Cardioaccelerator Nerve Research Articles

Effect of single bolus dose of intravenous magnesium sulfate in attenuating hemodynamic stress response to laryngoscopy and nasotracheal intubation in maxillofacial surgeries

Background: Nasotracheal intubation alters respiratory and cardiovascular physiology by reflex response mediated by both sympathetic and parasympathetic nervous systems and by the physical presence of the nasotracheal tube. Hypertension and tachycardia are the most common responses to intubation mediated by sympathetic efferent through cardio accelerator nerve and sympathetic chain ganglia. MgSO4 inhibits catecholamine release from adrenergic nerve endings and adrenal medulla resulting in attenuation of stress response. Aims and Objectives: In this study, we observed the effects of MgSO4 on the hemodynamic stress response. Materials and Methods: This prospective randomized controlled study was conducted on 60 patients after approval of the Institutional Ethics and Scientific Review committee over the period of 1 year. They were divided into two groups, Group M (MgSO4 group) received 40 mg/kg of intravenous magnesium sulfate in 100 ml normal saline and Group C (control group) received normal saline 10 min before induction. Hemodynamic parameters (HR, SBP, DBP, and MAP) were recorded at baseline, just before induction and at 1, 3, 5, 10, 15, and 30 min after intubation and every 15 min till the end of surgery. Results: After conducting this study, we observed that heart rates at 1, 3, 5, and 10 were significantly lower in the M group as compared to the C group (P<0.05). Systolic, diastolic, and mean blood pressure were also reduced significantly in the M group as compared to the C group (P<0.05). Conclusion: Magnesium sulfate when used at the dose of 40 mg/kg attenuates the hemodynamic stress response during laryngoscopy and nasotracheal intubation.

Conformationally restricted dopamine congeners--a molecular mechanics-based study.

Potential energies of several systems containing the phenylethylamine fragment were computed by the QCFF/PI method and some of them also by the PCILO method. The systems considered are: octahydrobenzo [f]- and [g]-quinolines, aporphine, 1-phenylbenzazepine, 4-phenyltetrahydroisoquinoline, 3-phenylpiperidine and 9-aminodihydrophenanthrene. No common set of torsion angles defining the stereostructure around the amine head is apparent if only the lowest energy conformations are considered. Leaving out the orientation of the N-CH3 group, and considering also some higher energy conformations, two groups of systems may be formed, A and B, the members of which are congruent amongst themselves in parameters defining the spatial relations of the amine site and the catechol ring, and in the orientation of the N+-H bond. The stereostructure of the rigid representatives of group A is postulated to be the one required by the brain and cardioaccelerator nerve receptor. A corresponding postulate for the vascular bed DA receptors cannot be made since systems forming group B, the derivatives of which are active both on brain and vascular bed receptors, have more conformation space and, moreover, they carry additional potential anchoring groups.

Alpha-adrenergic agonist and antagonist activity of dihydroergotoxine in rats.

The alpha-adrenergic activity of dihydroergotoxine had been studied in both pithed and urethane or pentobarbitone anaesthetized rats. In anaesthetized rats, blood pressure effects varied with the anaesthetic agent: hypotension with urethane, hypertension with pentobarbitone. This latter pressor response was a peripheral effect. In pithed rats, the vasopressor response to dihydroergotoxine was reduced competitively by yohimbine, and non-competitively by nifedipine, but not by prazosin or methysergide, showing that the vasoconstriction is mediated by alpha 2-adrenoceptors. Dihydroergotoxine decreases the tachycardia elicited by stimulation of the cardioaccelerator nerves, this effect being antagonized by yohimbine. It also reduced the pressor response to (-)-phenylephrine. These results indicated that, on the peripheral vascular system of the rat, dihydroergotoxine acts as an alpha 1-adrenoceptor blocker and an alpha 2-adrenoceptor agonist.

