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PubMed1998

Reversal of cerebral vasospasm using an intrathecally administered nitric oxide donor.

OBJECT: Intrathecal bolus administration of (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen++ +-1-ium-1,2-diolate (DETA/NO), a long half-life diazeniumdiolate-class nitric oxide (NO) donor, was evaluated for safety and efficacy in the treatment of delayed cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH). METHODS: The baseline basilar artery (BA) diameter of 25 dogs was measured with the aid of angiography on Day 0. Vasospasm was then induced by intracisternal injection of autologous arterial blood on Days 0 and 2. Repeated arteriography on Day 7 revealed an average BA diameter of 58% of baseline. Each dog was then randomized to one of four groups: a pathology control group (SAH only, four animals); a treatment control group (SAH plus 2 micromol of the inactive drug carrier DETA, eight animals); a low-dose treatment group (SAH plus 0.2 micromol DETA/NO, six animals); or a high-dose treatment group (SAH plus 2 micromol DETA/NO, six animals). The drugs were administered in a 2-ml intrathecal bolus via the cisterna magna. Arterial caliber was monitored by angiography over the subsequent 4 hours. A 2-micromol dose of the drug was then given and serial arteriography continued for an additional hour to screen for tachyphylaxis. Intracranial pressure and respiratory and hemodynamic parameters were continuously monitored. Histopathological analyses of the animals' brains were performed after the dogs were killed on Day 8. The drug DETA/NO produced reversal of vasospasm in a dose-dependent fashion that roughly followed a double exponential time course. Doses of 2 micromol DETA/NO resulted in restoration of the angiographically monitored BA diameter to the prevasospasm size at 1.5 hours posttreatment, and this was sustained at 88% of baseline at 4 hours (p < 0.01, independent samples t-test). By contrast, the treatment control group remained on average at 54% of baseline diameter. The low-dose treatment group achieved only partial and more transitory relaxation. Histopathological analyses showed findings consistent with chronic SAH but did not demonstrate any toxicity associated with the NO donor. No adverse physiological changes were seen. CONCLUSIONS: This study indicates that long-acting NO donors are potentially useful as agents to restore circulation in patients suffering from cerebral vasospasm.

Analysis of Variance↗
PubMed1999

Functional evidence for an angiotensin IV receptor in rat resistance arteries.

To distinguish between the different effects of angiotensin IV (Ang IV) on resistance artery vasoreactivity, freshly isolated rat mesenteric arteries were perfused and the changes in their diameter were recorded under various conditions. Ang IV exerted vasoconstrictor effects on both normal vessels and vessels that had been precontracted with phenylephrine or serotonin. This effect was abolished by losartan or candesartan cilexetil, two type 1 angiotensin receptor antagonists, but not by PD 123319, a type 2 angiotensin receptor antagonist. No tachyphylaxis was observed for the vasoconstrictor effect of Ang IV. N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, had no effect on Ang IV-induced vasoconstriction, whereas indomethacin, a cyclooxygenase inhibitor that was inactive by itself, influenced Ang IV-induced vasoconstriction, suggesting that Ang IV could stimulate the release of prostaglandins. Treatment of preconstricted vessels by candesartan cilexetil unraveled a vasodilator effect of Ang IV that was abolished by PD 123319, a type 2 angiotensin receptor antagonist. Unexpectedly, Ang IV still produced a vasoconstrictor effect on normal or preconstricted vessels after blockade of both type 1 and type 2 angiotensin receptors. Taken together, these results show that Ang IV influences resistance artery vasoreactivity via different mechanisms, one of which implicates a functionally active type 4 angiotensin receptor.

Animals↗
PubMed1975

[Dose-response relationship of repeated injections of pentagastrin on the vagally innervated rat stomach in perfusion experiments].

