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Objectives: Renal cell carcinoma (RCC) is often found incidentally in asymptomatic individuals undergoing abdominal computed tomography (CT) examinations. The purpose of our study is to develop a deep learning-based algorithm for fully automated detection of small (≤4 cm) RCCs in contrast-enhanced CT images using a multicenter database and to evaluate its performance., Materials and Methods: For the algorithmic detection of RCC, we retrospectively selected contrast-enhanced CT images of patients with histologically confirmed single RCC with a tumor diameter of 4 cm or less between January 2005 and May 2020 from 7 centers in the Japan Medical Image Database. A total of 453 patients from 6 centers were selected as dataset A, and 132 patients from 1 center were selected as dataset B. Dataset A was used for training and internal validation. Dataset B was used only for external validation. Nephrogenic phase images of multiphase CT or single-phase postcontrast CT images were used. Our algorithm consisted of 2-step segmentation models, kidney segmentation and tumor segmentation. For internal validation with dataset A, 10-fold cross-validation was applied. For external validation, the models trained with dataset A were tested on dataset B. The detection performance of the models was evaluated using accuracy, sensitivity, specificity, and the area under the curve (AUC)., Results: The mean ± SD diameters of RCCs in dataset A and dataset B were 2.67 ± 0.77 cm and 2.64 ± 0.78 cm, respectively. Our algorithm yielded an accuracy, sensitivity, and specificity of 88.3%, 84.3%, and 92.3%, respectively, with dataset A and 87.5%, 84.8%, and 90.2%, respectively, with dataset B. The AUC of the algorithm with dataset A and dataset B was 0.930 and 0.933, respectively., Conclusions: The proposed deep learning-based algorithm achieved high accuracy, sensitivity, specificity, and AUC for the detection of small RCCs with both internal and external validations, suggesting that this algorithm could contribute to the early detection of small RCCs., Competing Interests: Conflicts of interest and sources of funding: This research was funded by AMED JP19lk1010025., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A prospective radiographic study.The purpose of this study was to analyze whether a novel skull clamp positioning system and technique is useful for obtaining good, quantitative cervical sagittal alignment during posterior cervical surgery.Different surgical procedures depend on cervical spine positioning. However, maneuver of the device and cervical position depends on the skill of the operator.This study included 21 male and 10 female patients with cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament of the cervical spine, undergoing posterior cervical surgery using the novel skull clamp positioning system. The average patient age was 68.6 years (range: 56-87 years). The novel system has a scale to adjust the neck position and to enable intended cervical sagittal alignment. First, the patient was placed on the operating table in the prone position with preplanned head-neck sagittal alignment (neutral position in general). The head was rotated sagittally, and the head was positioned in the military tuck position with the novel device that was used to widen the interlaminar space. After completing the decompression procedure, the head was rotated again back to the initial preplanned position. During this position change, the scale equipped with the device was useful in determining accurate positions. The C0-C1, C0-C2, C1-C2, C2-C7, and C0-C7 angles were measured on lateral radiographs taken pre-, intra-, and postoperatively.This novel system allowed us to obtain adequate, quantitative cervical sagittal alignment during posterior cervical surgery. There were no clinically significant differences observed between the pre- and postoperative angles for C1-C2 and C2-C7.Sagittal neck position was quantitatively changed during posterior cervical surgery using a novel skull clamp positioning system, enabling adequate final cervical sagittal alignment identical to the preplanned neck position.

Objectives: This study aimed to investigate risk factors for pancreatic stones and atrophy in autoimmune pancreatitis (AIP)., Methods: Seventy-one patients with AIP observed for more than 1 year were enrolled. The frequency of pancreatic stone development and atrophy on computed tomography as well as their risk factors were examined., Results: Pancreatic stones and atrophy were observed in 13 and 43 patients, respectively. Alcohol consumption of greater than 50 g/d was the only significant risk factor for pancreatic atrophy in univariate analysis. Alcohol intake of greater than 50 g/d was observed in 6 of 13 patients with stones and 10 of 58 patients without stones (46% vs 17%, P = 0.059). Alcohol intake of greater than 50 g/d was observed in 14 of 43 patients with atrophy and 2 of 28 patients without atrophy (33% vs 7.1%, P = 0.018). In multivariate analysis, alcohol consumption was a significant risk factor both for pancreatic stone formation (odds ratio [OR], 7.47; P = 0.040) and atrophy (OR 6.24; P = 0.034). Higher age at onset was another significant risk factor for pancreatic atrophy (OR 1.07 per year; P = 0.029)., Conclusions: Alcohol consumption of greater than 50 g/d increases the risk of pancreatic stone development and atrophy in patients with AIP.

Objectives: We examined whether the presence of pancreatic cysts could be a risk for pancreatic cancer by comparing the incidence and characteristics of cysts found by magnetic resonance (MR) imaging in patients with and without pancreatic cancer., Methods: Half-Fourier rapid acquisition with relaxation enhancement images and MR cholangiopancreatography were performed in 116 patients with pancreatic cancer (PC group) and 1226 with nonpancreatic disease (NP group). Incidence and characteristics of cysts were analyzed., Results: Pancreatic cysts were detected in 65 patients (56%) of the PC group and in 123 patients (10%) of the NP group. According to the multivariate analysis, cyst presence was a significant risk factor for pancreatic cancer (odds ratio [OR], 10.27; P < 0.01), especially cysts larger than 10 mm (OR, 4.718; P < 0.01). When the definition of cyst presence in the PC group was restricted to the 33 cases with cysts considered to have existed before the development of cancer, the incidence was still high (OR, 2.976; P < 0.01) and size remained significant (OR, 4.428; P < 0.01)., Conclusions: Patients with pancreatic cysts, especially larger than 10 mm, were considered to be at an increased risk of pancreatic cancer over the entire pancreas.

