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Insomnia symptoms must be differentiated from insomnia disorder. The correct aiagnosis or insomnia aisoraer is important, as insomnia may also be a symptom of many other diseases. Cognitive behavioral methods are recommended as first-line treatment options. Treatment of acute insomnia with hypnotics should not exceed two weeks. In elderly persons adverse effects of hypnotics may exceed their beneficial effects in long-term use. Antidepressive medications acting on the histamine-1 system may be used in very small doses. The new guideline includes e.g. insomnia in pregnant and menopausal women and in cancer patients, and driving issues.

Biodistribution of the monoclonal antibody (mAb 9d9f9) against the vascular endothelial growth factor receptor- 3 (VEGFR-3) is studied here in the rat. VEGFR-3 is expressed on endothelial cells of lymphatic endothelium during the tissue growth. The mAb9d9f9 is the first specific molecular marker to the endothelial cells of high venules. The specificity was detected with immunohistochemistry of tissue samples. Materials The affinity of 125I-mAb 9d9f9 was determined in HEL leukemia cells expressing the extracellular receptor and the biodistribution was detected both by external imaging and tissue sampling in the tumor model. The imaging result with subcutaneous injections was compared to the imaging after intravenous injections. Results Targeting to the induced mammary tumors in rat was detected with immunoscintigraphy of 125I-mAb. The imaging after subcutaneous administration showed lower uptake in liver, spleen, heart and stomach than the imaging after intravenous administration. The mAb 9d9f9 accumulated to the parasternal lymphatic vessels at 16 days after the subcutaneous injections. Conclusion The mAb 9d9f9 visualized the routes of lymphatic circulation probably based on binding to this transmembrane lymphatic endothelial receptor. Immunodetection of the tumors in rat was, however, possible with these antibodies targeting to the endothelial cells lining the vascular system.

Vitamin K is not only essential for the synthesis of coagulation factors in the liver, but it also strengthens the bones and prevents calcification of the arteries. These effects are mediated through the same mechanism, i.e. carboxylation of Gla target proteins. The discovery of novel Gla proteins that are not associated with blood coagulation or calcium metabolism indicates that vitamin K has additional effects in the pancreas and the central nervous system, for example. As dietary supplements, vitamin K1 of plant origin and vitamins K2 of bacterial origin may exert different effects.

Endothelial dysfunction plays an important role in the development of atherosclerosis. Previous studies have shown that inoculation withChlamydia pneumoniaecontributes to atherosclerotic development in rabbits and hypercholesterolaemic mice and causes endothelial dysfunction in apolipoprotein E-deficient mice. The effect of acuteC. pneumoniaeinfection on endothelial function in normocholesterolaemic C57BL/6J mice was studied by measuring the force of contraction of the descending aorta after noradrenaline stimulation and in response to methacholine-induced relaxation. In addition, the effects of the nitric oxide synthase inhibitorNω-nitro-l-arginine methyl ester (l-NAME) and the cyclooxygenase inhibitor diclofenac on relaxation were assessed. Pre-treatment of the aortas withl-NAME decreased the relaxation response in both the infected and uninfected groups and no significant difference was detected between these groups, whereas diclofenac significantly attenuated the relaxation response only in the infected animals. In conclusion, infection shifted the balance of endothelium-derived relaxing factors from nitric oxide towards vasorelaxing prostanoids in C57BL/6J mice.

The risk for coronary events may rise during acute infection. Perturbation in coronary endothelial function emerges as one important link. We investigated whether simvastatin could protect the coronary arterial function from the adverse effects of acute infection in swine.Coronary endothelium-dependent and -independent vasomotor responses were assessed by Doppler velocimetry in 12 Chlamydia pneumoniae-infected and 6 sham-infected swine 2 weeks after intratracheal inoculation. Half of animals from the infection group were pre-treated with simvastatin (80 mg daily), while the remaining animals received placebo. The treatment was started 2 weeks prior to inoculation and continued until the end of the study. ANOVA was used for statistical calculations. Data are mean+/-S.D.All animals inoculated with C. pneumoniae developed IgM antibodies against this organism. As compared to noninfected animals, peak-to-baseline coronary flow velocity (CFV) ratio after bradykinin was significantly decreased in infected animals regardless of statin treatment (p=0.01). Intracoronary 10(-6) M acetylcholine caused slight dilatory responses in both noninfected and infected-treated animals (CFV ratio: 1.6+/-0.2 and 1.4+/-0.2, respectively; p0.1), while a velocity drop (CFV ratio: 0.7+/-0.1; p0.01 versus noninfected-infected and treated), indicating constriction, was observed in infected-nontreated animals; 10(-5) M acetylcholine caused vasoconstriction in all animals, with a significantly more prolonged response in the infected-nontreated group (p0.01). Intracoronary adenosine and SNP induced similar dilatory responses in all groups (p0.5). There were no differences in markers of systemic inflammation (fibrinogen, amyloid, and CRP) and lipid profile (HDL, LDL and total cholesterol) between the groups (p0.2).Acute infection is associated with impairment of the muscarinic and kinin-related reactivity of coronary circulation. These functional abnormalities are in part prevented by simvastatin through mechanisms unrelated to lipid lowering.

Hypertension is a major risk factor for atherosclerosis. We tested the hypothesis whether high salt intake aggravates endothelial dysfunction and promotes atherosclerosis in apolipoprotein E-deficient mice (ApoE(-)/(-) mice) and their littermate controls (C57Bl/6 mice). The role of increased oxidative stress was also examined. A high-salt diet (NaCl 7%) for 12 weeks increased blood pressure and induced cardiac hypertrophy and albuminuria more pronouncedly in ApoE(-)/(-) mice compared with C57Bl/6. Endothelium-dependent vascular relaxation in response to acetylcholine was almost maximally impaired in ApoE(-)/(-) mice during a normal sodium diet. A high-salt diet did not further impair NO-mediated vascular relaxation. A high-salt diet also markedly attenuated endothelium-dependent relaxation in C57Bl/6 mice. Preincubation with the superoxide scavenger Tiron normalized endothelial function almost completely in both mice strains indicating the central role of increased oxidative stress in the pathogenesis. Aortic superoxide production and the extent of atherosclerotic lesions were greater in ApoE(-)/(-) mice on a normal-salt diet compared with C57Bl/6. The high-salt diet increased vascular superoxide formation and promoted atherosclerosis in ApoE(-)/(-) mice. Changes in dietary salt intake did not influence serum lipids in either mouse strains. Our findings suggest a detrimental role for high salt intake in the development of atherosclerosis and underscore the importance of increased oxidative stress in the pathogenesis salt-induced vascular damage.

