Nerve Stimulation In Pithed Rats Research Articles

Blood pressure, the renin-angiotensin system and neurogenic vasoconstriction in pithed rats.

The influence of changing baseline blood pressure by various means, both related or unrelated to the renin-angiotensin system, on the pressor responses to spinal cord stimulation has been examined in the pithed rat. Mean arterial pressure and neurogenic vasoconstriction were higher in pithed rats with intact kidneys (2-kidney rats) than in nephrectomized pithed rats. Increasing blood pressure by infusion of vasopressin increased the pressor response to nerve stimulation in both 2-kidney and nephrectomized pithed rats. Decreasing blood pressure produced by administration of enalaprilat or hydralazine in 2-kidney pithed rats or by administration of hydralazine in nephrectomized pithed rats, decreased the pressor responses to nerve stimulation. Our results showed a positive correlation between the mean arterial blood pressure and the response to nerve stimulation in pithed rats. Therefore, we conclude that the pithed rat is an animal model which should be used with caution to study the interaction between the sympathetic nervous system and drugs which change baseline blood pressure.

(+)-Nantenine isolated from Nandina domestica Thunb. inhibits adrenergic pressor responses in pithed rats

The effects of (+)-nantenine on various pressor responses, recently reported exerting competitive antagonistic activity at the α 1-adrenoceptor/5-hydroxytryptamine (5-HT) 2A receptor, were examined in vivo. (+)-Nantenine (0.03–3 mg/kg) caused a dose-dependent inhibition of the pressor response to phenylephrine (α 1-adrenoceptor agonist) or 5-HT (5-HT receptor agonist) in both anesthetized and pithed rats. The pressor response to UK 14304 (5-Bromo- N-[2-imidazolin-2-yl]-6-quinoxalinamine) (an α 2-adrenoceptor agonist) was inhibited by (+)-nantenine (0.003–3 mg/kg) in pithed rats in a dose-dependent manner without affecting the angiotensin II-induced pressor response in anesthetized rats. The pressor response to sympathetic nerve stimulation was also inhibited by (+)-nantenine (0.3–3 mg/kg) in a dose-dependent manner. (+)-Nantenine (3 mg/kg) facilitated the norepinephrine release induced by sympathetic nerve stimulation in pithed rats. In the guinea pig vas deferens, the initial component of contractions induced by electrical field stimulation was enhanced by (+)-nantenine (1–30 μM) in a concentration-dependent manner, while the later component was inhibited by it. These data suggest that (+)-nantenine has antagonistic activities on α 1-adrenoceptors, α 2-adrenoceptors and 5-HT 2A receptors in pithed rats.

Participation of angiotensin II in pressor response and norepinephrine release to spinal nerve stimulation in pithed rats.

Experiments were carried out to examine whether endogenous angiotensin II (A-II) is involved in the regulation of release of norepinephrine (NE) elicited by the stimulation of spinal sympathetic nerves in pithed rats. It was assessed in terms of the alterations in concentrations of arterial blood plasma A-II and NE elicited by nerve stimulation (5 Hz, 50 V, 1 msec for 45 s) in pithed rats under vehicle or captopril (3 mg/kg, i.v.) treatment. Comparative study with pentobarbital anesthetized rats showed that pithing rats have the characteristics of lower basal blood pressure and lower NE level, whereas they have higher basal A-II level. In pithed rats treated with vehicle, pressor response to nerve stimulation was accompanied by increases in both A-II and NE level. In rats treated with captopril, the nerve stimulation caused about 40% lower increases in pressor response and NE level than those observed in rats treated with vehicle. These results suggest that the sympathetic nerve-induced NE release is facilitated by endogenous A-II in pithed rats, and that captopril exerts its inhibitory effect on the pressor response to nerve stimulation through the suppression of this interaction.

