Recent advances in the pharmacotherapy of epilepsy.

The therapeutic options for the treatment of epilepsy have expanded during the 1990s. Since 1993, four novel agents (felbamate, gabapentin, lamotrigine, and topiramate) have been approved by the US Food and Drug Administration, primarily for adjunctive treatment of partial seizures. In addition, a water-soluble pro-drug of phenytoin, fosphenytoin, and a sustained-release preparation of carbamazepine have been introduced. The novel anticonvulsants represent a potential improvement for patients whose seizures are incompletely controlled or who experience significant adverse effects with older anticonvulsants. Felbamate, lamotrigine, and topiramate appear to have a broad spectrum of action in seizure control, but felbamate use is limited by the potential for serious adverse effects. Gabapentin, lamotrigine, and topiramate are all well tolerated. Gabapentin has no known drug interactions, whereas lamotrigine and topiramate have limited interactions compared with older agents. The sustained-release preparation of carbamazepine may decrease the incidence of adverse effects and increase patient compliance. Fosphenytoin offers a safer method for intravenous administration of phenytoin and the added flexibility of intramuscular administration. Taken together, these recent advances in treatment may bring about improved efficacy and decreased adverse effects for many patients with epilepsy.

In vitro and in vivo evaluation of an endothelin inhibitor reveals novel K+ channel opening activity.

A low molecular weight endothelin (ET-1) inhibitor (Ex. 127, European Patent Application 404 525 A2, Takeda Chemical Ind., 1991), CGS 26061, was synthesized and evaluated to determine its mechanism of action. CGS 26061 (10 microM) failed to inhibit binding of [125I]ET-1 in porcine thoracic aorta and was without effect on ET-1-induced [3H]inositol phosphate accumulation in A7r5 cells. However, CGS 26061 relaxed porcine coronary arterial rings precontracted with ET-1. In addition, contractions to PGF2 alpha and low K+ (20 mM) but not high K+ were attenuated, suggesting that CGS 26061 (1, 10 microM) is a potassium channel opener. Patch-clamp experiments confirmed the K+ channel activity (0.1-10 microM). The originally re ported inhibition of ET-1-induced pressor responses by Ex. 127 (CGS 26061) was not replicated in the anesthetized dog or conscious rat nor was it shown to be antihypertensive in SHR. These data have identified CGS 26061 as a novel K+ channel opener with a unique cardiovascular profile.

Telemetric monitoring of cardiovascular parameters in conscious spontaneously hypertensive rats.

We compared cardiovascular values obtained with a telemetric system simultaneously with those recorded by an externalized catheter in spontaneously hypertensive rats (SHR). We also tested the hypothesis that telemetric monitoring reduces the amount of stress associated with performance of cardiovascular studies. Femoral arterial and venous catheters were implanted under methoxyflurane anesthesia in male SHR previously implanted 38 +/- 7 days earlier with radiotelemetric devices. Rats were then allowed 1 day to recover before undergoing experimentation. Baseline blood pressure (BP) and heart rate (HR) values obtained with the telemetric system and with the femoral arterial catheters were similar, and intravenous (i.v.) administration of phenylephrine (PE), angiotensin I (ANGI), acetylcholine (ACh), or nitroglycerin (NTG) evoked similar changes in BP and HR. Hemodynamic responses evoked by i.v. administration of nifedipine were also similar as recorded by telemetric monitoring and the femoral arterial cannula. Baseline cardiovascular parameters measured in SHR instrumented only with telemetric devices consistently yielded BP and HR values significantly lower than those recorded by tail-cuff or femoral catheters. In addition, SHR subjected to the tail-cuff procedure responded to oral administration of captopril with a greater degree of hypotension. These studies demonstrate that telemetric monitoring of cardiovascular parameters in conscious rats is a sensitive, accurate, and flexible method. The lower basal cardiovascular values and the insensitivity to the hypotensive effects of angiotensin-converting enzyme (ACE) inhibition, suggest that a decreased level of stress is associated with performance of cardiovascular studies by a radiotelemetric system.

