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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cerebral vasodilator response induced by topical nitroglycerin and nitroprusside was examined in cats equipped with cranial windows for the observation of the cerebral microcirculation. In cats subjected to chronic unilateral trigeminal ganglionectomy, the vasodilator responses to nitroprusside and nitroglycerin were markedly depressed on the denervated side. Application of a selective calcitonin gene-related peptide (CGRP) antagonist [CGRP(8-37)] on the innervated side reduced the response to nitrodilators to the same extent as seen on the denervated side. The vasodilator response to acetylcholine was unaffected by trigeminal ganglionectomy. CGRP(8-37) almost abolished the vasodilator response to nitroglycerin and sodium nitroprusside and to CGRP, but did not affect the response to adenosine or to adenosine diphosphate. Pretreatment with LY83583, a drug that lowers cyclic GMP levels, diminished the vasodilation to CGRP and to nitroprusside but not to adenosine. We conclude that the nitrovasodilators activate sensory fibers to release CGRP, which in turn relaxes cerebral vascular smooth muscle by activating guanylate cyclase. Hence, nitrovasodilators possess a novel mechanism of action within the cephalic circulation which may explain both the occurrence of vasodilation and headache.
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PMID:Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. 157 43

The rationale for intermittent nitrate therapy is based on the pathophysiology of nitroglycerin tolerance and the diurnal pattern of symptoms encountered in patients with chronic stable angina. Nitrate tolerance was first observed as tolerance to headache in industrial toxicology. When long-acting nitrates for chronic stable angina became available, similar tolerance was observed but not thought to indicate tolerance to a haemodynamic or therapeutic effect. Subsequently, Needleman and coworkers (J Pharmacol Exp Ther 1973; 187: 324) defined in vitro the phenomenology of vascular smooth muscle tolerance to nitroglycerin-induced relaxation and reversibility was demonstrated. More recently, a potential molecular explanation for nitrate tolerance has been proposed: sulfhydryl group depletion in smooth muscle cells resulting in reduced formation of S-nitrosothiols on nitrate exposure with resultant reduced activation of cyclic GMP. In vivo, other mechanisms, including fluid retention and neurohumoral responses to vasodilation may also be important. The first demonstration that nitrate tolerance affected the therapeutic efficacy of long-acting nitrates was reported by Parker and coworkers in 1982 (Circulation 1987; 76: 572-6). This landmark study was not given much credence at the time because it appeared to be in conflict with earlier reports. However, in the past 6 years development of tolerance has been demonstrated with a variety of oral nitrates, transdermal nitroglycerin and intravenous nitroglycerin. When plasma concentrations are held constant, tolerance to antianginal effects is demonstrable within 24h, but varies markedly in severity from individual to individual.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intermittent nitrate therapy in angina pectoris. 250 Oct 96

Nitrates are old drugs, introduced into medical treatment more than 100 years ago, initially as a homeopathic remedy against headache (1850), and only later against angina pectoris (1867). Their typical hemodynamic, antiischemic effects were described in man in the 1950s and 1960s. They include: a reduction in venous return, lowering of the abnormally increased left ventricular enddiastolic pressure during ischemia, a decrease in left ventricular systolic wall stress, and changes in left ventricular geometry resulting in a decrease of myocardial oxygen consumption. The vasodilatory effect on large epicardial coronary arteries, especially on eccentric stenoses through relaxation of vascular smooth muscle tone was described even more recently (1980). This effect proved to be of considerable clinical importance both in angina at rest, that is during a primary increase in vasomotor tone (coronary artery spasm) as well as in angina provoked by exercise, where the increase in vasomotor tone and in the degree of stenosis is often due to a rise in alpha-sympathetic tone. The relaxing effect on the large coronary arteries is regarded as additive to the one on venous tone. The real clinical importance of nitrates became, however, evident only in the last decade with the discovery of EDRF, the so-called endothelial-derived relaxing factor, an endogenous compound of endothelial origin at least partly consisting of nitrous oxide and therefore, like nitrates, it exerts its effect through the stimulation of cGMP. The tendency for coronary arteries to constrict in presence of atherosclerosis is explained by the lack of EDRF, especially in the region of atherosclerotic plaques where the endothelium is often absent or has lost its endocrine function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The mechanism of action of nitrates, 1988 status]. 251 90