Background: Upregulation of proinflammatory endothelial cell adhesion molecules and decreased bioactivity of endothelial nitric oxide (NO) are important in the pathogenesis of atherosclerosis. We investigated the effects of co-infection with Chlamydia pneumoniae and Helicobacter pylori on these two events in apoE-KO mice. Methods: Thirty-two apoE-KO mice, 8 weeks old, were equally divided into 4 groups. The first 2 groups were infected with either C. pneumoniae or H. pylori, while the 3rd group was infected with both C. pneumoniae and H. pylori. Mice from the 4th group and 4 wild-type mice served as controls. Thoracic and abdominal aortas were harvested after 10 weeks, and staining for vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 was analyzed by immunocytochemistry. The endothelial vasomotor responses of thoracic aortas to methacholine were studied in organ chambers in the absence and presence of L-NAME. The plasma levels of nitrate/nitrite were measured. Results: Staining for VCAM-1 was more intense at the branching sites of aortas from mice with co-infection than in mono-infected or noninfected apoE-KO mice. The relaxation responses to methacholine and the plasma levels of nitrate/nitrite were significantly less in the co-infected group than in the other groups (p < 0.05). Conclusion: Co-infection of apoE-KO mice with C. pneumoniae and H. pylori seems to be associated with impaired bioactivity of endothelial NO and increased expression of VCAM-1 at branching sites. The findings may suggest an additive interaction of these pathogens in atherogenesis.

In inflammatory bowel disease, increased production of prostaglandins by cyclooxy- genase-2 (COX-2) contributes to bowel dysfunction, inflammatory edema, and hyperemia suggesting that inhibitors of COX-2 may have beneficial effect in gut inflammation. We compared the effects of nimesulide, a preferential COX-2 inhibitor, with those of indomethacin, acetylsalicylic acid (ASA), and dexamethasone in a 24-h model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in the rat. TNBS-induced colitis was associated with enhanced COX-2 expression in the gut and increased circulating concentrations of PGE2 metabolite (PGEM). Treatment with nimesulide (10 mg/kg), indomethacin (10 mg/kg), or dexamethasone (1 mg/kg) reduced plasma PGEM concentrations and edema in the inflamed bowel. In addition, nimesulide and dexamethasone treatments decreased neutrophil infiltration into the inflamed colon mucosa. ASA (10 mg/kg) did not have a significant effect on any of these measures of inflammation. None of the studied drugs reduced the size of inflammatory mucosal lesions in the colon. In TNBS-induced acute inflammation of the colon, nimesulide reduced the formation of inflammatory edema, probably by a mechanism related to inhibition of PGE2 production by COX-2 pathway. In addition, nimesulide inhibited neutrophil infiltration into inflamed mucosa mimicking the action of dexamethasone.

Background —Arterial relaxation is largely regulated by endothelial nitric oxide (NO). Its diminished activity has been associated with incipient atherosclerosis. We investigated the endothelium-dependent relaxation of aorta in apolipoprotein E–knockout (apoE-KO) mice exposed to single or repeated Chlamydia pneumoniae inoculation. Methods and Results —Forty-eight apoE-KO mice, 8 weeks old, were inoculated intranasally with C pneumoniae (n=24) or saline (n=24) every 2 weeks over a 6-week period. Twenty mice (10 infected and 10 controls) were killed at 2 weeks and 6 weeks, respectively, after the first inoculation. The smooth muscle tone of aortic rings was measured in vitro at both time points. The norepinephrine-precontracted thoracic aortic rings were successively exposed to methacholine in the absence and presence of N G -nitro- l -arginine methyl ester (L-NAME) and diclofenac. The methacholine-induced relaxation was attenuated in the infected mice at 6 weeks in both the absence and presence of L-NAME ( P P P P Conclusions — C pneumoniae impairs arterial endothelial function, and the NO pathway is principally involved. Cyclooxygenase-dependent vasoconstricting products may also account for the infection-induced impaired relaxation. These findings further support the role of C pneumoniae infection in atherosclerosis development.

1. The aim of the present study was to investigate the effects of bradykinin and [des-Arg9]-bradykinin and their relaxant mechanisms in the mouse isolated trachea. 2. In the resting tracheal preparations with intact epithelium, bradykinin and [des-Arg9]-bradykinin (each drug, 0.01-10 microM) induced neither contraction nor relaxation. In contrast, bradykinin (0.01-10 microM) induced concentration-dependent relaxation when the tracheal preparations were precontracted with methacholine (1 microM). The relaxation induced by bradykinin was inhibited by the B2 receptor antagonist, D-Arg0-[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140, 0.01-1 microM) in a concentration-dependent manner whereas the B1 receptor antagonist, [des-Arg9,Leu8]-bradykinin (0.01-1 microM), had no inhibitory effect on bradykinin-induced relaxation. [des-Arg9]-bradykinin (0.01-10 microM) also caused concentration-dependent relaxation after precontraction with methacholine. The relaxation induced by [des-Arg9-bradykinin was concentration-dependently inhibited by the B1 receptor antagonist, [des-Arg9,Leu8]-bradykinin (0.01-1 microM), whereas the B2 receptor antagonist, Hoe 140 (0.01-1 microM) was without effect. 3. In the presence of the cyclo-oxygenase inhibitor, indomethacin (0.01-1 microM), the relaxations induced by bradykinin and [des-Arg9]-bradykinin were inhibited concentration-dependently. 4. Two nitric oxide (NO) biosynthesis inhibitors NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and NG-nitro-L-arginine (L-NOARG, 100 microM) had no inhibitory effects on the relaxations induced by bradykinin and [des-Arg9]-bradykinin. Neither did the selective inhibitor of the soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM) inhibit the relaxations induced by bradykinin and [des-Arg9]-bradykinin. 5. Prostaglandin E2 (PGE2, 0.01-33 microM) caused concentration-dependent relaxation of the tracheal preparations precontracted with methacholine. Indomethacin (1 microM) and ODQ (10 microM) exerted no inhibitory effects on the relaxation induced by PGE2. 6. The NO-donor, sodium nitroprusside (SNP; 0.01-100 microM) also caused concentration-dependent relaxation of the tracheal preparations precontracted with methacholine. ODQ (0.1-1 microM) concentration-dependently inhibited the relaxation induced by SNP. 7. These data demonstrate that bradykinin and [des-Arg9]-bradykinin relax the mouse trachea precontracted with methacholine by the activation of bradykinin B2-receptors and B1-receptors, respectively. The stimulation of bradykinin receptors induces activation of the cyclo-oxygenase pathway, leading to the production of relaxing prostaglandins. The NO pathway is not involved in the bradykinin-induced relaxation. The relaxation caused by NO-donors in the mouse trachea is likely to be mediated via activation of soluble guanylate cyclase.