Objective: Glucose intolerance is often observed in autoimmune pancreatitis (AIP), although its long-term prognosis after steroid treatment (ST) is still unclear., Methods: A total of 47 patients with AIP were enrolled. On the basis of the change in hemoglobin A1c (HbA1c) and the use of diabetic medication, prognosis was classified into 3 categories, namely, "improved," "aggravated," and "unchanged." The relation between the result of an initial glucagon tolerance test (ΔCPR) and the later use of insulin during maintenance ST was examined in 20 patients. The transitions of homeostasis model assessment β cell and insulin resistance (HOMA-β and HOMA-R) were analyzed in 16 patients., Results: Glucose tolerance was improved in 6 patients (13%), aggravated in 9 patients (19%), and unchanged in 32 patients (68%). All patients with ΔCPR less than 0.6 ng/mL were obliged to use insulin even after long-term observation, whereas all patients with ΔCPR more than 1.0 ng/mL were free from insulin therapy. Moreover, HOMA-β showed significant improvement after ST (43.9% → 56.0% in median, P = 0.030), and HOMA-R showed significant aggravation (1.30 → 1.78, P = 0.039)., Conclusions: Glucose tolerance that is too severely damaged may not recover fully even after ST. Thus, ST should be performed to preserve insulin secretion at the early stage of AIP.

Blood flow in oral tissues, including the tongue, salivary glands, gingiva, dental pulp, and lip, plays an important role in modulating the complex oral functions involved in food intake. Oral tissue circulation is regulated by nitric oxide (NO) synthesized by neuronal NO synthase mainly present in parasympathetic vasodilator neurons and also by endothelial NO sythase. Electrical stimulation of parasympathetic nerves causes vasodilatation and blood flow increase in the tongue, submandibular gland, and lip in various mammals in vitro and in vivo. Lingual arteries isolated from Japanese monkeys respond to perivascular nerve stimulation by electrical pulses and nicotine with relaxations that are mediated via neurogenic NO. There is evidence supporting the hypothesis that the superior salivatory nucleus delivers central information through the geniculate ganglion and greater petrosal nerve to the pterygopalatine ganglion, which sends off impulses through nitrergic nerves to oral tissues. Endothelial NO also plays an important role in improving oral blood circulation not only in resting conditions but also under conditions activated by chemical and physical stimuli in the tongue, submandibular and parotid glands, dental pulp/gingiva, and cheek pouch. Maintenance of health in oral circulation by minimizing factors responsible for impairment of endothelial and neurogenic NO bioavailability would be important for the prophylaxis of life-style related diseases.

Objective: The aim of this study was to investigate the effect of S-1 on the prognosis of advanced pancreatic cancer., Methods: In total, 112 patients with pancreatic cancer who received chemotherapy between April 2001 and April 2007 were divided into 2 groups: PreS-1 (53 patients who started chemotherapy before January 2005) and PostS-1 (59 patients who started chemotherapy after February 2005, the time of S-1 introduction). Patient characteristics and clinical outcomes were compared, and prognostic factors were analyzed., Results: Patient characteristics did not significantly differ between the 2 groups. S-1 was administered as a second-line monotherapy in 5.7% of the PreS-1 group and combined with gemcitabine as a first-line therapy in 27.1% or as second-line monotherapy in 23.7% in the PostS-1 group. Both progression-free survival and overall survival improved after introduction of S-1 (median progression-free survival, 4.4 and 5.3 months; P = 0.043; median overall survival, 9.5 and 13.1 months; P = 0.048 in PreS-1 and PostS-1 groups, respectively). Multivariate analysis revealed that the PostS-1 group (hazards ratio, 0.52; P = 0.003), performance status, and carcinoembryonic antigen were significant prognostic factors for survival., Conclusions: Introduction of S-1 may improve the prognosis of Japanese patients with advanced pancreatic cancer.

Nitric oxide (NO) plays pivotal roles in controlling physiological functions, participates in pathophysiological intervention, and is involved in mechanisms underlying beneficial or untoward actions of therapeutic agents. Endogenous nitric oxide is formed by three isoforms of nitric oxide synthase: endothelial, neurogenic and inducible. The former two are constitutively present mainly in the endothelium and nervous system, respectively, and the latter one is induced by lipopolysaccharides or cytokines mainly in mitochondria and glial cells. Constitutively formed nitric oxide modulates the actions of morphine and related analgesics by either enhancing or reducing antinociception. Tolerance to and dependence on morphine or its withdrawal syndrome are likely prevented by nitric oxide synthase inhibition. Information concerning modulation of morphine actions by nitric oxide is undoubtedly useful in establishing new strategies for efficient antinociceptive treatment and for minimizing noxious and unintended reactions.

There has been an explosive increase in the amount of interesting information about the physiologic and pathophysiologic roles of nitric oxide in cardiovascular, nervous, and immune systems. The possible involvement of the nitric oxide-cyclic guanosine monophosphate pathway in the effects of anesthetic agents has been the focus of many investigators. Relaxations of cerebral and peripheral arterial smooth muscle as well as increases in cerebral and other regional blood flows induced by anesthetic agents are mediated mainly via nitric oxide released from the endothelium and/or the nitrergic nerve and also via prostaglandin I2 or endothelium-derived hyperpolarizing factor. Preconditioning with volatile anesthetics protects against ischemia-reperfusion-induced myocardial dysfunction and cell death or neurotoxicity, possibly through nitric oxide release. Inhibition of nitric oxide synthase decreases the anesthetic requirement. Involvement of nitric oxide in the effects of volatile, intravenous, and local anesthetics differs. This review article includes a summary of information about the sites and mechanisms by which various anesthetic agents interact with the nitric oxide-cyclic guanosine monophosphate system.