Hemodynamic effects of amlodipine and benazeprilat in spontaneously hypertensive rats.

We wished to assess the hemodynamic effects of administration of the combination of the calcium channel blocking agent amlodipine and the angiotensin-converting enzyme (ACE) inhibitor benazeprilat in conscious spontaneously hypertensive rats (SHR). In SHR previously instrumented for measurement of mean arterial blood pressure (MAP) and heart rate (HR), intravenous (i.v.) injection of amlodipine (0.25-4 mg/kg) produced dose-dependent decreases in blood pressure (BP). Administration of benazeprilat (0.1-10 mg/kg i.v.) decreased arterial MAP, and benazeprilat (10 mg/kg) effectively blocked the effects of exogenously administered angiotensin I (AI). In animals surgically prepared for measurement of BP, HR, and hindquarter, renal, and mesenteric blood flows, administration (i.v.) of the combination of amlodipine (0.5 mg/kg) with benazeprilat (10 mg/kg) evoked a decrease in BP that was greater than that elicited by monotherapy. The tachycardic response observed after administration of the combination was no different from that observed after monotherapy with amlodipine. Simultaneous administration of amlodipine and benazeprilat produced reductions in vascular resistance in the hindquarter, renal and mesenteric beds that were greater than the responses evoked by injection of either agent. The major finding of these studies was that dual therapy with amlodipine and benazeprilat produced an additive hypotensive effect in conscious SHR. Regional vasodilation accompanied the large degree of hypotension evoked by the combination.

Sympathoexcitation from the rostral ventrolateral medulla is mediated by spinal NMDA receptors.

These studies examined the role of spinal N-methyl-D-aspartic acid (NMDA) receptors in mediating sympathoexcitation evoked by stimulation of neurons in the rostral ventrolateral medulla (RVLM). In urethane-anesthetized rats, blood pressure, heart rate, and splanchnic sympathetic nerve activity (SNA) were recorded. The NMDA receptor antagonist D-2-amino-7-phosphonoheptanoic acid (D-AP7) was administered to the spinal cord via intrathecal (IT) catheter. Blockade of spinal NMDA receptors reduced arterial blood pressure, heart rate, and SNA. Spinal administration of D-AP7 markedly attenuated the pressor and sympathoexcitatory responses evoked by L-glutamate stimulation of the RVLM. The small increases in heart rate evoked by stimulation of the RVLM were not affected by IT administration of D-AP7. These results indicate that NMDA receptors in the spinal cord mediate the pressor and sympathoexcitatory responses evoked by activation of a bulbospinal pathway originating from the RVLM. Moreover, these data suggest that excitatory amino acid neurotransmitters and NMDA receptors in the spinal cord play an important role in the maintenance and regulation of SNA and cardiovascular function.

Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats.

The present experiments describe the endothelin-1 (ET-1) antagonist activity of BQ123 (cyclic D-Asp-L-Pro-D-Val-L-Leu-D-Trp) in conscious Sprague-Dawley (SD) rats, and we also examined the effect blockade of ETA receptors had on blood pressure in four experimental models of hypertension. Rats were anesthetized with methoxyflurane and instrumented with femoral arterial and venous catheters. In SD rats, BQ123 (0.1-10.0 mg/kg i.v.) administered 5 or 60 min prior to ET-1 inhibited both the magnitude and duration of the ET-1 (0.25 nmol/kg i.v.) pressor response. In addition, BQ123 (10.0 mg/kg) inhibited the pressor response evoked by administration of the ET-1 precursor, proendothelin-1 (1.0 nmol/kg). However, BQ123 (10.0 mg/kg) had no effect on the pressor response evoked by ET-3 (0.75 nmol/kg). In Wistar-Kyoto rats, BQ123 (10.0 mg/kg) reversed the hypertension produced by an infusion of ET-1 (0.01 nmol/kg/min). Administration of BQ123 produced a mild antihypertensive effect in normal- to low-renin models of hypertension, but no blood pressure lowering was observed in high-renin models of hypertension. These studies demonstrated the selectivity of the ETA receptor antagonist, BQ123 for ET-1, but not ET-3-induced pressor responses. Furthermore, ET-1 does not appear to be a major contributing factor to the maintenance of elevated levels of blood pressure in four experimental models of hypertension.