The effects of K+ channel inhibitors on the relaxations induced by flufenamic and tolfenamic acids and lemakalim were examined in guinea-pig isolated trachea precontracted with prostaglandin F2alpha (PGF2alpha, 1 microM). Flufenamic and tolfenamic acids (0.1-33 microM) and lemakalim (0.01-33 microM) relaxed guinea-pig trachea in a concentration-dependent manner. Tetraethylammonium (0.5-2 mM), a nonspecific inhibitor of K+ channels, inhibited the relaxations induced by flufenamic and tolfenamic acids without affecting lemakalim-induced relaxation. Charybdotoxin (ChTX, 33-100 nM), an inhibitor of the large Ca2+-activated K+ channels (BK(Ca)), also inhibited the relaxations induced by flufenamic and tolfenamic acids without affecting lemakalim-induced relaxation. Glipizide (3.3-33 microM), an inhibitor of the ATP-sensitive K+ channels (K(ATP)) inhibited lemakalim-induced relaxation without affecting those induced by flufenamic and tolfenamic acids. Our results indicate that the relaxations of guinea-pig isolated trachea by flufenamic and tolfenamic acids are due to activation of BK(Ca). The relaxant mechanism of flufenamic and tolfenamic acids thus differs from that of lemakalim, an activator of K(ATP).

The present study examined the effects of K + channel inhibitors on the basal tone and on KCl- or methacholine-induced contraction of the mouse-isolated trachea. Glibenclamide and iberiotoxin, procaine, quinine and tetraethylammonium did not induce any contraction of the indomethacin-treated mouse trachea. 4-Aminopyridine induced concentration-dependent contraction. This action of 4-aminopyridine was abolished by atropine and reduced by tetrodotoxin and nifedipine. Glibenclamide failed to modify KCl- or methacholine-induced contraction. Iberiotoxin and 4-aminopyridine potentiated KCl- and methacholine-induced contractions. Nifedipine, procaine, quinine and tetraethylammonium inhibited KCl- and methacholine-induced contractions. These data suggest that the closure of large Ca 2+ -dependent K + channels can potentiate KCl- and methacholine-induced contraction. The effects of 4-aminopyridine on the mouse trachea reflect chiefly activation of muscarinic receptors. Procaine, quinine and tetraethylammonium inhibit depolarization-induced and receptor-mediated contractions of the mouse-isolated trachea.

Recent studies have shown that increased intake of dietary sodium chloride produces blood pressure-independent increase in cardiac and renal mass even in young normotensive rats. With advancing age the harmful cardiovascular effects of increased dietary sodium are not so well known. In the present study the influence of advancing age on the cardiovascular effects of increased intake of sodium (control diet, 0.3% and high-sodium diet, 2.6% sodium in the chow) were examined in young and aged (3 and 18 months old, respectively, at the beginning of the experiment) male normotensive Wistar rats in a six-week study. Moreover, the potential role of renin-angiotensin system in ageing during normal and a high-sodium intake was studied using a pharmacological tool, angiotensin converting enzyme (ACE) inhibitor ramipril. Ageing did not significantly modify basal systolic blood pressure measured by the tail cuff method. A high intake of sodium chloride increased blood pressure significantly only in aged rats, while in young rats it increased renal weight. Left ventricular weight was not affected by high-sodium diet in either age group. The ACE inhibition during control diet lowered blood pressure and decreased left ventricular weight in young rats only and these effects were completely blocked by a high-sodium diet. The maximal vascular contraction force of mesenteric arterial rings to noradrenaline was decreased with ageing while endothelium-dependent and -independent relaxation responses were unaltered with ageing. The sensitivity to sodium nitroprusside was impaired by the high-sodium diet in young rats. In both age groups the urinary excretion of calcium was increased during the high-sodium diet. In conclusion, the increased intake of sodium produced different changes in cardiovascular function in normotensive rats depending on age. With advancing age, the sensitivity to sodium-induced increase in blood pressure was increased. In aged rats a high intake of dietary sodium elevated blood pressure, while in young rats it increased renal mass without increase in blood pressure. In both age groups sodium did not affect left ventricular hypertrophy. Both high-sodium intake and ageing attenuated or even abolished the cardiovascular effects of ACE inhibition.

Econazole, miconazole, SK&F 96365 and nifedipine inhibited Ca2+- and depolarization-induced and receptor-operated contraction of guinea-pig isolated trachea. Econazole, miconazole and SK&F 96365 inhibited histamine- and methacholine-induced tracheal contraction more than nifedipine. Nifedipine was more potent in inhibiting KCl-induced contraction. Nifedipine, salbutamol and theophylline, but not econazole, miconazole or SK&F 96365, relaxed KCl, histamine-, and methacholine-precontracted trachea. It appears that in the guinea-pig tracheal smooth muscle, econazole, miconazole and SK&F 96365 behave differently from nifedipine, theophylline and salbutamol. Econazole, miconazole and SK&F 96365 are thus introduced as novel antagonists of receptor-operated airway smooth muscle contraction.

