am-404 and Hypertension

Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).. In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.. Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.

Topics: Animals; Arachidonic Acids; Arterial Pressure; Cerebrovascular Circulation; Endocannabinoids; Heart Rate; Hemodynamics; Hypercapnia; Hypertension; Hypoxia; Laser-Doppler Flowmetry; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

To explore the role of anandamide (AEA) transporter in regulating calcitonin gene-related peptide (CGRP) production and blood pressure.. Plasma levels of AEA, CGRP, asymmetric dimethylarginine (ADMA) and nitric oxide in patients with essential hypertension, spontaneously hypertensive rats (SHRs) and 2 kidney 1 clip hypertensive rats and the CGRP mRNA expression in dorsal root ganglion of rats were measured. Peripheral blood lymphocytes were isolated to examine the AEA transporter activity, the role of AEA transporter in regulating CGRP mRNA expression or the effect of exogenous ADMA on AEA transporter activity. In both hypertensive patients and SHRs, the plasma level of AEA was elevated, but the AEA transporter activity was attenuated concomitantly with decreased CGRP production. Moreover, plasma ADMA level in SHRs was elevated accompanied by decreased nitric oxide level. By contrast, the plasma AEA level was elevated accompanied by increased CGRP production in 2 kidney 1 clip hypertensive rats, and there were no significant changes in plasma levels of ADMA, nitric oxide and the AEA transporter activity. In vitro, exogenous administration of AEA upregulated CGRP mRNA expression in lymphocytes, which was inhibited by AEA transporter blocker, AM404, and the AEA transporter activity was reduced by ADMA.. Decreased plasma CGRP level in patients with essential hypertension or SHRs is likely due to the reduced AEA transporter activity, and the increased ADMA level may account for the reduced AEA transporter activity.

Topics: Animals; Arachidonic Acids; Arginine; Base Sequence; Blood Pressure; Calcitonin Gene-Related Peptide; Carrier Proteins; Case-Control Studies; DNA Primers; Endocannabinoids; Ganglia, Spinal; Humans; Hypertension; Hypertension, Renovascular; In Vitro Techniques; Lymphocytes; Male; Polyunsaturated Alkamides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; RNA, Messenger

Previously, we found that endocannabinoids acting at cannabinoid 1 receptors in the nucleus tractus solitarius prolonged baroreflex inhibition of renal sympathetic nerve activity in normotensive Sprague Dawley rats. The current study investigated whether endocannabinoid signaling was altered in spontaneously hypertensive rats, a model marked by elevated sympathetic activity and depressed baroreflex responses. The effects of endocannabinoids in the nucleus tractus solitarius on baroreflex control of renal sympathetic nerve activity evoked by systemic pressor changes or by direct stimulation of nucleus tractus solitarius neurons, which produced depressor and sympathoinhibitory responses, were studied in Sprague Dawley rats, Wistar Kyoto rats, and spontaneously hypertensive rats. Evoked responses were compared before and after microinjection of AM404, which prolonged actions of endogenous endocannabinoids, or microinjection of an endocannabinoid, anandamide, into the baroreceptive region of the nucleus tractus solitarius. AM404 microinjections significantly prolonged evoked sympathoinhibition in Sprague Dawley and Wistar Kyoto rats, but had little effect in spontaneously hypertensive rats. Microinjections of anandamide prolonged sympathoinhibition in Sprague Dawley rats, with lesser effects in Wistar Kyoto rats and no effects in spontaneously hypertensive rats. Parallel studies found that density of binding sites of endocannabinoids in the nucleus tractus solitarius was significantly reduced in spontaneously hypertensive rats versus the normotensive rats. Results indicate that attenuated function of the endocannabinoid system in the nucleus tractus solitarius of spontaneously hypertensive rats resulted in less modulation of baroreflex-evoked sympathoinhibition and that reduced cannabinoid 1 receptor density could contribute to blunted baroreflex-induced sympathoinhibition and elevated sympathetic tone characteristic of spontaneously hypertensive rats.

Topics: Analgesics; Animals; Arachidonic Acids; Baroreflex; Blood Pressure; Cannabinoid Receptor Modulators; Cyclohexanols; Endocannabinoids; GABA Antagonists; Hypertension; Male; Protein Binding; Pyridazines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Cannabinoid, CB1; Solitary Nucleus; Sympathetic Nervous System; Time Factors; Tritium

Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension.. In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats.. We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.

Topics: Amidohydrolases; Angiotensin II; Animals; Arachidonic Acids; Benzamides; Benzyl Compounds; Blood Pressure; Camphanes; Carbamates; Dronabinol; Endocannabinoids; Endothelium, Vascular; Hypertension; Male; Models, Cardiovascular; Myocardial Contraction; Myocardium; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Up-Regulation; Vascular Resistance; Vasodilation; Ventricular Function, Left