Neuronal and neurohormonal control of the heart in the stomatopod crustacean,Squilla oratoria

The heart of Squilla oratoria contains a cardiac ganglion that consists of 15 intrinsic neurons, supplied by a pair of inhibitory nerves and two pairs of excitatory nerves, arising from the central nervous system. These comprise the extrinsic cardiac innervation. The paired cardio-inhibitor (CI) nerves run out in the 10th pair of nerve roots emerging from the subesophageal ganglion (SEG). The cell bodies of the CI neurons are found in the hemisphere of the 1st segment of the SEG contralateral to the nerve roots in which the CI axons emerge. The two pairs of 1st and 2nd cardio-accelerator (CA1 and CA2) nerves run out in the 16th and 19th pairs of nerve roots of the SEG. The cell bodies of the CA1 and CA2 neurons are found in the hemispheres of the 3rd and 4th segments of the SEG ipsilateral to the nerve roots in which the CA1 and CA2 axons are found. The heartbeat was activated by application of glutamate, serotonin, dopamine, octopamine or acetylcholine, which were applied to the heart by perfusion into an organ bath. Joro-spider toxin (JSTX) blocked myocardial excitatory junctional potentials evoked by the cardiac ganglion. Neuronal cell bodies and processes in the heart were examined using immunocytochemical techniques. All 15 neurons of the cardiac ganglion showed glutamate-like immunoreactivity. Glutamate may be a neurotransmitter of the cardiac ganglion neurons. JSTX also blocked cardiac acceleration by activation of CA1 and CA2 axons. CA1 and CA2 axons showed glutamate-like immunoreactivity. It is likely that glutamate is a neurotransmitter for the cardio-acceleratory neurons. The heartbeat was inhibited by application of gamma-amino-butyric acid (GABA). Cardiac inhibition induced by activation of CI axons was blocked by picrotoxin. CI axons showed GABA-like immunoreactivity. These results may support the identification of GABA as an extrinsic inhibitory neurotransmitter.

Evidence for a sympatholytic effect of mibefradil in the pithed rat preparation.

The T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this particular type of calcium channel is known to be crucially involved in the neuronal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug. To evaluate the sympathoinhibitory action, the effects of 3 and 10 micromol/kg MIB on the tachycardic effect of electrical stimulation of the preganglionic cardioaccelerator nerves in the pithed rat were investigated. The effect of MIB on the dose-response curve of externally applied noradrenaline was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 micromol/kg verapamil (VER). The maximal increase in heart rate in response to electrical nerve stimulation was 96 +/- 7 bpm (control, n = 6), 70 +/- 6 bpm (3 micromol/kg MIB, n = 8), 57 +/- 6 bpm (10 micromol/kg MIB, n = 5), 93 +/- 5 bpm (3 micromol/kg VER, n = 6) and 46 +/- 7 bpm (10 micromol/kg VER, n = 5). The tachycardic response to electrical stimulation at 1, 5 and 10 Hz was completely blocked by 5 mg/kg intravenous guanethidine. The maximal increase in heart rate in response to noradrenaline was 96 +/- 4 bpm (control, n = 6), 103 +/- 6 (3 micromol/kg MIB, n = 6), 42 +/- 9 bpm (10 micromol/kg MIB, n = 5), 73 +/- 5 bpm (3 micromol/kg VER, n = 5) and 40 +/- 7 bpm (10 micromol/kg VER, n = 6). Under control conditions and in the presence of 3 micromol/kg MIB and VER the maximal effect of noradrenaline was reached at 0.1 micromol/kg whereas in the presence of 10 micromol/kg MIB and VER it was reached at a dose of 1 micromol/kg. MIB at a dose of 3 micromol/kg was significantly more effective in reducing the chronotropic response to electrical stimulation compared with externally applied noradrenaline. For VER the opposite holds true. These differences were not observed with doses of 10 micromol/kg MIB and VER. Mibefradil, besides its direct effect on cardiac T- and L-type calcium channels, reduces the release of noradrenaline from sympathetic nerve endings, most probably by inhibition of presynaptic N-type calcium channels. In the model used this effect is only observable at relatively low concentrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade.