Milk proteins have largely been considered as providing essential amino acids, but oligopeptides derived from milk proteins have been shown to possess biological functions. In vitro, opioid activity was first reported in bovine β-casein hydrolysate by Brantl et al. (1979). Precursors of biologically active peptides have been demonstrated in vivo after digestion of milk (Scanff et al. 1992). Peptides that inhibit platelet aggregation (Fiat et al. 1989), stimulate the immune system (Migliore-Samour et al. 1989), inhibit angiotensin I converting enzyme (Maruyama & Suzuki, 1982) and are involved in intestinal Ca solubilization and absorption (Sato et al. 1986) have also been isolated from bovine casein hydrolysates.Bioactive peptides from whey proteins and their physiological effects have received less attention than those from casein. Peptides with opiate-like activity include the lactorphins, residues 50–53 in bovine and human α-lactalbumin and 102–105 in bovine β-lactoglobulin (β-lg) (Chiba & Yoshikawa, 1986; Yoshikawa et al. 1986; Antila et al. 1991). Yamauchi (1992) has reported that a peptide derived from β-lg induced contraction of guinea pig ileum longitudinal muscle in the absence of electric stimulation and agonist. The fragment, containing residues 146–149 of β-lg (His–Ile–Arg–Leu), was called β-lactotensin.The purpose of this study was to determine whether β-lactotensin was released from bovine β-lg by in vitro proteolysis using different proteolytic enzymes. The pharmacological activity of this tetrapeptide was characterized in guinea pig ileum in vitro using a synthetic fragment.

Endogenously released nitric oxide (NO) in airways might contribute to physiological bronchodilation; induced production of NO might play a role in the pathogenesis of asthma, although it could also be a compensatory mechanism to other factors that cause bronchoconstriction or inflammation. To investigate the efficacy of NO donors on bronchial tone, the bronchorelaxing efficacies of NO donors, new experimental GEA compounds 3268 and 5145 (oxatriazole sulphonylamides) were compared with those of sodium nitroprusside and SIN-1 (3-morpholinosydnonimine) and to the standard β2-adrenergic agonist, salbutamol, in bronchi of guinea-pigs and rats in-vitro. Their relaxing effects were also studied in rat mesentery arteries to compare the selectivity for airways. The capacity of the NO donors to produce nitrites and nitrates was assayed by the Griess reaction. The novel NO donors GEA 3268 and GEA 5145 were more potent bronchorelaxing agents than the old NO donors sodium nitroprusside and SIN-1. In guinea-pig bronchi, however, salbutamol was most potent. In rat bronchi the GEA compounds induced the strongest relaxation effect when compared with the old NO donors or with salbutamol. The airway selectivity of the drugs studied decreased in the order of salbutamol, SIN-1, GEA 5145, GEA 3268, sodium nitroprusside. The nitrites and nitrates produced spontaneously did not correlate with the efficacy of the relaxants The results obtained suggest that NO is only partly responsible for the relaxation and the potency is dependent on the animal species and constricting agents used.

Objective: To evaluate the effect of transdermal estrogen for stress urinary incontinence in postmenopause. Study design: An open within patient, dose-finding study with transdermal 17-β-estradiol combined with cyclic medroxyprogesterone acetate was conducted over 9 months in 21 patients (mean age 57.3 years) suffering from urodynamically verified mild to moderate stress incontinence without detrusor instability. Results: Subjective improvement was noted in 16 out of 21 patients (76%). The dose level of 50 μg was better tolerated than 100 μg and sufficient enough to achieve continence. Conclusion: Transdermal estrogen therapy plays an adjuvant role in conservative therapy for mild to moderate stress urinary incontinence in postmenopausal women.

The majority of the data on nitric oxide (NO) in the central nervous system (CNS) relies on histochemical and immunohistochemical evidence concerning the distribution of the nitric oxide synthase (NOS), its inhibition by specific antagonists and its co-localization with the receptor enzyme guanylate cyclase (GC) in the same functional region. All three isoforms, endothelial (eNOS), neural (nNOS) and macrophage type inducible (iNOS), are of importance to the normal and pathological function of the CNS. In nNOS gene deleted mice eNOS seems to contribute to the maintenance of neuronal function. NO may contribute to synaptic plasticity as a retrograde mediator that is released by postsynaptic NMDA-receptor activation. Microglia contains membrane-bound inducible iNOS that may be important in host defence function. Glia and pericytes surrounding the blood vessels contain GC that is stimulated by NO released from endothelium and nerve endings. Excessive production of highly reactive NO may be responsible for the neurotoxicity mediated by NMDA receptors that contributes to the symptomatology of strokes and neurodegenerative diseases. Moreover, after initial stimulation by cytokines, large amounts of NO produced by iNOS in the microglia (brain-based macrophages) may cause cellular damage.

1. The influence of salt (sodium chloride; NaCl) (an additional 6% in the diet) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of ramipril was studied in stroke-prone spontaneously hypertensive rats in a 6-week study. The intake of sodium chloride was adjusted to the same level by adding the salt alternative at a 1.75 times higher amount than regular salt. 2. Salt produced a marked rise in blood pressure and induced cardiac hypertrophy and significant mortality, while the salt alternative neither increased blood pressure nor caused any mortality and produced less cardiac hypertrophy than salt. 3. Ramipril treatment at a daily dose of 3 mg kg-1 normalized blood pressure and prevented the development of cardiac hypertrophy of rats on control diet. These effects of ramipril were blocked by the addition of salt but were only slightly attenuated by the addition of the salt alternative. The mortality in the salt group was prevented by ramipril. 4. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Salt, but not the salt alternative, increased vascular contractile responses to noradrenaline. Ramipril treatment improved the arterial relaxation responses to acetylcholine and to sodium nitroprusside. The vascular relaxation enhancing effect of ramipril was blocked by salt but only slightly attenuated by the salt alternative. 5. Ramipril treatment did not significantly increase plasma renin activity in the presence or in the absence of salt supplementation. The salt alternative did not cause hyperkalaemia, either alone or in combination with ramipril treatment. 6. Both salt supplementations, irrespective of ramipril treatment, induced a six to eight fold increase in the urinary excretion of calcium. There was an expected 90 to 140% rise in the urinary excretion of magnesium and 200% rise in the urinary excretion of potassium in the salt alternative group. Salt also produced an approximately 50% increase in magnesuria.7. Our findings suggest that replacement of salt by the potassium-, magnesium- and L-lysine-enriched salt alternative improves the cardiovascular effects of ramipril. In the present study the beneficial effect was related to the increased intakes of potassium and/or magnesium and L-lysine from the salt alternative because the amount of sodium chloride was the same.

The possibility that mu-opioid-induced tachycardia and bradycardia could be mediated by different subtypes of the mu-receptor was studied in conscious Sprague-Dawley rats. The selective mu-receptor agonist dermorphin and its analog, TAPS (Tyr-D-Arg-Phe-sarcosine), a putative mu 1-receptor agonist, were given centrally. Tyr-D-Arg-Phe-sarcosine increased the heart rate, the response being inversely correlated to the dose (an increase of 71 +/- 22, 49 +/- 14 and 30 +/- 17 beats/min at doses of 0.3, 3 and 30 pmol, respectively). Dermorphin induced less clear changes in heart rate (maximum increase of 39 +/- 14 beats/min at the dose of 1 pmol). After treatment with the mu 1-selective antagonist naloxonazine (NAZ), TAPS 30 pmol and dermorphin 1 pmol decreased heart rate by -22 +/- 10 and -24 +/- 7 bpm, respectively. The bradycardiac effect of larger doses of dermorphin was potentiated by NAZ (from -25 +/- 8 to -97 +/- 22 bpm) but abolished by the non-selective antagonist naloxone. These data suggest that the high affinity mu 1-opioid receptors mediate tachycardic responses and mu 2-receptors mediate bradycardic responses.

The development of tachyphylaxis to the pressor, tachycardiac, ventilatory and smooth muscle effects of thyrotropin-releasing hormone (TRH) was studied. Subsequent administrations of increasing doses of TRH (0.1-1000 nmol/kg intracerebroventicularly), at 20 min. intervals in urethane-anesthetized rats dose-dependently increased the mean arterial blood pressure, heart rate and minute ventilation volume. At all doses the effect on mean arterial blood pressure was apparent at least 20 min. after each injection whereas at low doses (0.1-1 nmol/kg) the duration of the effects on heart rate or minute ventilation volume were shorter. The cardiorespiratory effects of TRH 10 nmol/kg intracerebroventricularly did not subside completely within an observation period of 1 hr. However, a repeated administration of TRH at 1 hr resulted in the levels of mean arterial blood pressure, heart rate and minute ventilation volume not statistically different from the peak levels of the first injection. While the cardiorespiratory effects of TRH were long-lasting, the TRH induced inhibition of the contractions of the rat duodenal smooth muscle lasted only 12-18 sec. The TRH-treated duodenal preparation responded normally to noradrenaline but remained unresponsive to further administrations of TRH until washed extensively. When the medium after cessation of the TRH response was transferred into another chamber with an untreated preparation, a full response was resulted. Inhibitors of TRH metabolism, bacitracin, EDTA and iodoacetamide, did not prolong nor enhance the response. Likewise, a stable TRH-analogue MK-771 did not produce any longer response than TRH. It is concluded that no tachyphylaxis was produced to the neurally mediated pressor, tachycardiac or ventilatory effects of TRH. However, the duodenal smooth muscle effect of TRH was attenuated due to rapid homologous tachyphylaxis not related to breakdown of TRH.

The formation of opioid peptides by in-vitro proteolysis of whey proteins was investigated. Bovine β-lactoglobulin (β-LG) or α-lactalbumin (α-LA) were predigested with pepsin and subsequently treated with either trypsin (Try) or trypsin+chymotrypsin (Try+Chy). For separation and identification of the peptides. HPLC chromatography, protein sequencing and amino acid analysis were used. Identified peptides were synthesized by Peninsula Laboratories Europe Ltd. UK. Binding to rat brain homogenates was tested against 3H-naloxone. The effects of the peptides on smooth muscle were tested in coaxially stimulated guinea pig ileum in vitro. Digestion of β-LG with pepsin plus Try, or Try+Chy yielded Tyr-Leu-Leu-Phe (β-lactorphin). Proteolysis of α-LA with pepsin alone produced Tyr-Gly-Leu-Phe (α-lactorphin) although a higher degree of hydrolysis was achieved by addition of Try. Among hydrolysates of whey proteins at least α-lactorphin exerted a weak but continuous opioid property both in terms of receptor binding and smooth muscle effects.

The biological activity of thyrotropin-releasing hormone (TRH) and its analogs 4(5)-I-Im-TRH and 2,4(5)-I2-Im-TRH was assessed by means of their effects on: 1) the mean arterial pressure (MAP), 2) heart rate (HR), 3) ventilation minute volume (MV), 4) contractility of the rat duodenum, and 5) concentrations of thyrotropin (TSH) or prolactin (PRL) in serum. Also their binding to TRH-receptors in brain homogenates was studied. In urethane-anesthetized rats TRH ICV increased MAP, HR and MV. 4(5)-I-Im-TRH was equally as active as TRH on HR and MV but a significant elevation in MAP was observed only at a dose 100-fold to that of TRH. However, the maximal responses of 4(5)-I-Im-TRH and TRH did not differ. In conscious rats, TRH 1A elevated MAP and HR but 4(5)-I-Im-TRH was active on MAP only. 2,4(5)-I2-Im-TRH was devoid of cardiorespiratory activity. TRH dose-dependently inhibited the contractions of the rat duodenum while the iodinated analogs lacked such an activity. To induce a significant release of TSH several hundred times more of 4(5)-I-Im-TRH and over 1000 times more of 2,4(5)-I2-Im-TRH were needed as compared to TRH. The iodoanalogs elevated PRL levels only at doses 2000-fold higher than those of TRH. The iodoanalogs displaced [3H][3-Me-His2]TRH [( 3H]MeTRH) from its binding sites at concentrations about 1000 times higher than those of TRH. Substitutions of the histidyl moiety of TRH in 4(5)-I-Im-TRH and 2,4(5)-I2-Im-TRH resulted in substantial loss of the endocrine activity. While the di-iodinated analog was practically devoid of any biological activity the monoiodinated analog exerted similar cardiorespiratory activity to that of TRH.

Background Impaired muscarinic receptor-mediated vasodilation is an important feature of early atherosclerosis. Earlier studies on apolipoprotein E-knockout mice (apoE-KO) mice suggested adverse effects of Chlamydia pneumoniae infection on the endothelial vasomotor responses of aortas to the muscarinic agonist methacholine. Using additional aorta samples the present study investigated the responses to bradykinin. Methods and Results ApoE-KO mice were repeatedly inoculated with either Chlamydia pneumoniae (C. pneumoniae) or saline. At 2, 6, and 10 weeks after the first inoculation, precontracted aorta rings from both groups were exposed to bradykinin in the absence and presence of L-NAME and diclofenac. In noninfected animals, the vasomotor responses to bradykinin were similar at all timepoints (p > 0.5). Compared with noninfected animals, the responses in infected animals tended to increase through the study period (p < 0.05 at 10 weeks). Although diclofenac and L-NAME had no effect in noninfected mice, they inhibited the responses to bradykinin in infected mice at 6 and, more markedly, 10 weeks (p < 0.05 for both). Conclusion Bradykinin stimulation of aorta endothelium from C. pneumoniae-infected apoE-KO animals appears to activate compensatory kinin receptor-related mechanisms that could involve nitric oxide and vasorelaxing prostanoids. Although the precise molecular mechanisms require further investigation, one could speculate that strategies increasing bradykinin availability might reverse the arterial dysfunction during chronic infectious disease.