Eleven patients with syndromic craniosynostosis were treated with gradual distraction fronto-orbital advancement using "floating forehead." The frontal and supraorbital area was cut and remolded. Bony orbits were widened in three patients. Frontal bone was let floating on the dura and fixed loosely with absorbable threads to remolded supraorbital bone. A pair of distracters with hinge plates (A.V.D. system, Bear Medic Corp, Tokyo, Japan) was fixed between the temporal area and supraorbital bone. Distraction was begun 5 to 7 days after the surgery, and 1.8 to 3.2 cm advancement was obtained. Distracters were taken off after 3 to 7 weeks of consolidation periods. Although no major complication was encountered, some minor complications related to the devices were experienced.

Study Design: A radiographic study in 32 patients with cervical myelopathy., Objective: To investigate postoperative interlaminar bony fusion, and its characteristics and relationship to clinical results in patients undergoing laminoplasty., Summary of Background Data: Laminoplasty is being increasingly performed for multi-segmental cervical myelopathy, and its superior long-term results have been reported in some articles. We often see cases that develop postoperative interlaminar bony fusion after laminoplasty., Methods: In 32 patients, lateral cervical radiographs were obtained every year after surgery, and postoperative interlaminar bony fusion was evaluated. Range of motion (ROM) of the cervical spine at last follow-up was compared with the respective preoperative values. Furthermore, the neurologic recovery rates at last follow-up were compared to preoperative values., Results: Postoperative interlaminar bony fusion was shown in 17 patients (53%, group 1), and in most, fusion appeared within 3 years after surgery. Average age at surgery in group 1 and the remaining 15 patients (group 2) was 64.6 years and 57.0 years, respectively (P < 0.04). Preoperative and postoperative ranges of motion in group 1 were 45.6 degrees and 28.1 degrees on average, respectively. However, those of group 2 were 50.3 degrees and 39.8 degrees on average, respectively. Postoperative ROM in group 2 was significantly better maintained than that in group 1(P < 0.04). In group 1, the average preoperative Japanese Orthopedic Association score was 9.56 points, which improved to 13.6 points at the final follow-up, providing a 55.6% average recovery. In group 2, it was 10.9 points, which improved to 14.1 points at the final follow-up, providing a 56.5% average recovery. There was no significant difference in the average percentage of recovery between the 2 groups (P > 0.93)., Conclusions: Postoperative interlaminar bony fusion occurred in 53% of patients, with marked frequency at C2/3 after laminoplasty. It did not influence neurologic recovery, but it did reduce the postoperative sagittal ROM of the cervical spine.

Objective: This investigation assessed the relationship between the duration of wearing a cervical collar and clinical results in patients undergoing laminoplasty., Methods: Twenty-five patients with cervical myelopathy who underwent laminoplasty and wore a cervical collar for 8 weeks postoperatively were followed for an average of 27.3 months. A second group of 26 patients who underwent laminoplasty and wore a cervical collar for 4 weeks was followed for an average of 32.8 months., Results: In both groups, neurologic recovery rate and range of motion on lateral cervical radiographs were longitudinally compared with those obtained preoperatively. There was no significant difference in neurologic recovery between the two groups. In patients who wore the cervical collar for 4 weeks, the total range of the cervical spine was better maintained, especially the extension range of the cervical spine, compared with that in the patients who wore the cervical collar for 8 weeks., Conclusions: It is speculated that early removal of the cervical collar prevents contracture of the facet joint and postoperative atrophy and dysfunction of the extensor musculature of the cervical spine.

Modifications by hyperlipidemia of endothelium-dependent and -independent relaxations were evaluated in cerebral and temporal arteries from control and hyperlipidemic (high cholesterol-fed) monkeys. Histologically atherosclerotic lesions were not observed in either group. Relaxations induced by histamine, abolished by N(G)-nitro->L-arginine (>L-NA), were significantly potentiated in the hyperlipidemic monkey cerebral arteries, compared with those in the arteries from control monkeys. Treatment with superoxide dismutase did not affect the histamine-induced relaxation. Conversely, endothelium-dependent relaxations induced by A23187, Ca2+ ionophore, in cerebral arteries did not differ between control and hyperlipidemic monkeys. In temporal arteries, relaxations by acetylcholine and A23187 did not differ between control and hyperlipidemic monkeys. Endothelium-dependent and -independent relaxations by adenosine diphosphate in cerebral and temporal arteries were not affected by hyperlipidemia. Endothelium-independent relaxations by exogenously applied nitric oxide did not differ in the arteries from control and hyperlipidemic monkeys. Nicotine-induced relaxations in cerebral arteries, which were mediated with nitric oxide released from nitroxidergic (nitrergic) nerves, and the contractions caused by nicotine in temporal and mesenteric arteries treated with >L-NA did not differ between control and hyperlipidemic monkeys. It is concluded that long exposure to hyperlipidemia did not affect endothelial functions of monkey middle cerebral and temporal arteries but enhanced nitric oxide-mediated relaxations caused by histamine, possibly due to upregulation of endothelial histamine receptor-mediated functions in the cerebral arteries. The nitroxidergic (nitrergic) and adrenergic nerve functions do not seem to be affected by hyperlipidemia.