Comparison of some properties of pronethalol and propranolol. 1965.

Comparison of some properties of pronethalol and propranolol. 1965.

A Novel Orally Active Dopamine (DA) Prodrug TA-870. IV. Renal Vasodilatory and Negative Chronotropic Effects in Anesthetized Dogs

We investigated the involvement of the activations of dopamine (DA) receptors DA1 and DA2 in the effects of a novel DA prodrug TA-870 in anesthetized dogs and compared the effects with those of DA. Intravenous (i.v.) administration of TA-870 in anesthetized dogs produced a dose-dependent increase in free DA in blood and caused a decrease in renal vascular resistance (RVR) and an increase in renal blood flow (RBF). It also produced a bradycardia at high doses. In phenoxybenzamine-treated anesthetized dogs, the renal vasodilatory action of intrarenally administered TA-870 was less than or equal to that of i.v. TA-870, whereas that of intrarenally administered DA was greater than that of i.v. DA. The renal vasodilatory effects of TA-870 and DA were almost completely inhibited by the DA1 selective antagonist SCH-23390 but were not affected by the DA2 selective antagonist domperidone. In bilaterally vagotomized dogs, both TA-870 and DA at high doses partially reduced the positive chronotropic responses to the right postganglionic cardioaccelerator nerve stimulation; this effect was abolished after treatment with domperidone. In isolated guinea pig right atria, unchanged TA-870 and deethoxycarbonyl metabolite of TA-870, the intermediate from TA-870 to DA, did not affect the spontaneous atrial rate even at high concentrations, whereas DA produced a concentration-dependent increase in the rate. In addition, neither compound showed antagonistic action to the positive chronotropic effect of DA, which was competitively inhibited by propranolol. We conclude that the renal vasodilatory effect of TA-870 results simply from the activation of DA1 receptors by DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Validation of a novel technique allowing assessment of the functional role of cardiac prejunctional receptors in the rat

1. The electrical stimulation of the thoracic portion of the spinal cord (preganglionic nerve fibres) in the pithed rat is a widely used technique to investigate drug effects on the sympathetic nervous system. However, it does not allow discrimination between ganglionic and neuronal ending sites of action of drugs. This report describes and validates an experimental approach in which postganglionic nerve fibres are stimulated in pithed rats, thereby overcoming the above mentioned difficulty. 2. Electrical stimulation of a nerve below the thymus gland produced frequency-related increases in heart rate which were not modified by the ganglion blockers, hexamethonium or mecamylamine, but were reduced by the beta 1-adrenoceptor antagonist, betaxolol. Thus, the studied nerve fibres can be classified as sympathetic postganglionic neurons. 3. The parameters for electrical stimulation of postganglionic cardioaccelerator nerve fibres giving optimal responses were of similar pulse widths as required for the stimulation of the thoracic spinal cord, but of lower strength of current, higher frequencies and shorter stimulation times to achieve steady-state responses. 4. Clonidine reduced the tachycardia evoked by sustained electrical stimulation of postganglionic cardioaccelerator nerve fibres. This effect was antagonized entirely by the selective alpha 2-adrenoceptor antagonist, idazoxan. Therefore, sympathetic cardiac postganglionic nerve fibres are endowed with alpha 2-adrenoceptors.

SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors.

