin (ANG) II (10(-7) M)-induced contraction rapidly developed. Contractions caused by ANG II in coronary arteries were attenuated by treatment with indomethacin and aspirin and also by endothelium denudation. Indomethacin inhibited the response of the arteries with and without endothelium to a similar extent. OKY 046, a thromboxane A2 synthesis inhibitor, failed to inhibit the response. In contrast, contractions of renal arteries were potentiated and prolonged by the cyclooxygenase inhibitors. ANG II-induced contractions of mesenteric veins were prolonged but those of femoral arteries were not altered by indomethacin. It is concluded that ANG II contracts monkey coronary arteries, possibly due to the release of vasoconstrictor prostanoids but not thromboxane A2 from endothelial and subendothelial tissues and also due to its direct action on smooth muscle, whereas contractions of renal arteries and mesenteric veins are blunted by vasodilator prostanoids, possibly PGI2. Cyclooxygenase products even if released do not appear to regulate femoral artery contractions produced by ANG II.

In dog duodenal longitudinal muscle strips, transmural electrical stimulation (10 Hz, 15 sec) elicited a transient contraction, which was abolished by tetrodotoxin and atropine but potentiated by treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor. The potentiation was reversed by L-arginine but not by its D-enantiomer. Acetylcholine-induced contractions were not influenced by L-NA. After treatment with atropine, the electrical neural stimulation relaxed the muscle strips partially contracted with bradykinin, the relaxation being abolished by tetrodotoxin and suppressed by L-, but not D-, NA. L-arginine reversed the L-NA-induced inhibition. Oxyhemoglobin abolished the relaxation caused by nerve stimulation and NO. The neurally-induced relaxation was not attenuated by adrenoceptor antagonists and indomethacin. It is concluded that electrical stimulation of non-adrenergic, non-cholinergic nerves relaxes dog duodenal smooth muscle, due possibly to NO produced upon neural excitation, and potentiation by L-NA of the contractile response to cholinergic nerve stimulation, would be derived from elimination of the neurally-induced relaxation.

Adrenomedullin (AM) inhibited the pressor action caused by transmural electrical stimulation in perfused isolated canine mesenteric arteries. The inhibitory potency of AM was greater than that of calcitonin gene-related peptide (CGRP) or proadrenomedullin NH2-terminal 20 peptide (PAMP). [8-37]CGRP did not affect the inhibitory action of AM, but suppressed the CGRP-induced inhibition. It may be concluded that AM has an ability to inhibit adrenergic neuronal transmission without the mediation of CGRP1 receptors in the peripheral vasculature, and this inhibition partly participates in the potent hypotensive action of AM.

In cerebral arteries isolated from most of mammals, nerve stimulation produces relaxations in contrast to contractions in peripheral arteries. The relaxant mechanism is found to be non-adrenergic and non-cholinergic, but the neurotransmitter is not clarified until recently. Based on several functional and histological studies with isolated cerebral arteries, nitric oxide (NO) is now considered to be a neurotransmitter of the vasodilator nerve and the nerve has been called a nitroxidergic (nitrergic) nerve. Upon neural excitation, calcium influxed through N-type Ca2+ channels activates neuronal NO synthase, and then NO is produced by the enzyme from L-arginine. The released NO activates soluble guanylate cyclase in smooth muscle cells, resulting in relaxation with a cyclic GMP-dependent mechanism. The functional role and neuronal pathway have also been investigated in anesthetized dogs and Japanese monkeys. The nitroxidergic (nitrergic) nerves innervating the circulus arteriosus, including the anterior and middle cerebral and posterior communicating arteries, are found to be postganglionic nerves originated from the ipsilateral pterygopalatine ganglion and tonically dilate cerebral arteries in the resting condition. Our findings suggest that the nitroxidergic (nitrergic) nerve plays a physiologically important role to maintain a steady blood supply to the brain.

The vascular tone, vascular resistance and blood flow in the brain are regulated by neural and humoral factors in quite a different way from those of peripheral organs and tissues. In contrast to the dominant vasoconstrictor control in the periphery, the intracranial vascular tone is predominantly influenced by vasodilator mediators over vasoconstrictor ones. Recent studies have revealed that nitroxidergic vasodilator nerve and endothelium-derived hyperpolarizing factor (EDHF) or K+ channel opening substance appear to play important roles in the regulation of cerebral arterial and arteriolar tone in primate and subprimate mammals, in addition to the accepted information concerning the crucial contribution of endothelium-derived relaxing factor (EDRF) or nitric oxide (NO), polypeptides, prostanoids, etc. This article summarizes characteristic properties of vasodilator factors in controlling the cerebral arterial and arteriolar tone that undoubtedly contribute to circulatory homeostasis. The content includes vasodilator nerve, endogenous vasodilator substances, and vasodilator interventions such as hypoxia, hypercapnia and hyperosmolarity.

