Hypotensive effect of hydroxylamine, an endogenous nitric oxide donor and SSAO inhibitor.

The endogenous compound hydroxylamine relaxes vascular smooth muscle in vitro, apparently through conversion to the vasodilator factor nitric oxide, but its effect on blood pressure has not been characterized. We found that in the anesthetized rat the amine elicits dose-related hypotension when administered by continuous iv infusion. In experiments designed to explore the mechanism of this effect, hydroxylamine was compared with the nitric oxide donor nitroprusside and the direct-acting vasodilator hydralazine, using pretreatments known to modify diverse mechanisms of vasodilation. Hydroxylamine hypotension was enhanced by the SSAO inhibitor isoniazid and the SSAO substrate methylamine, a pattern shared by hydralazine. Responses were blocked by the guanylate cyclase inhibitor methylene blue and were increased by the nitric oxide synthase inhibitor L-NAME, a pattern shared by nitroprusside. It was concluded that hydroxylamine exerts hypotension partly through conversion to nitric oxide and partly by a "hydralazine-like" mechanism involving SSAO inhibition.

Reflex bradycardia induced by hydralazine in sino-aortic deafferented conscious rats.

1. It is generally recognized that the vasodilator hydralazine produces hypotension accompanied by baroreflex-mediated tachycardia. In some experimental conditions, however, the accompanying heart rate change is bradycardia, a paradoxical response which has not been satisfactorily explained. The present study examined the possibility of hydralazine-induced bradycardia being mediated by vagal or sympathetic afferents activated by changes in left ventricular pressure. 2. Systolic blood pressure and heart rate responses to hydralazine were recorded in conscious normotensive intact rats by a tail cuff method and compared with responses in animals subjected to previous sino-aortic deafferentation (SAD) to remove the influence of the arterial baroreflex. Responses were also obtained after blockade of myocardial afferent vagal C-fibres with urethane, of efferent vagal impulses to the heart with methylatropine, of positive inotropic effects of hydralazine with atenolol, and of prostanoid sensitization of myocardial nerve fibres with indomethacin. 3. Hydralazine produced hypotension and tachycardia in intact rats, and hypotension and bradycardia in SAD animals. In intact rats, this pattern was not affected by any of the pretreatments, while in SAD rats, all pretreatments reversed the bradycardia to hydralazine. 4. The present results indicate that suppression of the arterial baroreflex by SAD propitiates the appearance of a bradycardiac response to hydralazine. This reaction probably results from activation of a vagal cardiodepressant reflex originating in the heart, as suggested by its blockade by drugs acting at various sites along the reflex arch.

Semicarbazide-sensitive amine oxidase: role in the vasculature and vasodilation after in situ inhibition.

1. The characteristics of semicarbazide-sensitive amine oxidase (SSAO) are reviewed and the unknown physiological or pathological role of this enzyme emphasized. 2. The various mechanisms of action proposed for the vasodilator drug hydralazine are considered. In particular, the inhibitory action on various enzymes, related or not to cardiovascular function, are discussed. 3. Studies linking inhibition of SSAO to hydralazine hypotension are reviewed and a general hypothesis relating both actions is presented. The hypothesis postulates that (a). vascular SSAO is involved in the regulation of vascular tone, and (b). hydralazine vasodilation is the consequence of vascular SSAO inhibition. 4. Evidence supporting these postulates is presented and vascular SSAO inhibition is proposed as a novel mechanism of vasodilation.

Influence of endothelium in dose-dependent inhibition and potentiation by isoniazid of isosorbide dinitrate relaxation of rat aorta.

The influence of in vivo administration of isoniazid on the relaxant effect of isosorbide dinitrate was determined by pretreating rats with various doses of isoniazid and obtaining concentration-response curves to isosorbide dinitrate in aortic rings from these animals. In rings with endothelium, isoniazid potentiated responses to isosorbide dinitrate at doses of 10, 30, and 100 mg/kg; 3 and 300 mg/kg were without effect. In endothelium-denuded preparations, potentiation was present only at 10 mg/kg; 3 and 300 mg/kg inhibited relaxation. Other experiments indicated that isoniazid potentiation was prevented by pyridoxine, was reproduced with theophylline, and did not occur with 3-morpholinosydnonimine or papaverine. These results were deemed compatible with the hypothesis that isoniazid inhibits transsulfuration of homocysteine and causes its accumulation in vascular smooth muscle and endothelial cells, where it functions as a thiol intermediate and leads to enhanced bioactivation of isosorbide dinitrate. Potentiation appeared to occur only with moderate increases of homocysteine.

Enhancement of hydralazine hypotension by low doses of isoniazid. Possible role of semicarbazide-sensitive amine oxidase inhibition.

The influence of pretreatment with 1 through 300 mg/kg ip of isoniazid (ISO) on blood pressure and heart rate responses to 0.1 mg/kg iv of hydralazine (HYD) was assessed in rats anesthetized with chloralose--urethane. HYD hypotension was significantly enhanced by ISO at doses between 3 and 300 mg/kg ip. Heart rate was not influenced by HYD in control or pretreated animals. Depressor responses to 0.2 mg/kg iv of pinacidil (PIN) were also potentiated by ISO at 100 and 300, but not at 30 mg/kg. Similarly, ISO decreased cerebral gamma-aminobutyric acid (GABA) at the two highest doses; 30 mg/kg was without effect. Pretreatment of rats with ISO at 1 through 300 mg/kg failed to influence HYD-induced relaxation of aortic rings. These results were interpreted as indicating that potentiation of HYD hypotension by high doses of ISO is not specific for that vasodilator and is related to decreased cerebral GABA, as postulated previously. Lower doses could specifically potentiate the HYD-induced hypotensive effect by inhibition of semicarbazide-sensitive amine oxidase (SSAO), since both ISO and HYD are potent inhibitors of this enzyme. In support of this hypothesis, the SSAO inhibitors, benserazide (100 mg/kg ip) and mexiletine (50 mg/kg ip), were also found to enhance HYD hypotension.

Pharmacology of Casimiroa edulis IV. Hypotensive effects of compounds isolated from methanolic extracts in rats and guinea pigs.

Bioassay-directed fractionation of the methanolic extract of seeds of Casimiroa edulis led to the isolation of seven constituents with cardiovascular activity, namely the new compound synephrine acetonide and the known compounds N-monomethylhistamine, N,N-dimethylhistamine, proline, N-methylproline, gamma-aminobutyric acid and casimiroedine. In anesthetized rats, both histamine derivatives produced transient hypotension mediated via H1-histaminergic receptors and in the case of N,N-dimethylhistamine, via nitric oxide release. Synephrine acetonide produced transient hypertension and tachycardia, mediated via alpha- and alpha- and beta-adrenergic receptores, respectively. The chromatographic zone containing N-methyproline, proline and gamma-aminobutyric acid elicited marked and prolonged hypotension. Finally, casimiroedine did not modify the blood pressure of anesthetized rats, but lowered it persistently in anesthetized guinea pigs. It was concluded that hypotension produced by C. edulis is due to several active components. The immediate effect can be attributed to the histamine derivatives acting on H1-receptors. More prolonged hypotension would be produced by the mixture of amino acids through an unknown mechanism, as well as by casimiroedine, possibly by activation of H3-receptors. Hypotension is partially offset by synephrine acetonide through adrenergic mechanisms.

Potentiation by isoniazid of relaxation induced by nitrovasodilators in rat aorta.

The influence of isoniazid (ISO) preincubation on the relaxant effects of a group of nitrovasodilators was examined in norepinephrine-contracted rat aortic rings with and without endothelium. ISO displaced to the left the dose-response curves to all nitrovasodilators and increased the negative logarithm of their median effective concentration (EC50) values. Potentiation was minimal with sodium nitrite and increased progressively with sodium nitroprusside, nitroglycerin (NTG), and isosorbide dinitrate. The phenomenon occurred in rings with and without endothelium and was not seen with the nitric oxide-releasing agent acetylcholine or with the nonspecific vasodilator hydralazine. These results confirm previous observations of potentiation of NTG vasorelaxation by ISO and extend them to other nitrovasodilators. Potentiation is attributed to the previously postulated inhibition by ISO of pyridoxal-requiring enzymes involved in the breakdown of homocysteine, leading to its intracellular accumulation. Increased availability of this sulfhydryl donor would lead in turn to enhanced bioactivation and vasorelaxant effects of nitrovasodilators. The different degrees of potentiation observed would be related to the sulfhydryl requirement of each compound for bioactivation. Alternatively, enhanced bioactivation of the nitrovasodilators could be due to induction by ISO of P-450 enzymes involved in this process.

Interaction between isoniazid and diverse vasodilators: role of decreased cerebral GABA.

OBJECTIVE: To determine if the interaction between isoniazid and hydralazine, consisting of increased hypotension accompanied by bradycardia, occurs with other vasodilators. METHODS: Blood pressure and heart rate responses to a number of vasodilators were determined in rats under chloralose-urethane, pretreated or not with 250 mg/kg of isoniazid. The influence of this dose of isoniazid on GABA levels in the hypothalamus and pons-medulla was assessed in other groups of rats. RESULTS: Increased hypotension and bradycardia following i.p. isoniazid were observed with dipyridamole, prazosin, pinacidil and hydralazine given i.v. Bradycardia without increased hypotension appeared with papaverine and verapamil, while increased hypotension with unchanged heart rate was observed with minoxidil and captopril. Isoniazid decreased GABA in the hypothalamus and pons-medulla. CONCLUSIONS: At the high dose used, isoniazid interacts with various vasodilators, irrespective of their mechanism of action. The interaction could be due to the influence of the drug on GABA levels at cardiovascular regulatory sites.

Enhanced bradycardia induced by beta-adrenoceptor antagonists in rats pretreated with isoniazid.

High doses of isoniazid increase hypotension induced by vasodilators and change the accompanying reflex tachycardia to bradycardia, an interaction attributed to decreased synthesis of brain gamma-aminobutyric acid (GABA). In the present study, the possible enhancement by isoniazid of bradycardia induced by beta-adrenoceptor antagonists was determined in rats anaesthetised with chloralose-urethane. Isoniazid significantly increased bradycardia after propranolol, pindolol, labetalol and atenolol, as well as after clonidine, but not after hexamethonium or carbachol. Enhancement was not observed in rats pretreated with methylatropine or previously vagotomised. These results are compatible with interference by isoniazid with GABAergic inhibition of cardiac parasympathetic tone. Such interference could be exerted centrally, possibly at the nucleus ambiguus, or peripherally at the sinus node.

Tachyphylaxis and sensitization to nicotine-induced tachycardiac and pressor effects after nicotine infusions.

This work examined the effects of nicotine on mean arterial pressure and heart rate in non-anesthetized spinal rats. Nicotine (200 mg/kg) was administered as a single bolus, as infusions lasting 7.5, 15 or 30 min, and as a post-infusion bolus. A nicotine bolus increased pressure and rate. These effects were less marked as the rate of infusion decreased. The infusions affected differentially the effects of a subsequent bolus. Thus, while tachycardia was decreased, the blood pressure rise was increased. An initial transient bradycardia was observed after bolus administration, but not during infusions; this effect was unchanged after post-infusion boluses. Pharmacological analysis indicated that tachycardia and bradycardia were predominantly due to ganglionic stimulation, while adrenal and sympathetic nerve catecholamine release played a major role in the pressor response. These results indicate that slow nicotine infusions do not induce tachyphylaxis for all of the cardiovascular effects of a subsequent bolus, and that development of acute tolerance appears to depend on the mechanism of action of the response.

Cardiovascular effects of (-)-11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl in rats.

The effects of the stereochemically pure psychoactive cannabinoid (-)-11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (HU-210) on blood pressure (BP) and heart rate (HR) were determined in rats. In pentobarbital-anesthetized animals, the compound produced dose-related, long-lasting hypotension and bradycardia at doses between 10 and 1,000 micrograms/kg. BP began to decrease immediately after drug administration, and in no case was an initial pressor response observed. Previous vagotomy (VX) or pretreatment with 6-hydroxydopamine (6-OHDA) did not affect hypotension. Bradycardia was inhibited by VX, but only 60 min after administration of HU-210; it was enhanced by 6-OHDA. The cannabinoid blocked reflex bradycardia induced by phenylephrine (PE). HU-210 also decreased BP and HR in conscious rats. Hypotension lasted 2 h, whereas bradycardia was still present 8 h after drug administration. HU-210 thus shares with delta 9-tetrahydrocannabinol (THC) the ability to decrease BP and HR, but is 5-10 times more potent than the natural compound. Its lack of an initial pressor effect, such as that described for THC, could be related to its specificity for the type-1 cannabinoid (CB1) receptor. Hypotension and bradycardia after HU-210 administration are not due to sympathetic withdrawal. Enhanced parasympathetic tone is involved in bradycardia only at a late stage of the response.

Patterns of heart rate responses to hydralazine in normotensive and hypertensive rats.

Hydralazine (H) induces hypotension accompanied by cardiac stimulation due to activation of the arterial baroreflex. Both clinical and experimental observations suggest, however, that in certain conditions H hypotension can be accompanied by unchanged or even depressed cardiac performance. The present study determined whether varying patterns of heart rate responses could be detected in large populations of conscious normotensive (n = 61) and renal hypertensive (n = 59) rats receiving a single dose of H. These patterns were compared with those of normotensive pentobarbital-anesthetized rats (n = 43). In the three groups, hypotension was accompanied by either tachycardia, unchanged heart rate or bradycardia. Tachycardia was found in 52% of normotensive conscious rats, in 51% of hypertensives and in only 14% of anesthetized animals. Heart rate did not change in 26, 35 and 23%, while bradycardia was detected in 22, 14 and 63%, respectively. These results were explained by postulating the initiation by H of two reflexes with opposite effects on heart rate: the arterial baroreflex producing tachycardia and a cardiac mechanoreceptor reflex producing bradycardia. These reactions would compete with each other, with results depending on their relative sensitivity in a given animal.

Pharmacology of Casimiroa edulis; III. Relaxant and contractile effects in rat aortic rings.

The relaxant and contractile effects of an aqueous extract of the seeds of the hypotensive plant Casimiroa edulis were investigated in rat aortic rings. The extract inhibited contractions elicited by noradrenaline, serotonin and prostaglandin F2 alpha, but did not affect responses to KCl. Inhibition did not require the presence of intact vascular endothelium and was not affected by histamine antagonists. In this preparation, the extract also elicited concentration-related contractions which were more marked in the absence of endothelium, were not blocked by histamine antagonists, and were completely suppressed by alpha-adrenergic blockade. It was concluded that the relaxant effect of the extract is not exerted through release of an endothelial relaxing factor nor through blockade of calcium channels or of specific smooth muscle receptors, and does not involve histaminergic mechanisms. The contractile effect is modulated by vascular endothelium and is alpha-adrenergic in nature.

Potentiation of cardiovascular responses to hydralazine by diverse hydrazine derivatives.

After the observation that in anesthetized rats the antitubercular agent isoniazid potentiates the hypotensive effect of the vasodilator hydralazine (H) and transforms the accompanying reflex tachycardia to bradycardia, a number of hydrazine (HYD) derivatives were tested for this interaction in pentobarbital-anesthetized rats. All HYDs studied elicited this response in varying degrees, isoniazid, thiosemicarbazide and thiocarbohydrazide being the most active. Experiments were then carried out to explore the possibility of an influence of the HYDs on reflex reactions to H due to interaction with pyridoxal, inhibition of glutamic acid decarboxylase and decreased levels of brain gamma-aminobutyric acid. Although the H-HYDs interaction was prevented by vagotomy, it was unaffected by exogenous pyridoxal, did not occur with the alpha adrenergic antagonist prazosin and was not mimicked by non-HYD pyridoxal reactors. In other experiments, pharmacokinetic interactions and monoamine oxidase inhibition were ruled out as alternative explanations for this phenomenon. It was concluded that the H-HYDs interaction is not related to a possible influence of these drugs on central gamma-aminobutyric acid cardiovascular regulation and that other presently unknown mechanisms are involved.

Low flow veno-venous ECMO: an experimental study.

Clinical use of extracorporeal membrane oxygenation (ECMO) and carbon dioxide removal (ECCO 2R) have become well established techniques for the treatment of severe respiratory failure; however they require full cardiopulmonary bypass, representing major procedures with high morbidity. We theorized the possibility of an efficient low flow veno-venous extracorporeal membrane gas exchange method. Four mongrel 12 kg dogs were submitted to veno-venous extracorporeal membrane gas exchange via a jugular dialysis catheter using a low flow (10 ml/min) roller pump and a membrane oxygenator for a period of four hours. Respiratory rate was set at 4 breaths/min with a FiO 2 of 21% and ventilatory dead space was increased. Adequate gas exchange was obtained (pO 2139, pCO 224, Sat 99.4%), without major hemodynamic changes or hematuria. Our results demonstrate the feasibility of a low flow, less aggressive system. Further research should be considered.

Pharmacology of Casimiroa edulis; II. Cardiovascular effects in the anesthesized dog.

The cardiovascular effects of an aqueous extract of seeds of Casimiroa edulis were assessed in pentobarbital-anesthetized dogs. The extract produced marked hypotension which lasted more than two hours; it was accompanied by moderate and less persistent bradycardia. The histaminergic nature of these effects was investigated in animals pretreated with the specific antagonists diphenhydramine, cimetidine, or a combination of both agents. These experiments showed that both H1- and H2-receptors were involved in the hypotensive response, while the bradycardia was mediated solely through an H1-mechanism. In open-chest dogs instrumented for recording cardiac output (ascending aortic flow), left ventricular contractility (dp/dt), central venous pressure (superior vena cava), systemic blood pressure, heart rate, total peripheral resistance and stroke volume, the extract decreased blood pressure and peripheral resistance and increased cardiac output and stroke volume, without modifying the other parameters. It was concluded that the cardiovascular pattern of Casimiroa edulis in the dog is that of a peripheral arterial vasodilator and that it increases cardiac output by reducing left ventricular afterload.

Pharmacology of Casimiroa edulis; Part I. Blood pressure and heart rate effects in the anesthetized rat.

The effect of an alcoholic extract of seeds of Casimiroa edulis on blood pressure and heart rate was determined in rats anesthetized with pentobarbital and compared with that of histamine. The extract induced hypotension, accompanied at high doses by tachycardia. Hypotension after histamine was more transient and was not accompanied by changes in heart rate. Experiments with a variety of autonomic antagonists revealed that extract-induced hypotension was not mediated by histamine H2, muscarinic, or beta-adrenergic receptors, but involved an H1 mechanism. After H1 blockade, the depressor response was reversed to a pressor effect, mediated by alpha-adrenoceptor stimulation. The increase in heart rate was due in part to H1 and in part to beta-adrenergic receptor activation. It was suggested that imidazole derivatives could be responsible for the depressor effect observed. The pressor response could be caused by these or other components of the extract.

Effects of histamine on atrial and ventricular contractility in the canine isovolumic heart.

The effects of intracoronary administration of histamine on atrial and ventricular contractility were determined in a paced canine isovolumic heart preparation. Contractility was assessed by recording the pressure developed in saline-filled balloons placed in each of the four cardiac chambers. At doses above 0.1 mg and up to 100 mg histamine produced dose-related positive inotropic responses in all chambers. These were preceded by transient negative effects. The positive responses were not affected by a combination of H1 and H2 receptor antagonists antazoline and cimetidine but were almost completely abolished by the beta adrenoceptor blocker timolol. The negative responses were uninfluenced by either treatment. It was concluded that, in the canine isovolumic heart not subjected to complicating chronotropic and extracardiac factors, moderate doses of histamine are devoid of inotropic effects. Higher doses do produce myocardial stimulation, not mediated by histamine receptors, but probably due to norepinephrine release. These responses are preceded by transient non-specific depressant effects.