Cardiovascular Effects of Oxymetazoline and UK14,304 in Conscious and Pithed Rats

Relatively selective α2-adrenoceptor agonists have proven useful in a variety of therapeutic situations including hypertension, glaucoma and withdrawal from opiate addiction. In particular, oxymetazoline (OXY) and UK14,304 (UK) have been used in subclassifying α2-adrenoceptors and imidazoline receptors. We evaluated the cardiovascular effects of OXY and UK in conscious and pithed rats in the presence and absence of efaroxan (EFA), idazoxan (IDA) and rauwolscine (RAU). Both OXY or UK (1, 5 and 10 μg/kg, i.v.) increased blood pressure (BP) and reduced heart rate (HR) in conscious rats. In pithed rats, OXY and UK each increased BP to a greater extent than that observed in conscious rats, but HR was not affected. BP increases following sympathetic nerve stimulation in the pithed rats were not affected by OXY but were reduced by UK at 0.1 Hz and 0.3 Hz. HR responses to nerve stimulation in pithed rats were reduced after OXY at all frequencies, but only at 0.1 Hz following UK. EFA, IDA and RAU inhibited the pressor responses of UK, with EFA being most potent. OXY-induced pressor responses were inhibited by all three antagonists, RAU being the least potent. HR responses to either OXY or UK were not affected by the antagonists. Taken together, the data suggest that: 1) α2-adrenoceptors contribute less to the vascular response to OXY than to UK based upon the antagonistic effect of RAU; 2) prejunctional I1 receptors maybe more prevalent in the heart than in vascular tissue based upon the response to OXY in pithed rats. Thus, the heterogeneity among receptors mediating cardiac and vascular responses are complex.

5-Hydroxytryptamine inhibits pressor responses to preganglionic sympathetic nerve stimulation in pithed rats

5-Hydroxytryptamine (5-HT) inhibits contractile responses to adrenergic nerve stimulation in several blood vessels and organs. We have now investigated the potential ability of 5-HT to inhibit the presser responses caused by preganglionic sympathetic stimulation (T 7-T 9) in pithed rats. Sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) resulted in frequency-dependent increases in diastolic blood pressure; these effects were augmented after i.v. treatment with desipramine (50 μg/kg). During continuous infusions of 5-HT (1.8, 3.1, 5.6 and 10 μg/kg.Min, I.v.), but not of saline, the pressor responses were dose-dependently inhibited in both control and desipramine-pretreated rats; this inhibitory effect of 5-HT was significantly more pronounced at lower frequencies of stimulation. In contrast, the above infusions of 5-HT did not inhibit the pressor responses induced by i.v. bolus injections of exogenous norepinephrine (up to 3 μg/kg). Taken together, the above findings suggest an operative 5-HT-induced prejunctional inhibition of sympathetic nerve activity on the systemic vasculature in vivo.

Endogenous Nitric Oxide Modulates Vasopressor Responses, but Not Depressor Responses, to Spinal Sympathetic Nerve Stimulation in Pithed Rats

Journal of Cardiovascular Pharmacology™ is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, clinical results with new and established agents and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases.

Endogenous Nitric Oxide Modulates Vasopressor Responses, but Not Depressor Responses, to Spinal Sympathetic Nerve Stimulation in Pithed Rats

The effects of N omega-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide (NO) synthase (1,5, and 10 mg/kg) on vasopressor and depressor responses to segmental sympathetic nerve stimulation were studied in the pithed rat preparation. Vasopressor responses were evoked by stimulation of the spinal sympathetic outflow at T6-T8 (30 V, 0.05 ms at 5 Hz with 10 pulses). This pressor response was biphasic: An initial transient response (to nerve stimulation) was followed by a later prolonged response (to adrenal catecholamine release). L-NAME 1, 5, and 10 mg/kg increased mean arterial blood pressure (MAP); this effect was maximal at 1 mg/kg L-NAME, but had no effect on heart rate (HR). L-NAME 1, 5, and 10 mg/kg potentiated both phases of the pressor response; the effect was maximal at 10 mg/kg. Vasodepressor responses were evoked by stimulation of the spinal sympathetic outflow at S2-L6 (30 V, 0.05 ms at 5 Hz with 10 pulses). L-NAME 1, 5, and 10 mg/kg did not inhibit these depressor responses. We conclude that inhibition of the synthesis of endogenous NO causes a hypertension in pithed rats that is associated with increased vasoconstriction in response to sympathetic nerve stimulation and adrenal catecholamine release. Systemic vascular depressor responses to segmental sympathetic nerve stimulation are not affected, however; therefore, NO cannot be the major mediator of these responses.