Dog hepatic arterial strips treated with prazosin responded to norepinephrine with concentration-related, endothelium-independent relaxations, the maximal response being 81.7% of the papaverine-induced maximal relaxation that was markedly greater than that in renal arteries. The norepinephrine-induced relaxation in hepatic arteries was significantly attenuated by metoprolol but not influenced by butoxamine. Relaxant responses to norepinephrine of dog hepatic arteries appear to be mediated by the beta1-adrenoceptor subtype, like those of coronary arteries. Evidence for functioning of the beta1-subtype in hepatic arteries would contribute to the analysis of neural and hormonal regulation of blood flow in the liver.

Adrenomedullin is known to induce profound hypotension in vivo, but the direct effect of this peptide on isolated arteries has not been demonstrated. This study estimated the vasodilative effects of adrenomedullin in comparison with those of calcitonin gene-related peptide (CGRP) in basilar, mesenteric, coronary, renal and femoral arteries isolated from the dog. Adrenomedullin (3 to 100 nM) and CGRP (1 to 30 nM) induced concentration-dependent relaxation of these arteries with and without endothelium, and the relaxing effects were slightly greater in endothelium-intact arteries than in denuded ones. The vasodilative potency of adrenomedullin relative to CGRP was smaller in the femoral artery than in basilar, mesenteric, coronary and renal arteries.

Isolated dog internal thoracic arteries (ITA) responded to norepinephrine and phenylephrine with concentration-related contractions, which were suppressed by prazosin, but not by yohimbine. Clonidine did not contract ITA. In coronary arterial strips, norepinephrine produced a relaxation. Isoproterenol relaxed coronary arterial strips contracted with serotonin but did not alter the tone of ITA. Forskolin and beraprost, an analog of prostaglandin I2, relaxed coronary and ITA strips to a similar extent. The beta-adrenoceptor density, assayed by [3H]dihydroalprenolol binding, was markedly less in ITA than in coronary arteries. Nicotine and transmural electrical stimulation did not alter the tension of ITA. Immunohistochemical study indicated that nerve fibers containing tyrosine hydroxylase immunoreactivity were markedly less in ITA than in coronary and mesenteric arteries. These results indicate that beta-adrenoceptor function and adrenergic innervation are considerably reduced in dog ITA. Norepinephrine-induced vasocontraction appears to be mediated by alpha 1-adrenoceptors in the arteries.

The endothelium-dependency of vasodilator responses was compared in helical strips of canine internal thoracic (ITA) and coronary arteries partially contracted with serotonin. The addition of acetylcholine produced a concentration-related relaxation in ITA and coronary arterial strips with an intact endothelium. The relaxations were not influenced by indomethacin, but were markedly inhibited or abolished by methylene blue, NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor, and endothelial denudation. The responses to low concentrations of acetylcholine were significantly greater in ITA than in coronary arteries, whereas relaxations induced by substance P, Ca2+ ionophore (A23187) or NO in ITA were significantly less. The substance P-induced relaxation in ITA and coronary arteries was endothelium-dependent, and it was almost abolished by L-NA. Relaxations induced by ATP in ITA were abolished by endothelium denudation and treatment with L-NA. In the coronary arteries, relaxing responses were inhibited only partially by removal of endothelium and L-NA. Acetylcholine, ATP and substance P relax canine ITA possibly by a mediation of endothelium-derived NO, but not prostaglandin I2. Coronary arterial relaxations induced by ATP appear to be mediated by an indirect action via NO released from the endothelium, in addition to a direct action on the smooth muscle.

Monkey cerebral artery strips partially contracted with prostaglandin F2 alpha responded to histamine with biphasic patterns of relaxation. The delayed and sustained relaxation was suppressed by cimetidine, whereas the phasic response was abolished by treatment with chlorpheniramine and NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor. The inhibition by L-NA was reversed by L-arginine. D-NA was without effect. Endothelium denudation abolished the phasic relaxation. We hypothesized that endothelium-dependent, phasic relaxations caused by histamine are mediated by NO that is released by H1-receptor stimulation, whereas the sustained relaxation is associated with the activation of H2-receptors in the smooth muscle of monkey cerebral arteries.

Transmural electrical stimulation caused a relaxation in the dog duodenal longitudinal muscle strips treated with atropine, phentolamine and propranolol, which was abolished by tetrodotoxin. The relaxation was suppressed by oxyhemoglobin and L-NG-nitro-arginine (L-NA), but not influenced by D-NA. Inhibition by L-NA was reversed by L-arginine, but not by D-arginine. The response to transmural electrical stimulation was similar to that caused by nitric oxide or nitroglycerin. Nitric oxide appears to participate importantly in non-adrenergic, non-cholinergic nerve-mediated relaxation.

Treatment with L-NG-monomethyl arginine (L-NMMA) increased the vasoconstriction induced by adrenergic nerve stimulation in perfused dog mesenteric artery segments and suppressed the relaxant response to transmural nerve stimulation in dog cerebral artery strips, the effects of L-NMMA being reversed by L-arginine. The observed changes in nerve function may be associated with the inhibition of synthesis of nitric oxide.