In the perfusion model under urethane anesthesia Wistar rats were two times injected pentagastrin subcutaneously in a distance of 150 minutes in dose rates of 50, 100, 150, 200, 250 and 300 microgram/kg b. w. The results may be summarized as follows: 1. The dose of 200 microgram/kg b. w. of pentagastrin produced the maximal answer. Higher doses showed a diminished acid secretion. 2. The diminished effect of higher doses of gastrin may be caused by a hypothetical inhibitor which may be more effective after truncal vagotomy. 3. The repeated injection of pentagastrin did not show a significant difference of the answer. The second injection was given after the acid secretion has returned to the basal level. No tachyphylaxy was seen under these conditions.

Animals↗
PubMedDate not supplied

[Clinical use of nitroglycerin as an hypotensive agent during general anesthesia (author's transl)].

Nitroglycerine has a direct vasodilating action on both venous and arterial smooth muscle fibers. On account of this, it has been used as hypotensive agent, in aqueous solution, on 22 surgical patients, 10 of them in neurosurgery. The total doses used were 0.76 +/- 0.12 mg/kg during 94 +/- 30 minutes (rate = 8.1 microgram/kg/min). Nitroglycerine induces a rapid onset of hypotension (3 to 4 min), spontaneously reversible in 27 +/- 8 minutes after the arrest of the infusion. The mean drop in mean arterial blood pressure achieved has been 34 p. cent. It is accompanied by a 67 +/- 9 p. cent fall of filling pressures and a fall 13 +/- 4 p. cent of cardiac index, without modification of the heart rate. Tachyphylaxis was noted 15 +/- 6 minutes following nitroglycerine infusion at rate lower than 2 microgram/kg/min, but not when the rate was above 10 microgram/kg/min. Therefore, if the drug is used to achieve controlled hypotension, high doses are necessary. No signs of toxicity were noted. In 4 cases, other hypotensive agents had been used to bring the mean arterial blood pressure below 50 Torr, which could not be achieved with nitroglycerine alone.

Adolescent↗
PubMed1979

Platelet aggregation evoked in vitro and in vivo by phosphatidic acids and lysoderivatives: identity with substances in aged serum (DAS).

In serum incubated at 36 degrees C for 18-24 hours a factor (DAS) develops which on intravenous injection into cats evokes platelet aggregation followed by an increase in pulmonary vascular resistance (PVR). This change in PVR is mediated via the platelets since it significantly correlates with the preinjection platelet count. There is evidence that phosphatidic acids (PA) and lysophosphatidic acids (LPA) are the active components of DAS. Investigations performed on platelet-rich plasma from man, cat, pig, dog, rabbit, guinea pig, and rat demonstrate that only human and feline platelets exposed to PA or to LPA are aggregated. Feline platelets are more sensitive to either compound than are the platelets from men; however, human platelets exhibit two exceptional properties, a) the sensitivity rapidly declines with time, b) pretreatment with subthreshold concentrations of LPA or PA induces a specific tachyphylaxis.

Adenosine Diphosphate↗
PubMed2001

[Properties of peroxynitrite-induced relaxation in rabbit pulmonary artery in vitro].

Vasodilatory properties of exogenous peroxynitrite (ONOO(-)) and effects of endothelial cells on ONOO(-) induced relaxation were investigated in isolated rabbit pulmonary arterial rings (PARs). In pre-contracted PARs, ONOO(-) gave rise to vasodilation in a dose-dependent manner, which was significantly higher than that of decomposed ONOO-. In contrast, relaxation of PARs to ONOO(-) was lower, as compared with sodium nitroprusside (SNP) or acetylcholine(ACh). ONOO(-) induced more significant relaxation in denuded endothelial PARs than in intact endothelial PARs. Relaxation of PARs to repetitively administered ONOO(-) appeared progressively decreased. Under this experimental condition, relaxation of PARs to ACh remained unchanged after administrating ONOO(-). These results suggest that ONOO(-) causes weak relaxation in pulmonary artery, which is down regulated by endothelium and is of tachyphylaxis.

Animals↗
PubMed2003

Organic nitrate tolerance and endothelial dysfunction: role of folate therapy.