Effect of blockade of spinal NMDA receptors on sympathoexcitation and cardiovascular responses produced by cerebral ischemia.

Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors in the spinal cord was produced by intrathecal administration of the NMDA receptor antagonist D-2-amino-7-phosphonoheptanoic acid. Blockade of spinal NMDA receptors significantly reduced arterial pressure, heart rate and sympathetic nerve activity and reduced by approximately 50% the pressor and sympathoexcitatory responses evoked by cerebral ischemia. These results indicate that NMDA receptors in the spinal cord participate in the maintenance and regulation of the sympathetic nervous system and suggest that excitatory amino acid neurotransmitters may play a role in sympathoexcitation produced by physiological activation of descending bulbospinal pathways.

Spinal NMDA receptors mediate pressor responses evoked from the rostral ventrolateral medulla.

These studies investigated the role of spinal N-methyl-D-aspartic acid (NMDA) receptors in the mediation of cardiovascular responses evoked by L-glutamate (L-Glu) stimulation of the rostral ventrolateral medulla (RVM). Microinjections of L-Glu into the RVM of urethan-anesthetized rats increased mean arterial pressure (MAP) and heart rate. Intrathecal administration of the NMDA receptor antagonists D-(-)-2-amino-7-phosphonoheptanoic acid (D-AP-7) or 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) reduced MAP and heart rate. Blockade of NMDA receptors by D-AP-7 or CPP in the caudal thoracic spinal cord markedly reduced RVM pressor responses with little effect on evoked tachycardia. Administration of D-AP-7 to the rostral thoracic spinal cord had no effect on RVM pressor or tachycardic responses. Intrathecal D-AP-7 and CPP abolished the cardiovascular effects of intrathecal NMDA without reducing those produced by intrathecal kainic acid or the quisqualate agonist DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). These results indicate that 1) tonic activation of spinal NMDA receptors participates in the maintenance of sympathetic outflow to the heart and blood vessels, 2) pressor responses evoked from the RVM require synaptic activation of spinal NMDA receptors, and 3) an excitatory amino acid may be the neurotransmitter of pressor pathways descending from the RVM to the spinal cord.

Blockade of parabrachial pressor responses by spinal administration of an N-methyl-D-aspartic acid receptor antagonist.

The purpose of these studies was to investigate a potential role for N-methyl-D-aspartic acid (NMDA) receptors in the spinal cord, in the mediation of pressor responses, evoked by electrical stimulation of supraspinal pressor sites. Graded electrical stimulation (10-40 Hz) of the lateral parabrachial complex increased the mean arterial pressure by 19 to 59 mmHg, and heart rate by 4 to 12 beats/min. Intrathecal administration of the NMDA receptor antagonist D-2-amino-7-phosphonoheptanoic acid (D-AP7; 200 nmol/10 microliters) reduced the arterial pressure from 101 to 68 mmHg and heart rate from 364 to 330 beats/min. Parabrachial pressor responses were virtually eliminated after spinal administration of D-AP7 while tachycardic responses were not significantly affected. Neither intravenous administration of D-AP7 nor intrathecal infusion of vehicle had any effect on parabrachial pressor responses. Intrathecal infusion of NMDA (50 nmol) increased arterial pressure by 43 mmHg and heart rate by 53 beats/min. Intrathecal infusion of kainic acid (3 nmol) increased arterial pressure by 38 mmHg and heart rate by 54 beats/min. Intrathecal infusion of D-AP7 eliminated the pressor and tachycardic actions of NMDA, without affecting those of kainic acid. These results suggest that the maintenance of sympathetic vasomotor tone as well as the mediation of pressor responses produced by electrical stimulation of the parabrachial complex, is dependent upon synaptic activation of spinal NMDA receptors and further, that excitatory amino acid neurotransmitters in the spinal cord may play a significant role in central cardiovascular regulation.