To assess the effects of nitroglycerin ointment (NTG) on hemodynamics and autonomic nervous activity, 17 normal subjects and 13 patients with severe congestive heart failure (CHF) were studied. In 12 normal subjects, NTG significantly increased the plasma norepinephrine concentration in association with a slight reduction in systolic blood pressure and a slight increase in heart rate, plasma cyclic adenosine monophosphate (cyclic AMP) concentration, and renin activity at 1 hr. All normal subjects complained of headache or felt heavy-headed after NTG administration. In the 13 patients with CHF, NTG significantly decreased plasma norepinephrine and cyclic AMP concentrations in association with a significant increase in the cardiac index and a significant reduction in pulmonary arterial diastolic pressure, systemic vascular resistance, systolic blood pressure, and heart rate. The effects occurred at 30 min after NTG administration and continued for 3 hr. Relief from dyspnea or orthopnea in patients with CHF was observed. NTG did not change the plasma cyclic GMP concentration in normal subjects and patients with CHF. We conclude that in patients with CHF, NTG decreases the enhanced sympathetic nervous activity, with concomitant beneficial effects on hemodynamics and improvement of clinical symptoms. In contrast, NTG increases sympathetic nervous activity in normal subjects.
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PMID:Effects of nitroglycerin ointment on plasma norepinephrine and cyclic nucleotides in congestive heart failure. 616 16

The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run-in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug.
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PMID:Antihypertensive effects of the neutral endopeptidase inhibitor SCH 42495 in essential hypertension. 784 19

Nitric oxide (NO) in platelets has been proposed as a promising tool for studying NO variations in migraine. In the present research the platelet response to collagen and the basal and collagen-induced production of NO and cGMP in platelet cytosol were assessed in migraine patients (25 with aura and 35 without aura) both interictally and ictally, and compared with the same parameters in 30 age-matched control subjects. A reduced responsiveness to collagen was found in migraine patients, particularly those with aura, and this was more marked during attacks (ANOVA interictal periods: p < 0.01, attacks: p < 0.02) The basal and collagen-stimulated production of NO and cGMP in the platelet cytosol was significantly higher in migraine patients with aura assessed in interictal periods than in control subjects, and this production was further increased during attacks (interictal period: NO ANOVA: p < 0.001, ictal period: p < 0.01; cGMP: interictal period p < 0.01, ictal period: p < 0.02). The increase in platelet NO and cGMP production was also evident, though to a lesser extent, in migraine patients without aura. The present research supports the hypothesis of an activation of the L-arginine/NO pathway in migraine patients, especially those with aura, and confirms the findings of a previous study of increased levels of L-arginine in platelets of migraine patients studied in headache free-periods, and decreased collagen aggregation in whole blood.
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PMID:L-arginine/nitric oxide pathway activation in platelets of migraine patients with and without aura. 889 Oct 62

Previous studies have reported the existence of an arginine/nitric oxide (NO) pathway and the involvement of a Ca2+, NADPH-dependent nitric oxide synthase enzyme (NOS) in the generation of NO in human platelets. In the present research, we determined the rate of production of NO and cGMP in the cytosol of platelets stimulated by collagen in 20 females with menstrual migraine (MM), (age range 24-40 years), assessed in the follicular and luteal phases, interictally and ictally in the latter period. The same patients were also assessed at mid-cycle. At the same time, the variations in the collagen response of platelets were evaluated. Moreover, these parameters were determined in the same periods in 20 age-matched control females and in 20 females affected by non-menstrually related migraine (nMM). The collagen-stimulated production of NO in the cytosol of the platelet cytosol was significantly higher in migraine patients with MM than in the control subjects. In MM patients, the increase was greater in the luteal phase of the cycle than during the follicular phase (p < 0.005). A rise in NO production in platelets was also present, although to a lesser extent, in females affected by nMM compared to the healthy females, but this rise was most evident at ovulation (p < 0.001). A slight but significant increase was also observed at mid-cycle in control women, but this increase did not reach the values determined in the migraine groups (p < 0.02). NO production in platelets stimulated by collagen was significantly increased during attacks with respect to the interictal period in both patient groups. Similar variations were observed in the production of cGMP in MM and nMM patients. The increase in NO production was accompanied by a decrease in platelet aggregation in the migraine groups compared with the control group; this decrease was most evident at mid-cycle in nMM patients and in the luteal phase in MM patients. These data suggest an activation of the L-arginine/ NO pathway in MM and nMM patients which could explain the modifications in the platelet response to collagen evidenced in migraine-free periods and during attacks. The activation of this pathway is more accentuated in the luteal phase in MM patients, and this could be the cause of the increased susceptibility to migraine attacks in perimenstrual and menstrual periods in these patients.
Cephalalgia 1996 Nov
PMID:Variations in the platelet arginine/nitric oxide pathway during the ovarian cycle in females affected by menstrual migraine. 893 90

Decreased serum and intracellular levels of magnesium have been reported in patients with migraine. It has been suggested that magnesium may play an important role in the attacks and pathogenesis of headaches. We measured ionized magnesium, cyclic AMP (adenosine monophosphate), and cyclic GMP (guanosine monophosphate) in platelets of patients with migraine, in patients with tension-type headache, and in healthy controls. The platelet level of ionized magnesium from patients with tension-type headache was significantly lower than the levels from the other two groups. The platelet level of cyclic AMP from patients with migraine was higher than those from the other groups. We found no significant differences in the platelet cyclic GMP levels among the three groups. It is suggested that reduced platelet ionized magnesium in patients with tension-type headache is related to abnormal platelet function, and that increased platelet cyclic AMP in patients with migraine is related to alteration of neurotransmitters in the platelet.
Headache 1997 Oct
PMID:Platelet ionized magnesium, cyclic AMP, and cyclic GMP levels in migraine and tension-type headache. 938 54