Objective: To investigate whether tin chloride pretreatment ameliorates renal injury in rats with ischemic acute renal failure (IARF) by virtue of its kidney-specific heme oxygenase-1 induction., Design: Randomized, masked, controlled animal study., Setting: University-based animal research facility., Subjects: Sprague-Dawley male rats, weighing 200-230 g (n = 359)., Interventions: Rats were injected with tin chloride subcutaneously, because subcutaneous administration of tin chloride is known to specifically and potently induce renal heme oxygenase activity in the rat. Anesthetized rats were subjected to bilateral flank incisions, and the right kidney was removed. Renal ischemia for 40 mins was performed by left renal microvascular clamping, followed by reflow of the blood., Measurements and Main Results: Tin chloride treatment specifically induced heme oxygenase-1 mRNA and protein in the proximal tubular epithelial cells of the kidney without apparent cell injury in the rat. Tin chloride treatment before renal ischemia augmented the induction of heme oxygenase-1 in IARF rats at both transcriptional and protein concentrations in the renal epithelial cells compared with IARF animals. Tin chloride pretreatment, which decreased microsomal heme concentration, ameliorated the ischemic renal injury as judged by the significant decrease in serum creatinine and blood urea nitrogen concentrations and the lesser tubular epithelial cell injuries. In contrast, inhibition of heme oxygenase activity by treatment with tin mesoporphyrin, which increased microsomal heme concentration, abolished the beneficial effect of tin chloride pretreatment., Conclusion: These findings indicate that tin chloride pretreatment significantly ameliorates renal injury in rats with IARF by virtue of its specific heme oxygenase-1 induction in renal epithelial cells. These findings also suggest that heme oxygenase-1 induction plays an important role in protecting renal cells from oxidative damage caused by heme.

The present study aimed to determine the action of angiotensin II and to pharmacologically analyze mechanisms of their action in isolated uterine arteries. Canine and human uterine artery strips were suspended in Ringer-Locke solutions for isometric tension recording. Canine and human uterine arteries responded to angiotensin II with transient contraction followed by relaxation, which were abolished by losartan, an AT1 receptor subtype antagonist. Cyclooxygenase inhibitors augmented the contraction and abolished the relaxation. The relaxation was also abolished or suppressed by tranylcypromine, a prostaglandin I2 synthesis inhibitor. The relaxant response of dog uterine arteries to angiotensin II was partially suppressed by endothelium denudation but was not influenced by nitric oxide synthase inhibitor. Conversely, the response of human uterine arteries to the peptide was unaffected by endothelium denudation. The antagonists used and endothelium denudation did not inhibit the relaxation caused by a prostaglandin I2 analogue. It appears that the angiotensin II-induced relaxation is mediated by vasodilator prostaglandins, possibly prostaglandin I2, released from both endothelium and subendothelial tissues in dog uterine arteries. In human uterine arteries, the vasodilator prostaglandin is released from subendothelial tissues due to AT1 receptor stimulation by the peptide.

Modifications by atherosclerosis of endothelium-dependent and -independent relaxations were evaluated in carotid arteries isolated from Watanabe heritable hyperlipidemic (WHHL; age 20-29 months) and age-matched Japanese white (JW) rabbits. Marked, patchy atherosclerotic lesions were observed in all WHHL rabbit arteries. Endothelium-dependent relaxations induced by acetylcholine, partly depressed by N(G)-nitro-L-arginine (L-NA), were significantly inhibited in the WHHL rabbit arteries with atherosclerosis, compared with those in the arteries without atherosclerotic lesions from JW and WHHL rabbits. No difference was observed in the relaxation caused by superoxide dismutase in these arteries. Conversely, endothelium-dependent relaxations by substance P were greater in the arteries with and without atherosclerosis from WHHL rabbits than in the arteries from JW rabbits. Endothelium-independent relaxations elicited by sodium nitroprusside and 2,2-(hydroxynitrosohydrazino)bis-ethanamine (NOC18) did not differ in the arteries from JW and WHHL rabbits. The responses to acetylcholine and substance P of JW rabbit arteries with the endothelium were not attenuated by treatment with pertussis toxin. L-NA-resistant, endothelium-dependent relaxations by substance P were almost abolished by charybdotoxin, and atherosclerosis did not alter the response. It is concluded that endothelial functions, evaluated by substance P, in rabbit carotid arteries are not impaired by atherosclerosis and by long exposure to hyperlipidemia in vivo. Dysfunction of muscarinic receptors may be involved in the depressed response to acetylcholine. As far as the arteries used in the present study are concerned, responses mediated possibly by endothelium-derived hyperpolarizing factor (EDHF) are unlikely to be modulated by atherosclerosis.

We have reported that a deficiency of tetrahydrobiopterin (BH(4)), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O(2)(-)) generation in the insulin-resistant state. To further confirm this hypothesis, we investigated the effects of dietary treatment with BH(4) on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats. Oral supplementation of BH(4) (10 mg. kg(-1). d(-1)) for 8 weeks significantly increased the BH(4) content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats). Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH(4) treatment. The BH(4) treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O(2)(-) production compared with those in fructose-fed rats. The BH(4) treatment also partially improved the insulin sensitivity and blood pressure, as well as the serum triglyceride concentration, in the fructose-fed rats. Moreover, BH(4) treatment of the fructose-fed rats markedly reduced the lipid peroxide content of both aortic and cardiac tissues and inhibited the activation of 2 redox-sensitive transcription factors, nuclear factor-kappaB and activating protein-1, which were increased in fructose-fed rats. The BH(4) treatment of control rats did not have any significant effects on these parameters. These results indicate that BH(4) augmentation is essential for the restoration of eNOS function and the reduction of vascular oxidative stress in insulin-resistant rats.