SK&F 89124 (4-[2-(N,N-di-n-propylamino)ethyl]-7-hydroxy-2(3H) indolone) can be considered as a derivative of N,N-di-n-propyldopamine (DPDA) in which the meta-hydroxyl is replaced by a cyclic amide function. SK&F 89124 is at least one order of magnitude more potent than DPDA as an agonist at peripheral inhibitory prejunctional dopamine receptors (DA2 receptors) in the isolated perfused rabbit ear artery. A potent agonist action of SK&F 89124 at the DA2 receptor can also be demonstrated by inhibition of radioactive overflow from prelabelled canine coronary artery or saphenous vein, and in the anesthetized dog as an inhibition of the tachycardia induced by cardioaccelerator nerve stimulation or the increase in hind-limb perfusion pressure induced by stimulation of the lumbar sympathetic chain. SK&F 89124 is a potent inhibitor of the binding of [3H]spiroperidol to D2 receptors in bovine pituitary homogenates. High concentrations of SK&F 89124 do not activate the adenylate cyclase D1 receptor in rat caudate homogenates, nor produce activation of alpha 2-adrenoceptors or H2-histamine receptors in the guinea pig atrium. Although some alpha 1-adrenoceptor mediated vasoconstriction is produced in the rabbit ear artery and rabbit aorta, the concentrations required are several orders of magnitude higher than those active at the DA2 receptor. From these data it is evident that this structural modification can increase both the potency and selectivity of DPDA as a DA2 receptor agonist. The potency and selectivity of SK&F 89124 make this agent a useful tool for determination of the functional role of the DA2 receptor.

Introduction of a putative dopaminergic prodrug moiety into a 6,7-substitution pattern characteristic of certain 2-aminotetralin dopaminergic agonists

On the basis of the premise that the dopaminergic agonist profile of 2-(di-n-propylamino)-5-hydroxy-6-methyltetralin (1a) is due to in vivo oxidation of the 6-methyl moiety and that 1a may represent a novel prodrug strategy, the vicinal methyl-hydroxyl substitution pattern was incorporated into the 6- and 7-positions of 2-(di-n-propylamino)tetralin to give the 6-methyl-7-hydroxy and 6-hydroxy-7-methyl isomers 8 and 9, respectively. A multistep synthetic approach was devised which permitted preparation of target molecules 8 and 9. Pharmacological data revealed that both target compounds exhibit modest dopamine-like effects in the cardioaccelerator nerve assay in the cat, but neither appeared to be metabolically activated as was the case with 1a. The effects of 9 (but not of 8) were antagonized by pretreatment with haloperidol. Thus, the 5-hydroxy-6-methyl substitution pattern in the 2-aminotetralins remains unique as a dopaminergic agonist prodrug structure.

Dopamine receptors in the stellate ganglion of the dog

Effects of fenoldopam, a selective DA 1 dopamine receptor agonist, and dipropyl dopamine and propylphenethyl dopamine, preferential DA 2 dopamine receptor agonists, on ganglion transmission were studied in pentobarbital-anesthetized, open chest dogs. Tachycardia induced by electrical stimulation (supramaximal voltage, 0.5 ms duration, 1–2 Hz) of the preganglionic cardio-accelerator nerves was monitored as a measure of ganglionic transmission. Drugs were injected into the costocervical artery (i.a.) close to the arterial supply of the ganglion. Doses required to produce 30–40% inhibition of ganglionic transmission by the i.a. route were 2–8 μg for dipropyl dopamine, 4–16 μg for propylphenethyl dopamine, and 100 μg for fenoldopam. At these doses none of the agonists affected tachycardia induced by electrical stimulation of the postganglionic nerve. Domperidone (5 μg/kg i.v.), a selective DA 2 dopamine receptor antagonist, markedly antagonized the effects of dipropyl dopamine and propylphenethyl dopamine, but had only minor (and statistically insignificant) effects on the inhibitory effect of fenoldopam. SCH 23390 (5 μg/kg i.v.), a selective and potent DA 1 antagonist, failed to modify the effects of any of the agonists. In a separate series, infusion of fenoldopam, 20 μg/kg per min i.v. for 5–7 min, facilitated postganglionic nerve stimulation and blocked the inhibitory effect of UK 14,304, an α 2-adrenoceptor agonist, on the postganglionic nerve. These results confirm and support the presence of DA 2 but do not support the presence of the prototypal DA 1 dopamine receptor in the mammalian ganglia. Furthermore, the α 2-adrenoceptor blocking property of fenoldopam points to the complication of using i.v. administration for studying its ganglionic actions while monitoring the target tissue effects in response to preganglionic nerve stimulation.

