zd-7155 and Disease-Models--Animal

In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar-Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Disease Models, Animal; Dopamine; Excitatory Amino Acid Agonists; Hippocampus; Kainic Acid; Male; Naphthyridines; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Status Epilepticus

The study was undertaken to examine the involvement of the renin-angiotensin system in the reversal by endogenous central histamine of critical haemorrhagic hypotension in anaesthetised Wistar rats. Histamine N-methyltransferase inhibitor metoprine (20 microg) administered intracerebroventricularly at 5 min of critical hypotension 20-25 mmHg produced increases in histamine concentrations as measured 20 min after treatment in the hypothalamus (581.33 +/- 63.23 vs. 488.26 +/- 56.34 ng/g of wet tissue; P < 0.01) and medulla oblongata (53.42 +/- 14.65 vs. 34.68 +/- 13.52 ng/g of wet tissue; P < 0.05). That was accompanied by 34.7% higher plasma angiotensin II concentration in comparison to the control group. Metoprine produced dose-dependent (5-20 microg) rises in mean arterial pressure (MAP) and heart rate, which were significantly higher than those in normotensive animals. The resuscitating action of metoprine (20 microg) was associated with rises in renal, mesenteric and hindquarters blood flows, and a 100% survival at 2 h after treatment, while in the saline-treated group, all the animals died within 30 min. Angiotensin type 1 (AT(1)) receptor antagonist ZD 7155 (0.5 mg/kg; iv) decreased regional vascular resistance and inhibited metoprine-induced increase in MAP, whereas AT(2) receptor blocker PD 123319 (10 mg/kg; i.v.) had no effect. Angiotensin-converting enzyme inhibitor captopril (30 mg/kg; i.v.) reduced the increase in plasma angiotensin II level and the haemodynamic effects of metoprine. Neither capropril, nor angiotensin receptor antagonists influence the survival at 2 h after treatment. In conclusion, the renin-angiotensin system is involved in central histamine-induced resuscitating action in rats.

Topics: Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Animals; Blood Pressure; Brain Chemistry; Captopril; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hindlimb; Histamine; Histamine N-Methyltransferase; Hypotension; Hypothalamus; Imidazoles; Injections, Intraperitoneal; Injections, Intravenous; Injections, Intraventricular; Male; Medulla Oblongata; Naphthyridines; Pyridines; Pyrimethamine; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Resuscitation; Shock, Hemorrhagic; Time Factors; Vascular Resistance