Mechanisms of neurogenic vasodilatation and its modification by superoxide, acetylcholine, and vasoactive intestinal peptide (VIP) in porcine cerebral arteries were investigated. Relaxant responses to transmural electrical stimulation and nicotine of cerebral artery strips without endothelium were abolished by tetrodotoxin and hexamethonium, respectively. N(G)-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished or markedly reduced the neurogenic response but did not affect the relaxation by exogenous NO. The inhibitory effect was reversed by L-arginine. Duroquinone, a superoxide-generating agent, did not alter the relaxations induced by electrical stimulation and nicotine. However, in the strips treated with diethyldithiocarbamate, an inhibitor of copper/zinc superoxide dismutase (SOD), the responses were significantly inhibited by duroquinone. The inhibition was partially reversed by SOD. Physostigmine inhibited, but atropine potentiated, the neurogenic response. The relaxation was attenuated by acetylcholine but not by VIP. There were nerve fibers and bundles containing NADPH diaphorase in the adventitia of cerebral arteries. It appears that porcine cerebral arteries are innervated by NO synthase-containing nerves that liberate NO on excitation as a neurotransmitter to produce muscular relaxation, and the nerve function is protected by endogenous SOD from degradation of NO by superoxide anions. The neurogenic relaxation is inhibited by acetylcholine released from cholinergic nerves, possibly because of an impaired production or release of NO.

In canine hepatic arterial strips responding to nicotine with contraction, prazosin abolished the response or reversed it to a relaxation. Mechanisms underlying the relaxation were analyzed in hepatic and coronary arterial strips denuded of the endothelium and treated with prazosin and indomethacin. In the hepatic arterial strips precontracted with prostaglandin (PG) F2alpha, nicotine-induced relaxations were not influenced by atropine but were inhibited by timolol and abolished by hexamethonium. Treatment with [8-37] calcitonin gene-related peptide ([8-37] CGRP), a selective CGRP1-receptor antagonist, also attenuated the nicotine-induced relaxation, but a vasoactive intestinal polypeptide antagonist was without effect. Combined treatment with timolol and [8-37] CGRP depressed the response to a greater extent than either antagonist alone. The slight relaxation remaining under the combined treatment was abolished by NG-nitro-L-arginine (L-NA) and restored by L-arginine. In coronary arterial strips precontracted with PGF2alpha, nicotine produced a moderate relaxation, which was abolished or markedly inhibited by treatment with hexamethonium or timolol but was unaffected by L-NA. It is concluded that the nicotine-induced relaxation is mediated by norepinephrine, CGRP, and NO released from perivascular nerves in dog hepatic arterial strips; the responses associated with activations of beta-adrenoceptors and CGRP1 receptors are predominant over those to NO. The coronary arterial relaxation seems to be mediated by neurogenic norepinephrine but not by NO.

Background: Pancuronium has sympathomimetic actions but does not change or lowers systemic blood pressure in some studies of anesthetized humans and dogs. The present study was done to determine the actions and mechanisms of action of pancuronium on coronary and renal arteries other than those as a sympathomimetic agent., Methods: Helical strips of coronary and renal arteries from mongrel dogs were suspended in oxygenated, warmed Ringer-Locke solution, and changes in the isometric tension were recorded. In some strips, transmural electrical stimulation (5 Hz for 40 s) was applied to activate perivascular adrenergic nerves., Results: Pancuronium (10[-7] to 10[-5] M) caused dose-dependent relaxation in coronary and renal arteries contracted with prostaglandin (PG) F2alpha, whereas no significant response was induced with vecuronium. The relaxation was endothelium independent and abolished by indomethacin or tranylcypromine, a PGI2 synthase inhibitor. Transmural electrical stimulation caused coronary arterial relaxation, which was augmented by pancuronium and vecuronium. Desipramine also increased the response, and additional potentiation of the response was not elicited by pancuronium and vecuronium. In renal arteries, electrical stimulation caused contraction, which was also augmented by pancuronium and vecuronium. With desipramine treatment, these muscle relaxants did not potentiate the response. Endothelium-dependent coronary arterial relaxation caused by bradykinin was not affected by pancuronium., Conclusions: Pancuronium-induced relaxations in canine coronary and renal arteries appear to be mediated by PGI2 released from subendothelial tissues. Potentiations by pancuronium and vecuronium of the response to adrenergic nerve stimulation are expected to be due to an inhibition of the norepinephrine uptake but not to facilitated release of the amine.

We wished to determine the action of prostaglandins (PG) and to analyze pharmacologically the mechanisms of their action in isolated human uterine arteries in special reference to mediators liberated from the endothelium and subendothelial tissues. Helical strips of the human uterine artery with and without the endothelium were suspended in the Ringer-Locke solution for isometric tension recording. The relaxant response to PGF2 alpha was reversed to a contraction by cyclooxygenase inhibitors and suppressed by tranylcypromine, a PGI2 synthase inhibitor, but was not influenced by endothelium denudation. Relaxations induced by PGE2 and beraprost, a PGI2 analogue, were augmented by cyclooxygenase inhibitors and tranylcypromine but were not affected by ONO3708, an antagonist of vasoconstrictor prostanoids, and endothelium denudation. The potentiating effect of indomethacin was observed in the strips both with and without the endothelium and was antagonized by treatment with beraprost. The relaxation caused by PGF2 alpha apparently is mediated by PGI2 released from subendothelial tissues, whereas the PGE2-induced relaxation is due to the direct action on smooth muscle; the action may be eliminated by the basal release of PGI2 from subendothelial tissues.