Background: Coronary endothelial dysfunction contributes to the pathogenesis of acute coronary syndromes (ACSs). Acute Chlamydia pneumoniae infection has been epidemiologically associated with ACS. In this study, we investigated whether acute C. pneumoniae infection could alter the endothelial vasomotor function of porcine coronary vessels. Methods and results: Twenty pigs, 7–9 kg in weight, were inoculated intratracheally with C. pneumoniae (n=12) or saline (n=8), and investigated at 3 days (five infected/four non-infected) and 2 weeks (5+2 infected/four non-infected) after inoculation. The endothelium-dependent reactivity of coronary microcirculation was assessed at both time points by measuring peak coronary flow velocity (CFV) in response to bradykinin, before and after infusions with glutathione, an antioxidant, and Image-arginine, a substrate for nitric oxide synthase (NOS). CFV after bradykinin was significantly decreased in infected animals at both time points. At 2 weeks, both glutathione and Image-arginine significantly improved CFV after bradykinin. CFV after sodium nitroprusside (SNP) was similar in both groups. At 3 days, the relaxation responses of bradykinin-induced pre-contracted left anterior descending (LAD) coronary rings to bradykinin were significantly less in infected animals. NG-nitro-Image-arginine-methyl-ester, an NOS inhibitor, had significantly greater inhibitory effect on bradykinin-induced relaxation in infected animals. Plasma nitrate–nitrite and fibrinogen, and NOS activity from LAD coronary samples were significantly increased in infected animals. Conclusion: Acute C. pneumoniae infection causes endothelial dysfunction of both resistance and epicardial coronary vessels, and favours a pro-coagulant status. These effects could in part account for the epidemiologically suggested association between acute infection and ACS. (Less)

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

The aim of this study was to assess whether oral delivery and transdermal delivery of sequential combined hormone replacement therapy have similar effects on systemic blood pressure, as measured by 24-hour automated ambulatory recordings.Eighty-two healthy postmenopausal women, of whom 73 completed the study, were randomly assigned to start hormone replacement therapy with either orally (n = 38) or transdermally (n = 35) administered medication. Ambulatory blood pressure was recorded for a 24-hour period before the start of hormone replacement therapy and again 2 and 6 months later. Analysis of variance was used for data analysis.Hormone replacement therapy by both oral and transdermal routes was associated with slight but nonsignificant drops in mean 24-hour systolic and diastolic ambulatory blood pressure. Daytime systolic ambulatory blood pressure (mean +/- SE) fell significantly (P.05) and similarly at 2 months in the oral (3.8 +/- 0.2 mm Hg) and transdermal (4.0 +/- 0.3 mm Hg) treatment groups. The daytime ambulatory blood pressure remained significantly lower than baseline at 6 months in the oral treatment group (-3.6 +/- 0.3 mm Hg), whereas the fall at 6 months in the transdermal group (-3.1 +/- 0.3 mm Hg) was not significant. Mean daytime diastolic ambulatory blood pressure was reduced in both the oral (-1.8 +/- 0.8 mm Hg) and transdermal (-3.5 +/- 0.7 mm Hg; P.05) treatment groups at 2 months but not at 6 months. Nighttime ambulatory blood pressures in both groups remained unaffected by hormone replacement therapy.Sequential combined hormone replacement therapy delivered by both oral and transdermal routes caused significant falls in the daytime ambulatory blood pressure of normotensive postmenopausal women at 2 months of treatment. This fall persisted as long as 6 months of treatment in the oral treatment group but not in the transdermal treatment group.

PURPOSE: The aim of this study was to assess the usefulness of thermography in detecting the postoperative inflammatory reaction after third molar removal. PATIENTS AND METHODS: Thermographic images (NovaTherm; Novamedix Ltd, Hampshire, England) of both cheeks were obtained on the first and seventh postoperative days after removal of impacted mandibular third molars under local anesthesia in 30 patients (15 men, 15 women). The unoperated contralateral side served as a control. One of the following pretreatments was given immediately before the operation: diclofenac (Voltaren; Novartis, Espoo, Finland) 150 mg orally (rapid-release 50 mg and prolonged-release 100 mg, n = 15), diclofenac 100 mg orally (prolonged-release) and 50 mg intramuscularly (n = 11), or placebo (n = 4). RESULTS: The postoperative skin surface temperature on the operated side was significantly higher than that on the unoperated side. The thermal difference was 0.9 degrees C +/- 0.1 degrees C on the first postoperative day and declined significantly by the seventh day to 0.3 degrees C +/- 0.1 degrees C (both P < .001). The thermal difference in patients receiving diclofenac preoperatively was significantly smaller (0.8 degrees C +/- 0.1 degrees C at day 1 and 0.2 degrees C +/- 0.1 degrees C at day 7) than in patients receiving placebo (1.6 degrees C +/- 0.1 degrees C at day 1 and 0.8 degrees C +/- 0.3 degrees C at day 7, P < .001). However, with equal doses of diclofenac, the combination of rapid-release and prolonged-release tablets orally was more effective in reducing skin temperature than an orally administered prolonged-release tablet combined with intramuscular injection (P < .001). CONCLUSION: Thermography is a suitable method to measure the inflammatory reaction related to third molar removal. Thermal changes are significant and are decreased by the nonsteroidal anti-inflammatory drug diclofenac.

The goal of nitric oxide (NO)-based pharmacotherapy is to attain proper homeostasis of NO metabolism in the target tissue or tissues where the endogenous production of NO is either too weak or excessively increased.

