cardiovascular-agents and anandamide

Despite their presence in many tissues and their potential implication in various disease states, low-voltage activated T-type calcium channels (T-channels) have only recently become targets of interest. Unfortunately, the lack of selective T-channel blockers has hampered further characterisation of these channels. The recent availability of cloned T-channels, the Ca(V)3 proteins, facilitates identification of novel T-channel blockers. Also, studies performed in knockout animals have fostered novel interest. Selective inhibition of T-channels may have clinical importance in cardiovascular diseases, some forms of epilepsy, sleep disorders, pain and possibly cancer. This review focuses on novel research approaches to discover potent and selective T-channel modulators. These molecules may be potential drugs for treating human diseases, as well as important tools to decipher the physiological role of these channels.

Topics: Analgesics; Animals; Anticonvulsants; Arachidonic Acids; Autistic Disorder; Calcium; Calcium Channel Blockers; Calcium Channels, T-Type; Cardiovascular Agents; Cardiovascular Diseases; Cations; Drug Design; Endocannabinoids; Epilepsy; Humans; Mice; Mice, Knockout; Polyunsaturated Alkamides; Scorpion Venoms; Sleep Disorders, Intrinsic

The prototypic endocannabinoid, anandamide, and synthetic analogues have been shown to elicit pressor and depressor effects, bradycardia, vasorelaxation, and inhibition of neurotransmission in the central and peripheral nervous systems. Cannabinoid-mediated inhibition of neurotransmission is mediated by inhibition of voltage-gated Ca(2+) channels and adenylyl cyclase and activation of inwardly rectifying K(+) channels. The precise mechanisms underlying the vasorelaxant actions of cannabinoids are currently unclear, but might involve both receptor-dependent and -independent and endothelium-dependent and -independent pathways. Mechanisms proposed have included the release of endothelial autacoids, activation of myoendothelial gap junctions, activation of the Na(+) pump, activation of K(+) channels, inhibition of Ca(2+) channels, and activation of vanilloid receptors, leading to the release of sensory neurotransmitters. Pathophysiologically, the vasodilator actions of endocannabinoids have been implicated in the hypotension associated with both septic and haemorrhagic shock, but their physiological significance remains to be determined.

Topics: Animals; Arachidonic Acids; Blood Vessels; Cannabinoid Receptor Modulators; Cannabinoids; Cardiovascular Agents; Endocannabinoids; Fatty Acids, Unsaturated; Humans; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Synaptic Transmission; Vasoconstriction; Vasodilation

Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems.. Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)(2) receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over-express recombinant CB(2) receptor.. Anandamide and S1P induced relaxation of the rat CA. CB(2) receptor antagonists attenuated anandamide-induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P(3). Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide-mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P(3), specifically within the vascular endothelium, was required for anandamide-mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB(2) receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB(2) receptor was also observed in HEK293 cells over-expressing the CB(2) receptor.. In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P(3). In addition, we report that S1P may exert some of its effects via a CB(2) receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P(3) to induce vascular relaxation.

Topics: Animals; Arachidonic Acids; Calcium Channel Blockers; Cardiovascular Agents; Cell Line; Coronary Vessels; Dronabinol; Endocannabinoids; Humans; Indoles; Indomethacin; Lysophospholipids; Male; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Sphingosine; Vasodilation