Cerebral vasoconstriction effects

There is some controversy concerning the cerebral vasoconstrictive effects of oxygen. Lambertsen et al. (L2) believe that the vasoconstrictive effect is due to the decreased Paooi brought about by hyperventilation (vide supra), rather than by a direct vasoconstrictive effect of oxygen. Jacobson et al. (J2) found that, under constant CO2 tensions, oxygen exerts a direct cerebral vasoconstrictive effect. 

Mecfianism of Action An ergotamine derivative, alpha-adrenergic blocker that directly stimulates vascular smooth muscle. May also have antagonist effects on sero-fonin. Therapeutic Effect Peripheral and cerebral vasoconstriction. Pharmacokinetics Slow, incomplete absorption from the gastrointestinal (GI) tract rate of absorption of intranasal route varies. Protein binding greaterthan 90%. Undergoes extensive first-pass metabolism in liver. Metabolized to active metabolite. Eliminated in feces via biliary system. Half-life 7-9 hr. 

Mechanism of Action An ergotamine derivative and alpha-adrenergicblocker that directly stimulates vascular smooth muscle, resulting in peripheral and cerebral vasoconstriction. May also have antagonist effects on serotonin. Therapeutic Effect Suppresses vascular headaches. 

Cocaine toxicity has both somatic and psychiatric manifestations. Somatic effects include myocardial depression, malignant dysrhythmias, stroke, and sudden death, partially due to cocaine-related myocardial sodium channel blockade and coronary and cerebral vasoconstriction. Such life-threatening conditions occur mainly when cocaine is combined with other abused drugs. Psychiatric effects can mimic the positive and negative symptoms of schizophrenia. 

Cerebral insufficiency refers to describe the people with age-related decline in mental function and decrease blood flow to the brain cause by clogged arteries. Platelet activating factor (PAF) is an inflammatory mediator, plays an important role in allergy, inflammatory processes, coronary, and cerebral vasoconstriction [178]. The production and release of PAF in the brain under various pathological conditions, including oxidant stress-induced ischemic injury [179]. The efficiency of EGb-761 on cerebral circulation and metabolism has been demonstrated in various models of cerebrovascular insufficiency and showed beneficial effect like cerebral edema in rats intoxicated with triethyltin chloride (TET) [180]. Moreover, oral or intravenous administrations EGb decrease cerebral edema development in gerbils [181]. In an animal study [182], EGb-761 and an extract of local ginkgo... 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

Baroreceptors are sensitive to changes in MAP. As VR, CO, and MAP decrease, baroreceptor excitation is diminished. Consequently, the frequency of nerve impulses transmitted from these receptors to the vasomotor center in the brainstem is reduced. This elicits a reflex that will increase HR, increase contractility of the heart, and cause vasoconstriction of arterioles and veins. The increase in CO and TPR effectively increases MAP and therefore cerebral blood flow. Constriction of the veins assists in forcing blood toward the heart and enhances venous return. Skeletal muscle activity associated with simply walking decreases venous pressure in the lower extremities significantly. Contraction of the skeletal muscles in the legs compresses the veins and blood is forced toward the heart. 

Prednisolone was observed to be effective in ameliorating the headache seen in 3 workers with elevated cerebral spinal fluid pressure and papilledema resulting from exposure to high levels of chlordecone (Sanborn et al. 1979). However, when prednisolone therapy was stopped, the headaches returned and did not dissipate until serum chlordecone levels were reduced. It is possible that the prednisolone blocked the headache by increasing vasoconstriction and decreasing intracranial cerebral spinal fluid volume. 

NIOSH-recommended exposure limits for NG, EGDN, or a mixture of the two were set at a level to prevent significant changes in the diameter of cerebral blood vessels during initial exposure, as indicated by the occurrence of headache or by decrease in blood pressure, thereby preventing the development of compensatory vasoconstrictive mechanisms that may eventually result in more serious effects. ... 

Xanthines (usually caffeine) are frequently combined with aspirin in the treatment of headaches. In combination with an ergot derivative, methylxanthines have been used to treat migraine. These effects are likely due to their ability to produce vasoconstriction of cerebral blood vessels. Aminophylline is useful in the rehef of pain due to acute biliary colic. 