Tolerance to organic nitrates has been demonstrated in patients with acute coronary syndromes following continuous, long-term therapy, and has been shown to occur within 24 to 48 h after administration of a nitrate preparation. Dosing schedules that include a nitrate-free period often fail to ameliorate the development of nitrate tolerance, and, in fact, can result in an increase in rebound ischemia. Several mechanisms have been suggested to explain the phenomenon of nitrate tolerance, notably, nitrate-mediated depletion of intracellular thiols, and enhanced reactive oxygen species formation. Recently, increased superoxide production, owing to the un-coupling of the endothelial isoform of nitric oxide synthase (eNOS) and/or increased NAD(P)H oxidase activity, has been implicated in the development of nitrate tolerance. Based on these observations, strategies to overcome tachyphylaxis to nitrates have been designed to modulate the production of reactive oxygen species. Folic acid and its derivatives have been shown to prevent nitrate tolerance by preventing eNOS uncoupling, and, thereby, eNOS-mediated superoxide production resulting in improved endothelial function. Folic acid, which has a benign side-effect profile, may, therefore, be a simple pharmacological intervention to prevent nitrate tolerance and may have broad application in the treatment of atherothrombotic vascular disease.

Animals↗
PubMed1992

Nitric oxide and endothelin-1 are important regulators of human ophthalmic artery.

The vascular endothelial cells have the ability to modulate local vascular tone by releasing relaxing factors such as nitric oxide or the vasoconstrictor peptide endothelin-1. Although this regulatory system is found in all vertebrates, there is a great heterogeneity in the release of these endothelium-derived substances, from one organ to an other, between large and small vessels, and between different species. Therefore, observations made in certain vascular beds or animals do not necessarily apply to human ophthalmic circulation. The present study was designed to investigate endothelial mediators in the human ophthalmic artery. The results show that in the human ophthalmic artery, nitric oxide is released under basal conditions and that its production can be markedly stimulated by bradykinin, acetylcholine, and particularly histamine, which cause profound vascular relaxation. In contrast, endothelin-1 evoked potent contractions, which were unaffected by the calcium antagonist nifedipine. However, upon re-exposure of the blood vessels to the peptide, marked tachyphylaxis occurred. These findings demonstrate that in the human ophthalmic artery, endothelium-derived nitric oxide and endothelin are very potent modulators of vascular tone, suggesting that they play an important role in the regulation of local blood flow in the eye. Hence, endothelium dysfunction may represent a new pathogenetic mechanism in disease states associated with altered blood flow to the eye, such as diabetes, hypertension, and some forms of low-tension glaucoma.

Acetylcholine↗
PubMed1991

The deficiencies of current medical therapy for the management of angina pectoris.

The prime management need in angina pectoris is to abolish or to minimize pain. Nitrates, calcium antagonists and beta-blockers are indicated for this purpose but they are not a complete answer to the problem. Selection of therapy for individual patients is not guided scientifically and, at present, treatment of angina follows general protocols rather than a personalized approach based on the underlying patho-anatomy and physiology. Medical therapy offers palliation of the disease rather than a cure, although recent evidence raises possibilities that some anti-anginal therapy, notably the calcium antagonists, may favourably affect disease progression. Tachyphylaxis, dosing, unwanted effects, and optimal sequences and combinations of medical therapy are important clinical problems about which remarkably little is known. The greatest deficiency of current medical therapy, however, is that, despite the amelioration of angina, beneficial effects on mortality have not been established. Thus, for the foreseeable future non-pharmacological therapy in the form of surgery or angioplasty will dominate management of high-risk anginal patients. At present, it is only in unstable angina that there is evidence of prognostic benefit from medical therapy with aspirin and anticoagulants. In more stable forms of angina, medical versus surgical comparisons reflect 'old' drugs and strategies. The prospects of reducing death and infarction by medical therapy in anginal patients should be re-examined.

Adrenergic beta-Antagonists↗
PubMed1991

Histamine induces endothelium-dependent relaxation of bovine retinal arteries.