Potentiation by Dopexamine of the Cardiac Responses to Circulating and Neuronally Released Norepinephrine

Dopexamine is a new dopamine receptor agonist which also inhibits the uptake of norepinephrine (NE) into sympathetic nerves. Dopexamine was infused intravenously (i.v.) in anesthetized dogs at a rate used for treatment of congestive heart failure (4 micrograms/kg/min) before and during i.v. infusions of NE (0.26 +/- 0.06 and 0.57 +/- 0.12 micrograms/kg/min) and before and during cardioaccelerator nerve stimulation (0.25 and 0.50 Hz). Increments in cardiac contractile force produced by both infusion rates of NE were greater during dopexamine infusion; increases in heart rate (HR) and mean arterial pressure (MAP) produced by the higher infusion of NE also were increased by dopexamine. During cardioaccelerator nerve stimulation, 0.25 and 0.50 Hz, the increments in HR were significantly greater during dopexamine infusion; MAP also increased significantly during cardioaccelerator nerve stimulation (0.50 Hz) in the presence of dopexamine. Plasma NE concentration was significantly elevated during infusion of dopexamine. However, dopexamine did not enhance the elevated plasma NE concentration produced by NE infusions. This study demonstrates that infusion of dopexamine potentiates the cardiovascular effects resulting from neuronally released and exogenously infused NE.

Potentiation by Dopexamine of the Cardiac Responses to Circulating and Neuronally Released Norepinephrine

Summary: Dopexamine is a new dopamine receptor agonist which also inhibits the uptake of norepinephrine (NE) into sympathetic nerves. Dopexamine was infused intravenously (i.v.) in anesthetized dogs at a rate used for treatment of congestive heart failure (4 μg/kg/min) before and during i.v. infusions of NE (0.26 ± 0.06 and 0.57 ± 0.12 μg/kg/min) and before and during cardioaccelerator nerve stimulation (0.25 and 0.50 Hz). Increments in cardiac contractile force produced by both infusion rates of NE were greater during dopexamine infusion; increases in heart rate (HR) and mean arterial pressure (MAP) produced by the higher infusion of NE also were increased by dopexamine. During cardioaccelerator nerve stimulation, 0.25 and 0.50 Hz, the increments in HR were significantly greater during dopexamine infusion; MAP also increased significantly during cardioaccelerator nerve stimulation (0.50 Hz) in the presence of dopexamine. Plasma NE concentration was significantly elevated during infusion of dopexamine. However, dopexamine did not enhance the elevated plasma NE concentration produced by NE infusions. This study demonstrates that infusion of dopexamine potentiates the cardiovascular effects resulting from neuronally released and exogenously infused NE.

Effects of human ANF-(99–126) on sympathetic nerve function, hemodynamic parameters and plasma cGMP levels in anesthetized, ganglion-blocked dogs

The ability of human ANF-(99–126) (ANF) to affect neuronal function, plasma cGMP levels or various hemodynamic parameters was tested in anesthetized dogs subjected to ganglionic blockade which prevented reflex changes in sympathetic tone. In each group of dogs, heart rate changes due to electrical stimulation of the cardioaccelerator nerve at 0.5, 1, 3 and 10 Hz were measured before and after ANF or vehicle infusion. A possible direct effect of ANF on the β-adrenoceptor mechanisms was assessed by evaluating changes in heart rate after i.v. administration of isoproterenol (a β-adrenoceptor agonist). The results showed that i.v. infusion of ANF (200 pmol/kg per min for 60 min), but not vehicle, produced significant inhibition of heart rate responses to low frequency nerve stimulation (0.5–1 Hz) when compared to vehicle 30 min after the end of infusion; high frequency (10 Hz) responses remained unaffected. A significant ( P<0.05) enhancement in isoproterenol responses was evident in ANF-treated animals at the end of infusion, and 30 min afterward. ANF increased plasma cGMP from pretreatment levels of 28 ± 4 to 149 ± 1 pmol/ml at the end of infusion, and falling to 63 ± 7 pmol/ml 30 min later ( t 1 2 = 25.1 ± 2.2 min) . Cardiac output also tended to fall during infusion and remained significantly reduced (−18%) 30 min after infusion's end; blood pressure fell without a decrease in total peripheral resistance. Thus, ANF produced a direct, frequency-dependent depressant action on sympathetic nerve function, reduced both cardiac output and blood pressure, and enhanced chronotropic responses to β-adrenoceptor stimulation. These persistent changes in hemodynamic parameters and neuronal function may contribute to the mechanism of action of ANF.

