Central endogenous histamine modulates sympathetic outflow through H(3) receptors in the conscious rabbit

1. This study examined the role of histamine H(3) receptors in vagal and sympathetic autonomic reflexes in the conscious rabbit, and in rabbit and guinea-pig isolated right atria. 2. The baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch-like and nasopharyngeal reflexes were assessed after these treatments (i.v.; with H(1) and H(2) receptor block): (i) vehicle (saline; n=11); (ii) H(3) receptor agonist, (R)-α-methylhistamine (R-α-MH) 100 μg kg(−1)+100 μg kg(−1) h(−1) (n=9); (iii) H(3) receptor antagonist, thioperamide 1 mg kg(−1)+1 mg kg(−1) h(−1) (n=11); (iv) R-α-MH and thioperamide (n=6); and (v) H(2) and H(3) antagonist, burimamide 6.3 mg kg(−1)+6.3 mg kg(−1) h(−1) (n=4). 3. R-α-MH caused a thioperamide-sensitive fall in mean arterial pressure (MAP) of 8±1 mmHg and tachycardia of 18±2 bpm (P<0.0005). Burimamide was without effect, however thioperamide elicited an increase in MAP of 4±1 mmHg (P<0.01), but no change in heart rate (HR). 4. R-α-MH caused a 44% decrease in the average gain of the baroreflex (P=0.0001); this effect was antagonised by thioperamide. Thioperamide caused a parallel rightward shift in the barocurve with an increase in MAP of 5 mmHg (P<0.05). Burimamide had no effect on the baroreflex. The vagally mediated bradycardia elicited by the Bezold-Jarisch and nasopharyngeal reflexes was unaffected by H(3) receptor ligand administration. 5. R-α-MH (⩽10 μM) caused a thioperamide-sensitive depression of both sympathetic and vagal responses in guinea-pig atria, but had no effect in rabbit atria. 6. As H(3) receptor activation caused a significant decrease in baroreflex gain without affecting HR range, the former is unlikely to be simply due to peripheral sympatholysis (supported by the lack of effect in isolated atria). Central H(3) receptors may have a tonic role in the baroreflex as thioperamide caused a rightward resetting of the barocurve. In contrast, the peripherally acting H(3) antagonist burimamide was without effect. These findings suggest a role for central histamine H(3) receptors in cardiovascular homeostasis in the rabbit

Direct inhibition by cannabinoids of human 5-HT(3A) receptors: probable involvement of an allosteric modulatory site

1. Excised outside-out patches from HEK293 cells stably transfected with the human (h) 5-HT(3A) receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5-HT-induced current using the patch clamp technique. In addition, binding studies with radioligands for 5-HT(3) as well as for cannabinoid CB(1) and CB(2) receptors were carried out. 2. The 5-HT-induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): Δ(9)-THC, WIN55,212-2, anandamide, JWH-015 and CP55940. The WIN55,212-2-induced inhibition was not altered by SR141716A, a CB(1) receptor antagonist. WIN55,212-3, an enantiomer of WIN55,212-2, did not affect the 5-HT-induced current. 3. WIN55,212-2 did not change the EC(50) value of 5-HT in stimulating current, but reduced the maximum effect. 4. The CB(1) receptor ligand [(3)H]-SR141716A and the CB(1)/CB(2) receptor ligand [(3)H]-CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5-HT(3A) receptor cDNA, WIN55,212-2, CP55940, anandamide and SR141716A did not affect [(3)H]-GR65630 binding, but 5-HT caused a concentration dependent-inhibition. 5. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5-HT(3A) receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5-HT(3A) receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs