Search

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.

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.

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.

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.

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.

In experiments designed to determine the nature of the coronary dilator effect of serotonin the influence of intracoronary administration of the amine on coronary perfusion pressure, heart rate and ventricular contractile force was assessed in anesthetized open-chest dogs in which the left coronary artery was perfused with blood at a constant rate. Serotonin elicited dose-related decreases in coronary perfusion pressure and increases in contractile force, and lowered heart rate slightly. The dilator response was antagonized by methysergide, slightly potentiated by practolol and unaffected by reserpine. The inotropic effect was partially antagonized by methysergide and completely blocked by practolol and reserpine. It is concluded that serotonin induces coronary dilatation by direct stimulation of specific receptors that this effect is independent of the cardiac stimulation produced by the amine, and the latter response is mediated through beta1-adrenoceptors activated by released norepinephrine.

The normal cardiovascular response to hydralazine in urethane-anesthetized rats, i.e. hypotension and tachycardia, was changed to hypotension and bradycardia if the body temperature of the animals was not maintained constant by external heating, but was allowed to decrease spontaneously throughout the experiment. A similar phenomenon was observed with diazoxide. In rats maintained at a rectal temperature of 31 degrees C, hydralazine bradycardia was partially blocked by a low dose of atropine and was reversed to tachycardia by a high dose of this agent; mecamylamine failed to influence heart rate lowering in this condition. Heart rate responses in unheated animals to acetylcholine and isopropylarterenol were respectively potentiated and depressed when compared to responses in heated rats. These findings suggest that cold-induced reciprocal changes in reactivity of cardiac muscarinic and beta-adrenoceptors may be responsible for reversal of hydralazine or diazoxide tachycardia in urethane-anesthetized hypothermic rats. As a result, cardiac stimulation by the sympatho-adrenal discharge induced by hypotension is inhibited, while cardiac depression which is apparently also induced by hypotension, is facilitated. It is speculated that vasopressin, released as a consequence of the blood pressure fall, could be this negative chronotropic factor.

Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine.

The correlation between hydralazine-induced tachycardia and overall cardiovascular reactivity to sympathetic stimulation was explored in 50 normal subjects. Blood pressure and heart rate changes after standing, immersion of a hand in cold water, the Valsalva maneuver, and moderate exercise were compared with pressure and rate responses to 20 mg oral hydralazine. The drug did not modify blood pressure but increased heart rate, mainly in the standing position. Because plotting the magnitude of this response suggested a two-population distribution, subjects were divided into hyporeactor and hyperreactor groups. Reactivity did not appear to be related to acetylator phenotype. The magnitude of the cardiac response correlated with heart rate responses to standing and to the Valsalva maneuver; when analyzed separately from hyporeactors, correlation was greater among hyperreactors. Because the orthostatic and Valsalva responses are reflex in nature, these results suggest that hydralazine tachycardia is also reflexly induced, that its magnitude depends on individual baroreceptor sensitivity, which is distributed nonnormally, and that it can be predicted by suitable tests of sympathetic responsiveness.