We determined involvement of nitric oxide (NO) derived from perivascular nerve in venous relaxation. In helical strips of dog superficial temporal veins contracted with prostaglandin F2 alpha (PGF2 alpha) nicotine produced a contraction, which was reversed to a relaxation by prazosin. The relaxation was partially attenuated by timolol or metoprolol. The residual relaxation was not influenced by treatment with atropine or indomethacin and by endothelium denudation but was abolished by NG-nitro-L-arginine (L-NA), a NO synthase inhibitor, and hexamethonium. L- but not D-arginine reversed the inhibition induced by L-NA. Relaxations induced by NO were not influenced by L-NA. Similar results were also obtained in relaxations induced by transmural electrical stimulation that were sensitive to tetrodotoxin (TTX). In the monkey venous strips, relaxations induced by nicotine under treatment with prazosin were reduced by timolol. The relaxation observed with combined treatment with alpha- and beta-antagonists was abolished by L-NA, and L-arginine restored the response. The presence of nerve fibers containing NO synthase immunoreactivity or NADPH diaphorase in the adventitia of dog and monkey veins was determined histologically. The findings so far obtained strongly suggest the presence of perivascular nerves that mediate venodilation via a release of NO. Contractions of the temporal vein appear to be mediated by norepinephrine (NE) released from adrenergic nerves that stimulates alpha 1-adrenoceptors, whereas relaxations are mediated by neurogenic NE, acting possibly on the beta 1-adrenoceptor subtype, in addition to NO derived from nerves.

In helical strips of dog distal superficial temporal artery denuded of endothelium and partially contracted with prostaglandin F2 alpha (PGF2 alpha), nicotine produced a moderate relaxation preceded by no contraction or a slight contraction. The contraction was less than that observed in proximal arterial strips obtained from the same dogs and was abolished by alpha-adrenoceptor antagonists. Relaxations under alpha-receptor blockade were greater in the distal than in the proximal arteries. Treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor, abolished the relaxation caused by nicotine and transmural electrical stimulation (5 Hz for 40 s), the response being reversed by L- but not by D-arginine. In monkey temporal arteries of the distal and proximal portions treated with alpha-antagonists, nicotine produced similar magnitudes of relaxation, which were abolished by treatment with the NO synthase inhibitor. Vasodilator nerves appear to play an important role in regulation of small arterial tone; noradrenergic vasoconstrictor function is less and vasodilator nerve function is more evident in dog distal arteries than in dog proximal arteries. The neurally induced relaxation in dog and monkey distal temporal arteries is postulated to be mediated by NO derived from nerves.

Background and Purpose: Oxyhemoglobin is a key substance in provoking cerebral vasospasm and a scavenger of nitric oxide. The present study was designed to determine whether suppression of the action of endothelium-derived nitric oxide is involved in oxyhemoglobin-induced cerebroarterial contraction., Methods: Dog and monkey cerebral artery strips with and without endothelium were immersed for isometric tension recording in modified Ringer-Locke solution aerated with 95% oxygen and 5% carbon dioxide., Results: NG-nitro-L-arginine, a nitric oxide synthase inhibitor, produced concentration-related contraction that was greater in the strips with intact endothelium than in those denuded of endothelium. The D-enantiomer caused no or only a slight contraction. In the presence of NG-nitro-L-arginine, oxyhemoglobin elicited additional contraction that is comparable to or even greater than that obtained in the absence of the inhibitor. The oxyhemoglobin-induced contraction was attenuated by endothelium denudation., Conclusions: Inhibition of the basal release of nitric oxide from endothelium results in dog and monkey cerebral arterial contraction. However, the inhibition of nitric oxide action is not a major mechanism involved in oxyhemoglobin-induced contraction; other mechanisms, such as the release of prostanoids, appear to be important.

Dopamine is widely used for the treatment of cardiogenic and hypovolemic shock. This study was undertaken to compare the response to dopamine in epicardial conduit coronary arteries of humans, Japanese monkeys, and dogs, and to determine the mechanism of vasoconstriction and vasodilation. In helical strips of coronary arteries from humans and monkeys partially contracted with prostaglandin F2 alpha, dopamine produced a concentration-related contraction; the human artery contraction was greater. The contractions were reversed to a relaxation by treatment with phentolamine. Relaxation of monkey arteries treated with the alpha adrenoceptor antagonist was not influenced by metoprolol, a beta 1 antagonist, or endothelium denudation, but was reversed to contraction by SCH23390, a dopamine1 receptor antagonist. On the other hand, dog coronary arteries responded to dopamine with a relaxation that was abolished by metoprolol, but not influenced by SCH23390 or butoxamine, a beta 2 antagonist. We conclude that dopamine in clinical doses elicits significant contractions, mediated possibly by alpha adrenoceptors, in human and monkey coronary arteries; thus, care has to be taken when the amine is used in patients with variant angina pectoris. Relaxation of monkey coronary arteries appears to be associated with activation of dopamine1 receptors, whereas those of the dog arteries are mediated mainly by beta 1 receptors.

Background and Purpose: Hypoxia alters the responsiveness to endogenous substances of cerebral arteries, possibly resulting in the modulation of blood supply to ischemic brain regions. The present study was undertaken to analyze the mechanism of potentiation by hypoxia of angiotensin II-induced cerebroarterial contractions., Methods: Monkey and dog cerebral arterial strips with endothelium were suspended for isometric tension recording in Ringer-Locke solution aerated with 95% O2-5% CO2 (partial pressure, 570-600 mm Hg) or 95% N2-5% CO2 (approximately 10 mm Hg)., Results: Contractions induced by angiotensin II and substance P were potentiated by exposure to hypoxia, whereas contractile responses to prostaglandin F2 alpha were not influenced. Treatment with cyclooxygenase inhibitors abolished the peptide-induced contraction but did not alter the prostaglandin F2 alpha-induced contraction. Relaxations induced by arachidonic acid were suppressed by indomethacin and hypoxia, whereas those caused by a prostaglandin I2 analogue were unaffected., Conclusions: The potentiation by hypoxia of cerebroarterial contractions caused by angiotensin II and substance P appears to be due to an interference with the synthesis of prostaglandin I2 from arachidonic acid and a resultant increase in the production of vasoconstrictor prostaglandins.