The effect of histamine on bovine isolated retinal small arteries (internal diameter, approximately 240 microns) was studied. Histamine induced a concentration-dependent relaxation in 43 of 53 vessels. The histamine-induced relaxation involves primarily activation of H1-receptors, with H2-receptors also affected as evidenced by the effect of selective histamine-receptor agonists and antagonists. The histamine-induced relaxation was dependent on the endothelium and seem to involve release of both endothelium-derived relaxing factor (EDRF) and a product which was inhibited by indomethacin, probably prostaglandin I2 (prostacyclin). The development of tachyphylaxis to the action of histamine seemed to rely on desensitization of the vascular smooth muscle cells to the relaxing effect of EDRF.

Acetylcholine↗
PubMed1990

Factors determining whether cocaine will potentiate the cardiac effects of neurally released norepinephrine.

The purpose of the present study was to re-evaluate the effects of cocaine on cardiac responses elicited by sympathetic nerve stimulation. Cats anesthetized with pentobarbital and subjected to spinal cord transection were used. Control heart rate increases were obtained to submaximal stimulation of postganglionic accelerator nerves, before and after i.v. bolus doses of cocaine ranging from 0.0625 to 2.0 mg/kg. Maximal potentiation of heart rate increases elicited by nerve stimulation were observed with 0.25 mg/kg. In precocaine controls, stimulation increased sinus rate by 31 +/- beats/min; 30 sec to 1 min after cocaine (0.25 mg/kg), stimulation increased sinus rate by 55 +/- beats/min. Maximal potentiation (80 +/- 10%) was observed at 30 sec to 1 min after cocaine administration, and was usually over by 45 to 60 min later. Cocaine was repeated twice (0.25 mg/kg i.v.) at hourly intervals and the magnitude of potentiation was only 19 +/- 6 and 24 +/- 4%, respectively, indicating that tachyphylaxis had developed toward cocaine's potentiating effect. Dose-response studies indicated that as little as 0.0625 mg/kg of cocaine can potentiate heart rate increases elicited by sympathetic nerve stimulation. Doubling the dose to 0.125 mg/kg, and again to 0.25 mg/kg, resulted in a linear dose-related increase in the magnitude of potentiation. However, doubling the dose again to 0.5 mg/kg and increasing this dose by 4-fold to 2 mg/kg did not result in additional potentiation. Indeed, there was a significant drop-off in the magnitude of potentiation to nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Histamine and methacholine aerosol bronchial challenge in awake guinea pigs.

Cardiopulmonary responses to histamine and methacholine aerosol challenge were examined and compared in unanesthetized spontaneously breathing guinea pigs. All animals had surgically implanted intrapleural catheters and some had arterial or right heart catheters as well. Animals were placed in plethysmographs and exposed to ascending doses of aerosolized agonists. The provocative dose, i.e., the dose that caused a clear bronchospastic response, was defined as the concentration that increased intrapleural pressure to at least 20 cm H2O. Results showed that bronchospasm was characterized further by decreases in dynamic lung compliance and arterial PO2 and an increase in airway resistance. The accumulation of trapped gas in the lung, after challenge, measured in the excised collapsed lung correlated with the increase in intrapleural pressure and with the fall in lung compliance. Male guinea pigs between 3- and 15-weeks of age did not vary in sensitivity to histamine. Methacholine and histamine were equipotent and produced similar responses. Tachyphylaxis was not demonstrated for either compound. In addition, the provocative dose for the drugs remained stable on a day-to-day basis. These results offer insight into the nature of the bronchospastic response in guinea pigs and provide new data on response to methacholine.

Aerosols↗
PubMed1985

On the role of substance P and serotonin in the pyloric motor control. An experimental study in cat and rat.

