Yvonne Vulliemoz

Cyclic phosphodiesterase activity and the action of papaverine

Abstract Papaverine, a smooth muscle relaxant, inhibits phosphodiesterase activity in homogenates of rabbit aorta, rat uterus and rat diaphragm.This inhibitory effect of papaverine is about 15–30 times greater than that of theophylline. In rat diaphragm, papaverine increased glycogenolysis to the same extent as epinephrine and had a synergistic effect with epinephrine on glycogen breakdown. These results suggest that the relaxing effect of papaverine might be due to its action on phosphodiesterase and are in agreement with the postulation that cyclic 3′, 5′-AMP participates in the control of smooth muscle tone and contractility.

Adenylcyclase-phosphodiesterase system in arterial smooth muscle

Abstract Isoproterenol, epinephrine, and norepinephrine increase cyclic AMP formation in rat aorta through their stimulatory effect on adenyl cyclase. Isoproterenol, and epinephrine and norepinephrine in the presence of phentolamine, have a relaxing effect on the rat aortic strip. Propranolol prevents the rise in cyclic AMP with the three catecholamines and modifies the epinephrine-induced contraction. Inhibition of phosphodiesterase is also accompanied by relaxation of arterial smooth muscle.

Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats

BACKGROUND Central alpha adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, alpha adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective alpha -adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats. METHODS Sprague-Dawley rats received a cocaine infusion (1.25 mg x kg(-1) x min(-1)) followed 15 min later by the coinfusion of either dexmedetomidine (20-microg/kg intravenous bolus followed by an infusion of 1 microg x kg(-1) x min(-1), CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 microm) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group. RESULTS Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold. CONCLUSIONS These data suggest that dexmedetomidine increases the cocaine-induced seizure threshold possibly a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.

Intra-arterial Nitrovasodilators Do Not Increase Cerebral Blood Flow in Angiographically Normal Territories of Arteriovenous Malformation Patients

BACKGROUND AND PURPOSE The mechanism of adaptation to chronic cerebral hypotension in normal brain adjacent to cerebral arteriovenous malformations (AVMs) is unknown. To clarify these mechanisms, we performed cerebral blood flow (CBF) studies in structurally and functionally normal vascular territories during 53 distal cerebral angiographic procedures in 37 patients with AVMs. METHODS CBF was measured using the superselective intra-arterial 133Xe method before and after a 3-minute infusion of either verapamil (1 mg.min-1, n = 23), acetylcholine (1.33 micrograms.kg-1.min-1, n = 7), nitroprusside (0.5 microgram.kg-1.min-1, n = 16) or nitroglycerin (0.5 microgram.kg-1.min-1, n = 7). RESULTS Mean +/- SD systemic (76 +/- 13 mm Hg) and distal cerebral arterial (55 +/- 16 mm Hg; range, 20 to 97 mm Hg) pressures were not different among groups. Verapamil increased CBF (45 +/- 12 to 65 +/- 21 mL.100 g-1.min-1, P < .001). There was no effect of acetylcholine (no change [46 +/- 9 to 46 +/- 9 mL.100 g-1.min-1], NS) or nitroglycerin (36 +/- 14 to 36 +/- 13 mL.100 g-1.min-1, NS). Nitroprusside decreased CBF (40 +/- 12 to 31 +/- 11 mL.100 g-1.min-1, P < .001). The percent change in CBF after drug administration was proportional to cerebral arterial pressure for verapamil only (r = .57, P = .0051). CONCLUSIONS When infused intra-arterially in clinically relevant doses in both hypotensive and normotensive normal vascular territories remote from an AVM nidus, calcium channel blockade caused vasodilation, but there was an absence of response to nitric oxide-mediated vasodilators. These data suggest that (1) the nitric oxide pathway probably is not involved in the adaptation to chronic cerebral hypotension in AVM patients and (2) if our findings in vessels remote from or contralateral to the AVM are applicable to vessels of patients with other forms of cerebrovascular disease, clinically relevant doses of intra-arterial nitrovasodilators may not be useful in the manipulation of cerebrovascular resistance.

The effect of catecholamines on adenyl cyclase activity in rat uterus.

Abstract Adenyl cyclase (AC) activity was assayed in uterine tissue homogenates from estrogen-pretreated rats. Epinephrine, norepinephrine and isoproterenol activate AC to the same maximum, 80–88% above control; a 20 times higher concentration of norepinephrine than of epinephrine is needed to produce the same effect. A beta adrenergic blocking agent (propranolol) antagonizes this action of catecholamines. Epinephrine in lower concentrations, unlike isoproterenol, when combined with propanolol has an inhibitory effect on AC. An alpha adrenergic blocking agent (phentolamine) does not prevent the activation of AC by catecholamines. On the contrary, the activity tends to be higher. The results show that the increase in uterine muscle AC activity is caused by the component of catecholamine action which apparently relaxes the uterus and gives some support to the possibility that another component of epinephrine action inhibits AC activity.

Effects of halothane on the cyclic 3',5'-adenosine monophosphate enzyme system in human platelets.