Dependence of non-adrenergic inhibition of cardiac vagal action on peak frequency of sympathetic stimulation in the dog.

1. It is known that stimulation of the sympathetic cardioaccelerator nerve is followed by prolonged inhibition of cardiac vagal action. This prolonged inhibitory action of the sympathetic nerve is not blocked by alpha- or beta-adrenoceptor blockade, and is not duplicated by administration of noradrenaline. It has been proposed that it is due to the release of neuropeptide Y (NPY) from the sympathetic nerve terminals (Potter, 1984, 1985). 2. The present experiments examined whether prolonged inhibition of cardiac vagal action could be preferentially produced by sympathetic stimulation of different temporal distribution. The experiments were performed on anaesthetized, vagotomized dogs, with pharmacological beta-adrenoceptor blockade. 3. In six animals intermittent supramaximal sympathetic stimulation at 20 Hz (1/2 s stimulation, 1/2 s off; train duration 2 min; total 1200 stimuli) produced significantly greater inhibition (P less than 0.01) of cardiac vagal action than did continuous stimulation at 5 Hz (stimulus duration 4 min; 1200 stimuli). 4. In another series the same total period of stimulation (2.5 min; 1200 stimuli) was used and it was found that intermittent sympathetic stimulation of 16 Hz (1/2 s stimulation, 1/2 s off) produced significantly greater cardiac vagal inhibition (P less than 0.02) than continuous stimulation at 8 Hz. In this case the mean frequency of stimulation was constant but the higher peak stimulation frequency attenuated cardiac vagal action more effectively.

Presynaptic inhibition by dihydroergotoxine of the response to peripheral sympathetic nerve stimulation in rats

Dihydroergotoxine decreased the heart rate in both intact and pithed rats but increased blood pressure in pithed rats only. Dihydroergotoxine did not inhibit the postsynaptic effect of isoprenaline and noradrenaline but reduced the neurally induced pressor responses and tachycardia in the rat. The first effect was antagonized by sulpiride, and the second by yohimbine. It was concluded that dihydroergotoxine stimulates presynaptic α 2-adrenoceptors at the cardioaccelerator nerve endings, and presynaptic dopamine receptors at the sympathetic terminations innervating the vascular bed.

Cardiovascular characterization of the DA2 dopamine receptor agonist quinpirole in rats.