Vagal nerve stimulation caused a release of substance P (SP) and serotonin (5-HT) into the feline portal circulation. Both substances are gut spasmogens and were demonstrated in gut nerves by immunocytochemistry. In anesthetized cats gastric and pyloric motility were studied simultaneously at stimulation with SP or 5-HT via the splenic artery or at stimulation of the extrinsic nerves to evaluate their role in the motor control of these regions. The vagally induced pyloric contraction was noncholinergic and nonadrenergic but sensitive to hexamethonium in contrast to the cholinergic gastric contraction, which was resistant to ganglionic blockade. Splanchnic nerve stimulation caused relaxatory gastropyloric responses; the gastric relaxation was sensitive to adrenergic or ganglionic blockade in contrast to the pyloric relaxation. Infrequent contractile responses were seen, which were antagonized by atropine. Injection of SP via the splenic artery elicited contractile gastropyloric responses, which were sensitive to atropine and an antagonistic SP-analogue (SPA) but resistant to hexamethonium, indicating SP activating a final cholinergic neuron. The vagally induced pyloric contraction was resistant to atropine but sensitive to SPA and hexamethonium, indicating involvement of SP in the activation of preganglionic neurons as well. Involvement of SP in a vagal afferent mechanism is possible, since heat activation of the distal end of the divided vagal nerve induced a gastric contraction, sensitive to atropine and SPA but not to ganglionic blockade, indicating antidromic activation of SP afferents which via axon collaterals excite cholinergic neurons. A regional difference between stomach and pylorus was suggested by the different motor responses after pharmacological blockade, heat-activation or i.a. injection of capsaicin. The contractile pyloric responses to 5-HT were antagonized by peripheral blockade of 5-HT2 receptors. However, such blockade did not influence the motor responses to extrinsic nerve stimulation, suggesting that 5-HT is not essential for the mediation of these responses. The contractile responses to SP or 5-HT were studied in vitro in antral and pyloric strips from the rat. These responses were antagonized by SPA or SP tachyphylaxis and peripheral blockade of 5-HT2 receptors respectively. The responses were not reduced by tetrodotoxin, indicating main activation of muscular receptors. However, the contractile responses were reduced by atropine or hexamethonium, except the SP-induced pyloric contraction, which was atropine-sensitive but hexamethonium-resistant.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

The sensitivity of uremic and normal human skin to histamine.

Cutaneous reactions induced by intradermal histamine injection were studied in uremic patients with and without pruritus who were undergoing maintenance hemodialysis and also in healthy subjects. Flare reactions were significantly smaller in both groups of patients than in controls. However, the itch responses following histamine injection were greater in patients with pruritus than in non-pruritic patients and healthy subjects, indicating an augmented sensitivity to pruritogens in these patients. The development of histamine tachyphylaxis was demonstrated in healthy human skin. After repeated histamine injections at intervals of 90 min, both itch and flare responses decreased rapidly. A similar decline in histamine reactivity occurred when the interval between injections was extended to 24 h. The phenomenon of histamine tolerance was confirmed in 2 uremic patients.

Adult↗
PubMed1989

[Beta-2 adrenergic stimulants in the treatment of asthma: myths and realities].

In this review paper the authors describe the reasons, sometimes complex, which have given birth to such myths as the abuse of beta 2-stimulants generating status asthmaticus, or patients developing clinical tachyphylaxis to this type of drug. While there is no solid ground to believe that beta 2-stimulants can be blamed for the overmortality due to asthma, and while the indications of beta 2-stimulants delivered by metered-dose aerosols can be extended to chronic asthma, it is still necessary to apply certain safety rules when these drugs are inhaled in high doses or given parenterally. Some patients must be encouraged to use inhaled beta 2-stimulants prophylactically, sometimes combined with cromolyn or inhaled corticosteroids, but these patients, their relatives and their doctor should be taught to evaluate lung function by means of a peak-flow meter. A lack of response to beta 2-stimulants must be taken as a warning that systemic corticosteroids and in some cases admission to hospital are needed.

Adrenal Cortex Hormones↗
PubMed1989

Reactions of isolated rat aorta to X-irradiation.