Failure of selective antagonists (CH‐38083 and idazoxan) to distinguish between prejunctional and postjunctional α2‐adrenoreceptors

1. The prejunctional alpha 2-adrenoreceptor antagonist activity of CH-38083 (7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl), idazoxan and prazosin was determined against B-HT 920 on the tachycardia induced by cardiac nerve stimulation in pithed rats. Antagonism of cirazoline and B-HT 920 pressor responses was used to assess postjunctional alpha 1- and alpha 2-adrenoreceptor antagonist activities. 2. CH-38083 was more potent than idazoxan in blocking pre- and postjunctional alpha 2-adrenoreceptor sites. There was no difference between the activities of the two selective alpha 2-adrenoreceptor blocking agents on pre- and postjunctional alpha 2-adrenoreceptors. 3. These data classify CH-38083 as a potent and highly selective alpha 2-adrenoreceptor antagonist in vivo and further support evidence of the homogeneity of pre- and postjunctional alpha 2-adrenoreceptors.

Resistance of sympathetic cardiac nerve function in the pithed rat to prejunctional effects of angiotensin II.

1. The spinal sympathetic outflow (C7-T2) of pithed male Wistar rats was electrically stimulated (30-50 V, 0.5 ms, 0.1-1.0 Hz) and heart rate and arterial blood pressure were recorded. D-Tubocurarine (1 mg/kg) and atropine (1 mg/kg) were administered intravenously (i.v.) to reduce voluntary and parasympathetic nerve activity. 2. Angiotensin II (0.39-3.4 micrograms/kg per min) was infused at a rate which caused a sustained rise in diastolic blood pressure of at least 25 mmHg but which did not alter basal heart rate. 3. Chronotropic responses to sympathetic nerve stimulation were not affected by infusion of angiotensin II, and were also unaltered by pretreatment of rats with indomethacin (5 mg/kg, i.v.) 10 min prior to commencement of stimulation. 4. These results suggest that positive chronotropic responses to cardiac sympathetic nerve stimulation in pithed rats are not affected by increased angiotensin II levels. Indomethacin had no effect, which indicates that cyclo-oxygenase products were not involved in modulation of chronotropic responses to cardiac sympathetic nerve stimulation.

The effects of two pyrethroids, cismethrin and deltamethrin, on skeletal muscle and the trigeminal reflex system in the rat

The actions of a cyano pyrethroid (deltamethrin) and a non-cyano pyrethroid (cismethrin) upon trigeminal motor reflexes and isolated muscle responses were studied in the rat. Deltamethrin caused a marked facilitation of the muscle response to nerve stimulation in pithed rats at 2.5 μmol kg −1. In intact anaesthetised rats this was associated with abnormal repetitive EMG discharges and, at 4 μmol kg −1 with a suppression of late components of the reflex response to sensory stimuli in the spinal trigeminal nucleus and trigeminal motor nucleus. In contrast cismethrin had no effect on the muscle response to direct nerve stimulation at up to 15 μmol kg −1, but produced abnormal extra responses to sensory stimuli in the trigeminal ganglion, spinal and motor nuclei, and jaw muscles at 9 μmol kg −1. It is concluded that whilst deltamethrin produces reflex excitation within the trigeminal system at a primarily muscular site, cismethrin produces excitation at all stages of the reflex loop. This contrast is consistent with the known difference in duration of sodium current prolongation produced by the two pyrethroids. These findings, together with other known central actions of deltamethrin suggest that it has multiple sites of action in the intact animal, both central and peripheral, whilst most of the simpler symptoms produced by cismethrin may adequately be explained by action at a reflex level.

Presynaptic modulation of heart rate responses to cardiac nerve stimulation in pithed rats.

The effects of presynaptic alpha-adrenoceptor blockade with phentolamine, before and after inhibition of uptake-1 with cocaine, on the positive chronotropic response to cardiac sympathetic nerve stimulation in pithed rats was investigated. Phentolamine or cocaine each enhanced the cardiac responses to stimulation at 1 Hz for 15 sec by 10-25%; the combination of the drugs caused no greater enhancement than did either drug alone. Cocaine considerably potentiated the tachycardia produced during prolonged stimulation at 0.1 but not at 0.2-1 Hz. Phentolamine potentiated the responses to stimulation at 0.2 and 0.5 Hz by 21 and 12%, respectively, but not those at 0.1 or 1 Hz. After cocaine, phentolamine caused a further small increase in the response at 0.1 Hz but not other frequency. It is concluded that presynaptic alpha-adrenoceptors exert only modest control over the responses of the rat heart to cardiac nerve stimulation and that this modulation is little influenced by uptake-1.