The cardiovascular effects of intracerebroventricularly administered thyrotropin-releasing hormone (TRH) were studied in anesthetized rats in the presence of serotonin (5-HT) depletion induced by pretreatments with p -chloroamphetamine (PCA) or p -chlorophenylalanine (PCPA). After PCA the reduction of the whole brain 5-HT and 5-HIAA (5-hydroxy-indoleacetic acid) was 53% and 32% of control, respectively. PCPA reduced the brain 5-HT and 5-HIAA levels even to a greater extent, corresponding levels were 9% and 17% of control. TRH 1–100 nmol/kg increased dose dependently blood pressure and heart rate. PCPA pretreatment significantly attenuated the pressor effect and the tachycardia induced by TRH, whereas PCA did not modify the effects of TRH, which may be related to its weaker capacity to deplete 5-HT in TRH sensitive brain areas. These results suggest the involvement of the central serotonergic system in the TRH-induced cardiovascular stimulation.

Most of the modern non-sedating H1 receptor antagonists (antihistamines) penetrate the brain poorly, allowing the use of doses large enough to counteract allergic processes in peripheral tissues without important central effects. The antihistamines reviewed here are acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine. However, these drugs are not entirely free from central effects, and there are at least quantitative differences between them. Although psychomotor and sleep studies in healthy subjects in the laboratory may predict that an antihistamine does not cause drowsiness, the safety margin can be narrow enough to cause a central sedating effect during actual treatment. This might result from a patient's individual sensitivity, disease-induced sedation, or drug dosages that are for various reasons relatively or absolutely larger (patient's weight, poor response, reduced drug clearance, interactions). Mild to even moderate sedation is not necessarily a major nuisance, particularly if stimulants need be added to the regimen (e.g. in perennial rhinitis). Furthermore, patients can adjust doses themselves if needed. Sedating antihistamines are not needed for long-term itching, because glucocorticoids are indicated and more effective. It is wise to restrict or avoid using antihistamines (astemizole, terfenadine) that can cause cardiac dysrhythmias, because even severe cardiotoxicity can occur in certain pharmacokinetic drug-drug interactions. Histamine H1 receptor antagonists (antihistamines) are used in the treatment of allergic disorders. The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects causing dry mouth and blurred vision. Non-specific "quinidine-like" or local anaesthetic actions often led to cardiotoxicity in animals and man. Although such adverse effects varied from drug to drug, there was some degree of sedation with all old antihistamines. Non-sedating antihistamines have become available during the past 15 years. Some of them also have antiserotonin or other actions that oppose allergic inflammation, and they are not entirely free from sedative effects either. In small to moderate "clinical" concentrations they are competitive H1 receptor antagonists, although large concentrations of some of them exert non-competitive blockade. Daytime drowsiness and weakness are seldom really important, and they restrict patients' activities less than the old antihistamines. Some new antihistamines share with old antihistamines quinidine-like effects on the cardiac conducting tissues, and clinically significant interactions have raised the question of drug safety. This prodysrhythmic effect has also been briefly mentioned in comparisons of non-sedative H1 antihistamines.

Objectives: based on autopsy material from children this study investigated the possible relationship of clinically evident infection prior to death with intimal thickening of the coronary arteries. Background: viral infections are suggested to be associated with intimal thickening in the coronary arteries both in animals and man. Methods: the coronary arteries were examined in 175 autopsied children 0–15 years of age (median 7 days). Semi-serial cross sections of the coronary arteries were screened for maximal intimal thickening at 0.2 mm intervals. The length of the internal elastic lamina, the areas of arterial media and intima were measured from cross-sections. Irregular linings of the arteries were mathematically transformed to circles. The percentage of intimal and musculoelastic layer area to luminal area encircled by arterial media was calculated. Results: intimal thickening increased with age but was also associated with the presence of infectious disease at death. Already in the newborn children, who died shortly after the birth, the percentage of intimal and musculoelastic layer area to luminal area encircled by arterial media was big, maximally 55%. In the left coronary artery the mean percentages were 32 and 21% in the groups with viral and bacterial infections, respectively as compared to 16% in the group with no evidence of infection. Conclusion: infections in general and viral infections in particular, seem to be associated with intimal thickening, which may predispose coronary arteries to atherosclerosis. Atherogenesis might have a rapid dynamic component.

Objective: Oral postmenopausal hormone replacement therapy (HRT) decreases the risk of cardiovascular disorders, but the mechanisms of this protection are largely unknown. We compared the long-term effects of sequential oral HRT and transdermal HRT on vasodilatory nitric oxide and prostacyclin as well as vasoconstrictive endothelin-1 and thromboxane A 2 , all of which may be factors in the protective effect of HRT against cardiovascular disorders. Design: Prospective, randomized study. Setting: Department of Obstetrics and Gynecology at a university hospital. Patient(s): Fifty-two healthy postmenopausal female nonsmokers (n = 42) or smokers (n = 10) who had climacteric symptoms. Intervention(s): The women received either oral HRT (2 mg of estradiol on days 1–12, 2 mg of estradiol plus 1 mg of norethisterone acetate on days 13–22, and 1 mg of estradiol on days 23–28; n=21) or transdermal HRT (50 μg/d of estradiol on days 1–28 followed by 250 μg/d of norethisterone acetate on days 14–28; n=21) for 1 year. Ten female smokers received transdermal HRT for 1 year. Main Outcome Measure(s): Plasma levels of nitrate as an index of nitric oxide production, endothelin-1, and urinary output of the prostacyclin metabolite (2,3-dinor-6-keto-PGF 1α ) and that of the thromboxane A 2 metabolite (2,3-dinor-thromboxane B 2 ) were measured before and during the combined phases of the 2nd, 6th, and 12th treatment months. Result(s): Both regimens increased plasma estradiol levels and alleviated vasomotor symptoms. Neither regimen caused significant changes in nitrate, endothelin-1, prostacyclin, or thromboxane A 2 in nonsmoking women. Female smokers had significantly higher levels of endothelin-1, which were significantly reduced by transdermal HRT at 6 months of treatment. Conclusion(s): Nitric oxide, endothelin-1, prostacyclin, and thromboxane A 2 are not of primary importance in the protective effect of sequential oral HRT against cardiovascular disorders in otherwise healthy nonsmoking postmenopausal women. In this regard, transdermal HRT appears comparable to oral HRT. Postmenopausal female smokers have high levels of endothelin-1 that are reduced by transdermal HRT.