The reaction of isolated helical strips of rat aorta to X-irradiation was studied: X-rays (50 kV) induced a reproducible, reversible contractile response at threshold doses of 2.5 Gy (60 Gy/min) and 10 Gy (30 Gy/min). After repeated irradiation with the same doses at equal time intervals and constant dose-rate (for example 50 Gy every 15 min, dose-rate 60 Gy/min) the contractile response was progressively diminished, i.e. a tachyphylaxis appeared. The preparations still reacted even after total doses over 1000 Gy. The X-ray induced contractile responses were dose- and dose-rate dependent. Quantitative analysis indicated no essential differences in the radiation-induced contractile response when recorded under isometric or isotonic conditions. After hypothermia (20 degrees C) or hyperthermia (42 degrees C) no visible radiation response could be induced. Part of the aortic strips were spontaneously active: X-ray doses of 5 to 10 Gy stimulated, while doses of 100 to 200 Gy inhibited or blocked the spontaneous phasic activity. A comparison between the immediate X-ray reaction of vascular and non-vascular smooth muscle preparations is given. Participation of cholinergic and adrenergic mechanisms in the X-ray induced contractions of rat aorta seems to be ruled out, because the blocking agents atropine, phentolamine, and bretylium had no effect.

Animals↗
PubMed1985

[Role of adrenergic beta receptor partial agonists in left ventricular failure of ischemic origin. Value of xamoterol (ICI 118,587, Corwin)].

The ideal sympathomimetic derivative should possess the positive inotropic and relaxing effects of catecholamines whilst remaining free of their side-effects. Theoretically, such properties could be present in beta 1-adrenoceptor partial agonists. Xamoterol (ICI 118,587, Corwin; ISA 43 p. 100) seems to be the most promising beta 1 partial agonist. The aim of the study was to determine if the beneficial effects of Xamoterol were maintained during long term administration. Xamoterol (200 mg twice dialy) was administered to 14 patients with anterior myocardial infarction and moderate heart failure (class II-III NYHA). After 3 months' therapy, left ventricular function improved as indicated by reduction in left ventricular (LV) end-diastolic pressure (23 +/- 5 to 16 +/- 5 mm Hg; P less than 0.0005), LV end-diastolic volume (153 to 140 ml/m2; P less than 0.05) and in LV end-systolic volume especially in 11 patients with a control end-systolic volume less than 100 ml/m2 (- 15 p. 100; P less than 0.05). LV inotropic state was also enhanced as indicated by 21 p. 100 increases in EMax, the maximal LV pressure/volume ratio (P less than 0.02) and 20 p. 100 increases in the ratio end-systolic stress/ end-systolic volume (P less than 0.02). Myocardial oxygen consumption was unchanged, global lactate extraction fraction increased from 20 +/- 18 to 33 +/- 14 p. 100 (P less than 0.05) and LV alanine release was reduced (-1.7 to -0.2 muMol/min; P less than 0.05). The rate of LV pressure fall accelerated from 57 to 52 ms (P less than 0.05) and the mean diastolic wall stress was reduced by 35 p. 100 (P less than 0.05), reflecting the improvement in LV relaxation and diastolic function. Thus, the beneficial effects of Xamoterol were maintained after prolonged therapy particularly in patients with class II-III heart failure; patients in class IV benefited less from this therapy. No tachyphylaxis or side-effects were observed.

Administration, Oral↗
PubMedDate not supplied

Some fundamental points concerning the clinical aspects of desensitization.

Continued exposure of target cells to a hormonal agonist frequently leads to a blunted response to that agonist. This process has been termed desensitization, refractoriness, tolerance or tachyphylaxis. The receptor involved in case of beta-sympathomimetics is the beta-adrenergic receptor. When the clinical aspects of beta-adrenergic receptor desensitization are considered, a number of points need serious attention: 1) the route of administration of the drug and the concentration of the drug reached at the receptor site; 2) other factors which may cause reduced responsiveness of the beta-adrenergic receptor besides beta-sympathomimetics and interfere with this process; 3) the different cell-types which are studied and thought to be representative for processes taking place at lung tissue level; 4) the in vivo parameter(s) chosen to describe desensitization; 5) the difference between normal and asthmatic subjects; 6) the mechanism behind desensitization. The paper concerns a review of these points. Since the clinical findings with respect to the induction of desensitization by beta-sympathomimetics are rather controversial, the therapeutic advice should be: use it with caution.

Adenylyl Cyclases↗