In isolated porcine coronary arteries, acetylcholine elicited contractions that were potentiated by endothelium denudation. In endothelium-intact strips, the contraction deteriorated by repeated trials and was reversed to a relaxation. NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor, abolished the relaxation or reversed it to a contraction. Endothelium-dependent relaxations caused by serotonin were also reversed to a contraction by treatment with L-NA. Relaxations caused by substance P were dependent on the endothelium and were abolished by oxyhemoglobin; however, L-NA did not completely abolish the relaxation. It may be concluded that porcine coronary arteries respond to acetylcholine with contractions by a direct action on smooth muscle that are minimized by stimulated release of NO from the endothelium. It appears that the relaxation caused by serotonin is due to NO released from the endothelium, whereas the substance P-induced relaxation is associated mainly with endothelium-derived NO produced by NO synthase sensitive to L-NA and also with NO produced via a L-NA-resistant process or via a pathway distinct from that through NO synthase.

Histochemical study revealed that transcutaneous injection of ethanol into the vicinity of the pterygopalatine ganglion greatly decreased the positive staining for NADPH diaphorase activity after 1 week in the ipsilateral ganglion of a dog and abolished the staining of perivascular nerves in the middle and posterior cerebral arteries. Transmural electrical stimulation or nicotine produced a relaxation in middle and posterior cerebral arteries isolated from the side with the nontreated ganglion (control side), whereas the relaxation was abolished or reversed to a contraction in the arteries from the side with the ethanol-treated ganglion. Nitric oxide-induced relaxations did not differ in the arteries from both sides. The response to nerve stimulation of the control arteries was suppressed by treatment with NG-nitro-L-arginine (L-NA), an inhibitor of nitric oxide synthase, and the inhibition was reversed by L-arginine. Nicotine produced a contraction followed by a relaxation in central retinal arterial strips obtained from the control side; the relaxation was abolished and the contraction was potentiated in the arteries from the treated side. The nicotine-induced relaxation was abolished by L-NA, and the contraction was suppressed by phentolamine. On the other hand, the nicotine-induced relaxation in superficial temporal arteries, susceptible to L-NA, was not attenuated by treatment with ethanol. The findings obtained so far support our hypothesis that nitric oxide released from the vasodilator nerve acts as a transmitter to produce arterial smooth muscle relaxation and suggest that the nerve fibers to the cerebral and retinal arteries arise from the pterygopalatine ganglion.

The functional role of the endothelium in conversion of angiotensin (Ang) I to Ang II was studied in helical strips of dog renal arteries. In the arteries precontracted with PGF2 alpha, Angs I and II caused a moderate relaxation, which was abolished by treatment with saralasin and reversed to a contraction by indomethacin. Removal of the endothelium attenuated the response to Ang I but did not abolish it. The Ang I-induced relaxation in the arteries without endothelium was not significantly attenuated by an Ang-converting enzyme inhibitor, SA446, but was markedly suppressed by chymostatin. On the other hand, in the arteries with endothelium, the relaxation was suppressed but not abolished by SA446, and the remaining relaxation was abolished by additional treatment with chymostatin. Relaxation induced by prostaglandin I2 was unaffected by these enzyme inhibitors. These results strongly suggest that the conversion of Ang I to Ang II is due mainly to the Ang-converting enzyme in the endothelium and to the chymostatin-sensitive Ang II-generating enzyme in subendothelial tissues.

The effect of mepivacaine on adrenergic neuroeffector junction was studied in the isolated rabbit aorta. Mepivacaine, 5 X 10(-5) to 5 X 10(-4) M, attenuated the contractile response to transmural neural stimulation, the attenuation being greater in the response at high frequency stimulations. The attenuation of the responses by mepivacaine was not prevented by prior application of cocaine. The concentration-response curve for norepinephrine was shifted to the right by mepivacaine, 5 X 10(-5) to 2 X 10(-3) M. The attenuation of the response to transmural stimulation was greater than that of the response to an equipotent concentration of exogenous norepinephrine. Pretreatment with mepivacaine, 5 X 10(-5) to 2 X 10(-3) M, protected alpha-adrenoceptors from persistent blockade by phenoxybenzamine in a dose-dependent manner. The contractile response to histamine was not significantly altered by mepivacaine in concentrations up to 5 X 10(-4) M. Mepivacaine, 5 X 10(-4) and 2 X 10(-3) M, decreased the response to high concentrations of KCl. Ca2+-induced contractions in aortic strips previously exposed to Ca2+-free media and depolarized by excess K+ were significantly inhibited by mepivacaine, 5 X 10(-4) and 2 X 10(-3) M. It may be concluded that mepivacaine causes vasodilation through an alpha-adrenoceptor antagonism in addition to a sympathetic nerve conduction blockade. High concentrations of mepivacaine appear to interfere with the transmembrane influx of calcium in the vascular smooth muscle.

In helical strips of dog cerebral arteries soaked in Ca2+-free media and treated with prostaglandin (PG) F2 alpha or K+, the addition of Ca2+ produced a transient contraction, transient relaxation, and slowly developing, persistent contraction. Treatment with 2 X 10(-7) M ouabain did not alter the contractile response to PGF2 alpha in Ca2+-free media, but potentiated the response to Ca2+. Relaxations following the transient contractions were abolished by ouabain. On the other hand, ouabain potentiated the contractile response to serotonin in Ca2+-free media, and also the response to Ca2+. In mesenteric arterial strips soaked in Ca2+-free media, ouabain at 2 X 10(-7) M insufficient to produce contractions increased the contractile response to Ca2+, and the increase in the concentration to 2 X 10(-5) M potentiated the response to PGF2 alpha and serotonin. It may be concluded that ouabain increases the influx of Ca2+ across cell membrane caused by vasoconstrictors and enhances the drug-induced release of Ca2+ from intracellular storage sites.