Contrast-enhanced MRI with Gd-DTPA has been applied to the evaluation of several compounds in man, some focusing on the hemodynamic effects of the drugs on cerebral blood volumes. Kolbtisch and others compared the anesthetic agents nitrous oxide and sevofhirane, noting them to produce compound-specific patterns of diffuse increases in cerebral blood volume (Kolbitsch et al., 2001). Intravenous cocaine, on the other hand, was observed to produce dose-dependent vasoconstriction of cerebral blood vessels (Kaufman et ul., 1998). 

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of Di receptors. Activation of the Di receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates Bj receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a. receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. 

Sumatriptan Partial agonist at 5-HT1B/1D receptors Effects not fully understood may reduce release of calcitoningene-related peptide and perivascular edema in cerebral circulation Migraine and cluster headache Oral, nasal, parenteral duration 2 h Toxicity Paresthesias, dizziness, coronary vasoconstriction Interactions Additive with other vasoconstrictors... 

NPY produces a variety of central nervous system effects, including increased feeding (it is one of the most potent orexigenic molecules in the brain), hypotension, hypothermia, respiratory depression, and activation of the hypothalamic-pituitary-adrenal axis. Other effects include vasoconstriction of cerebral blood vessels, positive chronotropic and inotropic actions on the heart, and hypertension. The peptide is a potent renal vasoconstrictor and suppresses renin secretion, but can cause diuresis and natriuresis. Prejunctional neuronal actions include inhibition of transmitter release from sympathetic and parasympathetic nerves. Vascular actions include direct vasoconstriction, potentiation of the action of vasoconstrictors, and inhibition of the action of vasodilators. 

Sumatriptan and several other "triptans" are selective agonists for 5-HTiD and 5-HTiB receptors. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neurons and probably function as presynaptic inhibitory receptors. These drugs have proved to be very effective in the treatment of acute migraine headache. The mechanism of action is discussed in more detail below under Clinical Pharmacology of Ergot Alkaloids. 

In addition to cardiac tissue, leptin receptors have also been identified in both cerebral and coronary vessels (Bjorbaek et al. 1997 Knudson et al. 2005). With respect to the latter it was proposed that OBR-mediated leptin-induced vasodilation occurs through an NO-dependent process and which was abolished by hyperleptinemia. This finding emphasizes the potential dual role of leptin on vascular tissue, a direct NO-dependent vasodilation and vasoconstriction occurring secondarily to central stimulation of the sympathetic nervous system. These effects will be discussed below in greater detail. 

The clinical effects following overdose depend on the receptor selectivity (alpha and/or beta effect). Most patients require only observation for a period of 4-8 h. Pharmacologic intervention is required only in severely symptomatic patients (cardiac arrhythmias, hypertensive crisis, seizures, hyperthermia). Severe overdose effects may most commonly result in hypertension, tachycardias, followed by bradycardia, and arrhythmias, seizures, cerebral hemorrhages and ischemia or vasoconstriction, psychosis, and hyperthermia. 

Transgenic mice overexpressing EC-SOD have better neurological outcome and cognitive performance after severe cranial impact [171]. Such animals were, however, more susceptible to hyperbaric oxygen than control animals, an effect ascribed to sparing excessive levels of nitric oxide and thus blocking the normal vasoconstrictive response of the cerebral vasculature to hyperoxia [ 172]. 

The lack of response in the other patients suggests that pulmonary vasoconstriction is not the cause of the desaturation and that perhaps other factors, such as cerebral blood flow requirements, have a significant effect on pulmonary blood flow (superior vena cava flow) in these patients. We have delivered nitric oxide to two patients following the total cavopulmonary anastomosis (Fontan), with an elevated transpulmonary gradient in the presence of left atrial hypertension due to a restrictive atrial septal defect in one patient and pulmonary venous obstruction by the Fontan baffle in another. Inhaled nitric oxide produced a reliable decrease in transpulmonary gradient in both, with an increase in saturation in one (with a fenestrated... 

---