In normotensive anesthetized rats, 15-min IV infusions of quinpirole (2.5-40.0 micrograms/kg/min) produced dose-related, rapidly appearing, and long-lasting decreases in mean carotid artery BP and HR. Hemodynamically, the hypotensive effects of quinpirole (10.0 micrograms/kg/min) were due to a fall in total peripheral vascular resistance inasmuch as CO did not undergo significant changes. Mesenteric, hindquarter, and renal blood flows were, respectively, reduced, unchanged, and increased by quinpirole; thus, the renal vascular resistance fell more than either the total peripheral or hindquarter vascular resistance. Biochemically, the hypotensive effects of quinpirole were accompanied by a decrease in the plasma level of norepinephrine and plasma renin activity. The peak fall in blood pressure produced by quinpirole was not significantly modified by atenolol, idazoxan, ranitidine, SCH 23390 (DA1 dopamine receptor antagonist), enalapril, or SK&F 100273 (V1 vasopressin receptor antagonist), but was entirely blocked by S-sulpiride or removal of autonomic nerve drive to the cardiovascular system with chlorisondamine. The effect of quinpirole on systemic and regional vascular resistances was antagonized by S-sulpiride. Furthermore, SK&F 100273 prevented the fall in mesenteric flow produced by quinpirole. Intracerebroventricular injection of quinpirole (10.0 micrograms/kg over 2 min) in saline- or SK&F 100273-pretreated rats produced the same hypotensive effects as an identical IV dose of the compound. In pithed rats, quinpirole (10 micrograms/kg/min IV over 15 min) decreased pressor responses to electrical stimulation of spinal cord outflow without affecting those to exogenously injected angiotensin II, B-HT 920, cirazoline, norepinephrine, or 5-hydroxytryptamine. This inhibitory effect was antagonized by S-sulpiride. The bradycardia produced by quinpirole in intact rats was mediated by the autonomic nervous system inasmuch as it was slightly modified by bilateral vagotomy, partly reduced by atenolol, and entirely prevented by pithing even when the low HR of the last preparation had been raised by IV infusion of isoprenaline. Furthermore, S-sulpiride, but not SCH 23390 or idazoxan, antagonized this effect. In pithed rats, quinpirole similarly inhibited the tachycardic responses elicited by electrical stimulation of either the spinal cord outflow (preganglionic) or postganglionic cardioaccelerator nerve fibers. This effect of quinpirole was susceptible to S-sulpiride but not idazoxan blockade. Finally, in conscious spontaneously hypertensive rats (SHR) but not in normotensive rats, quinpirole (10 micrograms/kg/min IA over 15 min) lowered blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Electrical stimulation in perifornical lateral hypothalamus decreases coronary blood flow in cats.

Based on evidence implicating the central nervous system in the regulation of coronary vascular resistance and the knowledge that the hypothalamus is a central site for integration of cardiovascular control, studies were undertaken to determine if electrical stimulation in the hypothalamus produced coronary vasoconstriction. In anesthetized cats, following beta-adrenergic receptor blockade, stimulation in perifornical lateral hypothalamus produced a transient decrease in coronary blood flow velocity (30 +/- 5%), a small pressor effect (7 +/- 2 mmHg), and an initial decrease in hindquarter blood flow velocity (51 +/- 5%). The decrease in coronary flow velocity, which had an onset latency of 1-3 s and a duration of 5-15 s, was abolished by ipsilateral stellate ganglionectomy and by intravenous and intracoronary prazosin. The coronary vasoconstriction produced by hypothalamic stimulation was not different from that produced by cardioaccelerator nerve stimulation. These results suggest that electrical stimulation of a hypothalamic site produces an alpha-adrenergic receptor-mediated decrease in coronary blood flow that is unmasked by beta-adrenergic receptor blockade, requires the integrity of ipsilateral cardiac sympathetic innervation, and mimics the coronary response to cardioaccelerator nerve stimulation.

Synthesis and pharmacological evaluation of some 6-substituted 7-methyl-1,4-dioxa-7-azaspiro[4.5]decanes as potential dopamine agonists.

Three 7-methyl-1,4-dioxa-7-azaspiro[4.5]decanes that contained either the benzyl, 3-indolylmethyl, or 4-indolylmethyl group at the 6-position were synthesized via alkylation of the pyrrolidine enamine of the key intermediate, ethyl 3-oxopiperidine-1-carboxylate. The spirodecane derivatives were evaluated for in vivo central and peripheral dopamine agonist activity. None of the compounds displayed central nervous system activity; however, the 4-indolymethyl analogue exhibited potent dopamine agonist activity in the cat cardioaccelerator nerve assay and possesses an ID50 of 0.095 mumol/kg compared to apomorphine, which possesses an ID50 of 0.0348 mumol/kg in the same assay.

Direct effects of diltiazem, nifedipine and verapamil on peripheral sympathetic nerve function, cardiac impulse conduction and cardiovascular function in anesthetized dogs subjected to ganglionic blockade

The Ca 2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P<0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct β-adrenoceptor stimulation by isoproterenol (0.1 μg/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25–35 V, 5 ms), but not high frequency (10 Hz, 25–35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca 2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical Ca 2+ blockers as compared to other direct-acting vasodilators.