In helically-cut strips of dog cerebral, coronary and mesenteric arteries, contracted with prostaglandin (PG) F2 alpha or K+, the addition of verapamil caused a dose-related relaxation. Verapamil-induced relaxations were greater in cerebral than in the other arteries when contracted with PGF2 alpha, but did not significantly differ in the arteries contracted with K+. Similar results were obtained with diltiazem and nifedipine. The contractile response to PGF2 alpha was attenuated by pretreatment with verapamil, the ateenuation being greater in cerebral than in mesenteric arteries. Nitroglycerin and sodium nitroprusside relaxed cerebral, coronary and mesenteric arteries contracted with PGF2 alpha to a similar extent. It may be concluded that dog cerebral arteries contracted with PGF2 alpha, one of endogenous vasospastic substances, are more susceptible to agents which interfere with the influx of Ca++ across cell membranes than coronary and mesenteric arteries; these agents may thus be of value in the treatment and prophylaxis of cerebral vasopasm.

The possible role of vascular angiotensin converting enzyme (ACE) in the maintenance of one-kidney, one clip (1-K,1C) hypertensive rats was studied in comparison with age-matched, one-kidney (1-K) normotensive rats. Mean blood pressure was elevated after partial occlusion of the left renal artery with unilateral nephrectomy, and the high blood pressure persisted for at least 11 weeks, whereas no significant changes in mean blood pressure were observed in 1-K rats. Plasma and vascular renin activities and plasma ACE activity did not differ between the two groups of rats, both 5 and 11 weeks after operation. In contrast, ACE activity in lung and mesenteric arteries in 1-K,1C hypertensive rats was significantly elevated 11 weeks after operation, but not 5 weeks after operation, compared with the matched 1-K normotensive rats. In addition, the decreases in mean blood pressure induced by ACE inhibition were significantly greater in 1-K,1C rats than those in 1-K rats. These results indicate that the elevation of vascular ACE activity may play an important role in the maintenance of high blood pressure and may result in hypotension in response to ACE inhibitors in the chronic stage of 1-K,1C hypertension.

In helically-cut strips of cerebral and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, carbocyclic thromboxane A2 (cTxA2) or K+, the addition of nicardipine caused a dose-related relaxation. Nicardipine-induced relaxation was greater in cerebral than in mesenteric arteries when contracted with PGF2 alpha and cTxA2, but did not appreciably differ in the arteries contracted with K+. Cerebral arteries contracted with hemolysate and PGF2 alpha relaxed in response to nicardipine to a similar extent. The contractile response to PGF2 alpha was attenuated by pretreatment with nicardipine, the attenuation being greater in cerebral than in mesenteric arteries. Ca++-induced contractions in cerebral and mesenteric arteries previously exposed to Ca++-free media and depolarized by excess K+ were attenuated by nicardipine to a similar extent. PGF2 alpha-induced contractions of cerebral arteries exposed to Ca++-free media were attenuated by nicardipine, whereas those of mesenteric arteries were unaffected. Attenuations by nicardipine of the Ca++-induced contraction in PGF2 alpha-treated cerebral arteries were greater than those seen in mesenteric arteries. It may be concluded that nicardipine produces a greater relaxation of cerebral arteries than mesenteric arteries, possibly due to a greater inhibition of the Ca++-influx and to a decrease in the release of Ca++ from intracellular storage sites in cerebral arteries. As far as the concentrations used are concerned, nicardipine appears to attenuate the inward movement of Ca++ across cell membrane in mesenteric arterial smooth muscle, but not the release of intracellularly stored Ca++.

The effects of ketamine on isolated canine cerebral (middle cerebral and basilar) and mesenteric arteries were studied. In arteries contracted with KCl, ketamine in concentrations above 5 X 10(-6)M (cerebral arteries) or 2 X 10(-5)M (mesenteric arteries) caused significant relaxation in a dose-dependent manner. The relaxation was not significantly influenced by aminophylline, aspirin, atropine, or propranolol. In concentrations above 5 X 10(-6)M ketamine attenuated the contractile response to high concentrations of KCl in the middle cerebral arteries, and in concentrations above 5 X 10(-5)M it attenuated the contractile response to high concentrations of KCl in the basilar and mesenteric arteries. The attenuation was greater in cerebral than in mesenteric arteries. The contractile response of cerebral arteries to high concentrations of serotonin was also attenuated by ketamine in concentrations above 5 X 10(-5)M. Ketamine attenuated KCl-induced contraction of cerebral arteries more than it attenuated serotonin-induced contraction. When basilar arteries were exposed to Ca2+-free media and depolarized by KCl, the addition of Ca2+ caused biphasic (transient and sustained) contractions, while in the mesenteric arteries the addition of Ca2+ produced sustained contractions. Ketamine at 5 X 10(-5) and 5 X 10(-4)M attenuated both transient and sustained contractions in basilar arteries, while in mesenteric arteries 5 X 10(-4)M ketamine attenuated only sustained contractions. In both instances, ketamine-induced attenuation was partially reversed by excess Ca2+. It is concluded that ketamine has a direct dilating effect on both cerebral and mesenteric arteries, but the effect is more pronounced in cerebral than in mesenteric arteries. The direct action of ketamine on those arteries may be due in part to interference with transmembrane influx of Ca2+.