Previous studies suggest that nitric oxide (NO) is involved in headaches induced by i.v. infusion of the vasodilator and NO donor glyceryl trinitrate (GTN) in healthy subjects. Extending these studies to sufferers of migraine without aura, it was found that migraineurs experienced a stronger headache than non-migraineurs. In addition, most migraineurs experienced a delayed migraine attack at variable times (mean 5.5 h) after GTN provocation. This biphasic headache response in migraineurs may be linked to hypersensitivity in the NO-cGMP pathway. Thus, compared to controls, migraineurs were found to be more sensitive to GTN-induced intracranial arterial dilatation, which is known to be mediated via liberation of NO and subsequent synthesis of cGMP Furthermore, histamine infusions in migraineurs induced headache responses and intracranial arterial responses resembling those induced by GTN in migraineurs. Histamine is known to liberate NO from the endothelium via stimulation of the H1 receptor, which is present in the large intracranial arteries in man. Because both immediate histamine-induced headache and intracranial arterial dilatation and delayed histamine-induced migraine are blocked by H1-receptor blockade, a likely common pathway for GTN and histamine-induced headaches/migraines and intracranial arterial responses may be via activation of the NO-cGMP pathway. The delay in the development of these experimental migraines may reflect activation of multiple physiological processes. The intracranial arteries of migraineurs were found supersensitive to the vasodilating effect of GTN (exogenous NO). This relates to clinical findings suggesting dilatation of the large intracranial arteries on the headache side during spontaneous migraine attacks. The function of arterial regulatory mechanisms involving NO in migraine was therefore studied. In peripheral arteries, no endothelial dysfunction of NO was found and cardiovascular and intracranial arterial sympathetic function was normal. A mild parasympathetic dysfunction may be involved and may, via denervation supersensitivity, be responsible for the observed supersensitivity to NO. Another possibility is that NO initiates a perivascular neurogenic inflammation with liberation of vasoactive peptides. NO also mediates a variety of other physiological phenomena. One of these, the pain-modulating effect observed in animals, was evaluated in a human study using GTN infusion and measurements of pain thresholds. No definite effects of GTN were demonstrated. The precise mechanisms involved in NO-triggered migraines and which part of the NO-activated cascade that is involved remain to be determined. The possibilities for pharmacological stimulation and/or inhibition of several steps of the NO-activated cascade increase rapidly and soon may be available for human studies.
Cephalalgia 1997 Dec
PMID:Investigations into the role of nitric oxide and the large intracranial arteries in migraine headache. 945 77

Erectile dysfunction may have psychological as well as a variety of organic causes. This necessitates in each case a careful medical evaluation. Various commonly used drugs, as well as alcohol and narcotics, may interfere with erection and should, whenever possible, be discontinued before starting treatment. Organic diseases should be identified and, if feasible, specially treated. In the remaining majority of afflicted men, psychological treatment and partner counseling may produce an improvement, but ultimately what is necessary remains an effective and safe medication. The drug, Sildenafil, introduces a new therapeutic principle. During sexual nerve stimulation, nitric oxide (NO) is released from nerves into the cells of the penile erectile bodies. NO activates in turn its "second messenger", the substance cyclic GMP, and the latter induces the vasorelaxation and blood filling of the erectile bodies. Orally administered Sildenafil competitively inhibits phosphodiesterase type 5, which physiologically inactivates cyclic GMP in the erectile bodies. Thus, Sildenafil increases in men with erectile dysfunction the NO-stimulated cyclic GMP concentration and, thereby, improves erection. This new therapy is attractive because 1. Sildenafil is the first pill (for oral use) with established efficacy that benefits most men with insufficient erection; 2. compared with previous therapeutic approaches (such as drug injections in the penis, instillations into the urinary duct, vacuum pumps or even prostheses), Sildenafil is at least as effective, is easy to take and appears well tolerated with no risk of a prolonged erection; 3. remarkably, this medication stimulates erection only during sexual arousal and, thus, has a rather "natural" effect, and 4. side effects (including headache, facial flushing and dyspepsia or epigastric discomfort) were mostly of mild degree and transient, so that only 4% of men interrupted treatment for this reason. Sildenafil does not need to be taken daily, but may be taken, when needed, 1 hour before a planned sexual activity. The new pill has the potential to enliven the boys "wunder horn" with fresh sound.
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PMID:[New principle in therapy of erectile dysfunction: sildenafil]. 965 82


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