Relaxing effects of the nitric oxide donors GEA 3175 (3-aryl-substituted oxatriazole derivative), SIN-1 and sodium nitroprusside (SNP) were compared in the rat bronchial rings in vitro. In epithelium intact rings, after metacholine precontraction ED50 of GEA 3175 and SNP were similar (2 and 3.5 microM respectively) while the maximum effect of the former was bigger (92% and 54% respectively). SIN-1 was less potent (ED50 50 microMx, maximum 55%). In the absence of the epithelium the effect of GEA 3175 was attenuated, while that of SIN-1 or SNP were abolished. In the KCl precontracted rings the effects of all compounds were smaller than after metacholine precontraction. Removal of the epithelium did not alter the effects of GEA 3175 or SIN-1 but clearly increased that of SNP (change of EC50 from 10 to 0.7 microM).

Fifty patients undergoing a standard removal of an impacted lower third molar were given a single dose of 75 mg sodium diclofenac or saline (placebo) intravenously before operation, on a double-blind basis. Pain was measured postoperatively by means of a visual analogue scale hourly for the first 8 h and during the first and second days after operation. Administration of diclofenac resulted in greater pain relief than administration of placebo for the first 3 h after surgery, whereafter the treatments did not differ. The results suggest that intravenous preoperative diclofenac may be useful in some clinical situations but generally it probably offers little benefit over the corresponding oral treatment.

The efficacy of 40 mg of methylprednisolone given intravenously before operation in combination with orally administered rapid-release and sustained-release diclofenac preparations in preventing postoperative pain after third molar removal was studied. The administration of methylprednisolone and diclofenac resulted in greater pain relief than did administration of diclofenac alone.

Interactions of μ-opioid receptors with the benzodiazepine system were studied by examining the modulatory effects of flumazenil (a benzodiazepine antagonist) and alprazolam (a benzodiazepine agonist) on the respiratory effects of the opioid peptide dermorphin. Dermorphin, 1–30 nmol administered i.c.v., to conscious, unrestrained rats decreased ventilation rate (VR) and minute volume (MV) dose-dependently. The ventilatory depression was antagonized by naloxone and by the benzodiazepine antagonist flumazenil. The benzodiazepine alprazolam potentiated the respiratory inhibition of a small (1 nmol) dose of dermorphin but antagonized that of a higher dose (3 nmol). The results suggest that the benzodiazepine/GABA receptor complex modulates respiratory depression induced by central μ-receptor stimulation in the rat.

The modulation of cardioventilator effects of thyrotropin-releasing hormone (TRH) by histaminergic mechanisms was studied in anaesthetized rats pretreated with histamine receptor antagonists. TRH (1–10. nmol/kg) into the lateral cerebral ventricle dose-dependently elevated mean arterial pressure, heart rate and stimulated respiration. The respiratory stimulating effect of TRH remained unchanged after pretreatments with histamine H1-receptor antagonist diphenhydramine or H2-receptor antagonists cimetidine and ranitidine, while the TRH-induced hypertension and tachycardia were attenuated by cimetidine. This antagonism was not due to an interation between TRH and cimetidine at their central binding sites, since there was no displacement of [3H]MeTRH binding in the presence of cimetidine nor did TRH displace [3H]cimetidine in rat brain homogenates. Inability of diphenhydramine to modify the cardiovascular effects of TRH indicates that these effects are not due to histamine liberation, as cardiovascular stimulation after central administration of histamine is mainly mediated via H1-receptors. The antagonism of the cardiovascular responses to TRH by cimetidine was not due to blockade of H2-receptors, since another potent H2-receptor antagonist ranitidine was unable to affect the cardiovascular effects of TRH. Therefore, we suggest that cimetidine exerted antagonism of TRH by some non-specific action.

Respiratory interactions of μ opioid agonist heptapeptide dermorphin and kappa agonists MR-2034 and U-50,488, all injected i.c.v., were studied in conscious rats. Respiratory depression induced by dermorphin 1–10 nmol was antagonized by pretreatment with κ agonist MR-2034 (5 nmol) but not by the more selective κ agonist U-50,488 (20 nmol). κ antagonist norbinaltorphimine (nor-BNI, 2.5–10 nmol) abolished the effect of MR-2304 on dermorphin-induced respiratory depression. Low doses of dermorphin (10–30 pmol) induced respiratory stimulation which was not antagonized by κ agonists. The μ 1 receptor antagonist naloxonazine (10 mg/kg) prevented the respiratory stimulating effect of dermorphin.

Cardioventilstor responses were studied in anaesthetized rats after injections of TRH into either the lateral (i.c.v. lat) or the fourth (i.c.v. IV) cerebral ventricles. TRH induced a more rapid hypertensive effect i.c.v. IV than i.c.v. lat. Blocking of the cerebral aqueduct abolished the hypertensive and tachypnoeic effects of TRH i.c.v. lat but not those of TRH i.c.v. IV. It is concluded that TRH increased blood pressure and ventilation rate via brain stem structures close to the fourth ventricle.

In urethane-anaesthetized rats the administration of imidazole acetic acid (IAA), 34–272 μg per rat intracerebroventricularly (i.c.v.), induced a dose-related fall in blood pressure. Rolipram (ZK 62 711), a potent and selective inhibitor of cyclic AMP phosphodiesterase (cAMP-PDE), also lowered the blood pressure in a dose-dependent manner when administered at the doses of 1–64 μg per rat i.c.v. A subhypotensive dose of rolipram (0.25 μg per rat i.c.v.) did not change the hypotensive effect of IAA. Pretreatment of the rats with metiamide, 1.1. mg per rat i.c.v., shifted the dose-response curve for IAA significantly to the right. The present results make it unlikely that the central hypotensive effect of IAA could be due to the stimulation of cAMP-PDE by this agent. Central histamine H2-receptors may be involved in the hypotensive effect of IAA.

In urethane-anaesthetized rats clonidine was administered intravenously (i.v.), intra-cerebroventricularly (Lev.) or onto the surface of the area postrema which protrudes into the fourth cerebral ventricle. In each Instance clonidine induced a dose-dependent lowering of the blood pressure. The region of the area postrema appears to be the most sensitive site for the action of clonidine so far studied. In order to obtain similar blood pressure effects, approximately 8 times higher amounts were needed i.c.v., and about 80 times higher amounts i.v., than onto the surface of the area postrema. A pretreatment of the rats with the specific histamine H2-receptor blocking drug, metiamide (4.5 μmoles/rat i.c.v.) shifted the dose-response curve of clonidine (i.c.v.) to the right. The results suggest that clonidine exerts its hypotensive effect in the rat via a stimulation of histamine H2-receptors in, or in the vicinity of, the area postrema.