A study of the effects of halothane on the cyclic 3′,5′-adenosine monophosphate (cAMP) system in human platelets was undertaken since cAMP has been implicated in the regulation of the process of platelet aggregation and this anesthetic has been reported to decrease platelet aggregation and, in other tissues, to increase adenylate cyclase activity. When exposed to halothane 0.5 to 10 vol%, adenylate cyclase activity was increased in the platelet preparation in a dose-dependent manner, reaching a maximum at 5 vol% (93% increase above basal activity). Platelet aggregation was also inhibited by halothane in a dose-dependent manner, with a maximum effect at about 5 vol% halothane (a decrease of 70%). Kinetic analysis of platelet cAMP-phosphodiesterase suggested two forms of activity, neither of which was altered by halothane. The results suggest that the impairment of platelet aggregation observed with halothane may be brought about by the halothane-induced activation of platelet adenylate cyclase, which may result in a higher cAMP level, inhibiting platelet aggregation.

Acetylcholine and the cyclic AMP system in smooth muscle

Abstract The effect of acetylcholine on the cyclic AMP system and its interaction with the epinephrine effect on this system was studied in vitro in rat uterus. In the presence of acetylcholine (1–100 μMolar), epinephrine-induced cyclic AMP formation in intact tissue is decreased; this inhibitory effect of acetylcholine is more pronounced at higher concentrations of epinephrine and is reversed by atropine. In broken cell preparations, acetylcholine does not alter the activity of adenyl cyclase or phosphodiesterase, nor the stimulatory effect of epinephrine. It appears that acetylcholine has an effect on the cyclic AMP system of rat uterine smooth muscle only when the structural and functional relationships in the cell are preserved. The possible mechanisms are discussed.

Cardiac surgery causes desensitization of the β-adrenergic receptor system of human lymphocytes

Thirteen patients undergoing cardiac surgery were studied to examine whether beta-adrenergic desensitization occurs in the perioperative period surrounding cardiac surgery, using peripheral blood lymphocytes as a model. Lymphocytes were isolated before induction of anesthesia (PRE) and on the morning of the first postoperative day (POST). Cyclic adenosine monophosphate (cAMP) production from the lymphocytes was assayed in the untreated (BASAL) state, and after treatment with 5 microM isoproterenol, 10 microM prostaglandin E1, or 20 mM sodium fluoride with 10 microM AlCl3 (NaF). All cAMP values are reported as picomoles per 10(6) cells, mean +/- SEM. BASAL cAMP production did not change significantly between the PRE and POST samples (PRE, 1.2 +/- 0.1; POST, 1.0 +/- 0.1). Isoproterenol-stimulated cAMP was significantly lower postoperatively (PRE, 8.36 +/- 0.9; POST, 5.1 +/- 0.5; P less than 0.005). Prostaglandin E1-stimulated cAMP did not change (PRE, 21.7 +/- 2.4; POST, 25.3 +/- 2.5), and NaF-stimulated cAMP was increased postoperatively (PRE, 8.8 +/- 1.6; POST, 14.3 +/- 2.0; P less than 0.05). These findings suggest that cardiac surgery and/or cardiopulmonary bypass results in significant desensitization of the beta-adrenergic receptor/adenylate cyclase system of lymphocytes, which may parallel changes in the adrenergic response of other organ systems.

Dexmedetomidine decreases extracellular dopamine concentrations in the rat nucleus accumbens

The effects of dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, on extracellular dopamine (DA) concentrations in the nucleus accumbens of awake rats were collected via in vivo cerebral microdialysis and measured using HPLC with electrochemical detection. The administration of dexmedetomidine (DEX) at a low dose (2 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 0.1 microg/kg per min) and a high dose (20 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 1 microg/kg per min), significantly decreased extracellular dopamine concentrations in the nucleus accumbens. The observed decrease was dose-dependent, occurring sooner and to a greater magnitude in the rats receiving a high dose of DEX. This inhibitory modulation of accumbal dopamine was receptor-specific, as the decrease in extracellular DA produced by DEX was no longer evident following pre-treatment and co-infusion with the highly selective alpha(2)-adrenoceptor antagonist, atipamezole (ATZ). Thus, these data suggest that adrenoceptor agonists and antagonists may modulate dopaminergic neurotransmission via mechanisms that are specific to the alpha(2)-adrenoceptor.

The nitric oxide-cGMP system of the locus coeruleus and the hypnotic action of alpha-2 adrenergic agonists

Dexmedetomidine (Dex), a potent, selective alpha-2 adrenergic agonist, injected bilaterally directly into the locus coeruleus (LC), 7 microgram/LC, or ip, 100 microgram/kg, produced a maximum decrease in LC cGMP (-38 and -46%, respectively). Atipamezole, a selective alpha-2 adrenergic antagonist, given into the LC, 10 microgram/LC, prevented the decrease in LC cGMP induced by Dex, given i.p. or into the LC. Dex produced a loss of righting reflex in about 80% of the animals, an effect which was prevented by pretreatment with atipamezole. The nitric oxide synthase antagonist L-Name injected bilaterally into the LC, 20 microgram/LC, produced by itself a maximum decrease in LC cGMP of 54.5%. Dex, 100 microgram/kg, ip, given after L-Name, did not further decrease LC cGMP. L-Name, by itself, did not produce a loss of righting reflex, while 6 out of 9 rats pretreated with L-Name lost their righting reflex in response to Dex. A role of the nitric oxide-cGMP system of the LC in the modulation of the hypnotic effect of alpha-2 adrenergic agonists remains uncertain.