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(-)-Δ9-trans-Tetrahydrocannabinol (Δ9-THC), when given intravenously (2 mg kg−1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C1-C2) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ9-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ9-THC administration. These observations support the hypothesis that Δ9-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ9-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ9-THC did not interact with α- or β- adrenoceptors. The possible action of Δ9-THC on central sympathetic structures was investigated by perfusion of Δ9-THC into the lateral cerebral ventricle. Δ9-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or 14C-Δ9-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ9-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.

Nicorandil, the specific K+ channel opener aprikalim, and the stimulant of guanylate cyclase, nitroglycerin, overcame in a concentration-dependent manner the sustained contractile responses evoked by KCl (10-25 mM) and norepinephrine (25-300 nM) in endothelium-denuded rings from rabbit aorta and pulmonary and mesenteric arteries. Nicorandil exhibited similar vasorelaxant potency (EC50, 1.6-3.1 microM) in all preparations investigated. The responses to nicorandil or nitroglycerin for pulmonary artery rings contracted with the two spasmogens and for aorta rings contracted with norepinephrine were not substantially modified by the K+ channel blocker glibenclamide at a concentration (1 microM) that displaced to the right the concentration-response curve to aprikalim obtained with these preparations. However, glibenclamide shifted to the right 2- to 3-fold the concentration-response curve obtained with nicorandil in aorta rings contracted with KCl and in mesenteric artery rings contracted with either KCl or norepinephrine, but not that obtained with nitroglycerin. Methylene blue (5-10 microM), an inhibitor of guanylate cyclase, displaced to the right the control concentration-response curves to nitroglycerin 3- to 21-fold and those to nicorandil 1.5- to 11-fold, but not those to aprikalim. In rabbit mesenteric artery rings, nicorandil both stimulated guanylate cyclase and opened K+ channels, regardless of whether KCl or norepinephrine was used to contract the vessels. However, nicorandil-induced relaxation of the pulmonary artery contracted with these spasmogens and the aorta contracted with norepinephrine was mediated almost entirely by the stimulation of guanylate cyclase, whereas the dual mechanism of action was again demonstrable when the latter vessel was contracted with KCl.(ABSTRACT TRUNCATED AT 250 WORDS)

In human polymorphonuclear leukocytes (PMNs), the tritiated platelet activating factor ([3H]PAF) labels in a saturable manner a single class of binding sites with a Kd of 3.5 +/- 0.5 nM (n = 7) and a maximum binding capacity (Bmax) of 206 +/- 13 fmol/2.5 X 10(6) PMNs (n = 7). 52770 RP, a nonphospholipid antagonist of PAF receptors, fully and competitively displaced the [3H]PAF from its binding sites with a Ki of 7.0 +/- 0.7 nM (n = 4). The high potency and the low solubility in cellular membranes of this compound led us to prepare [3H]52770 RP. This ligand was characterized by a binding which was rapid, reversible, confined to a single site, saturable, specific and stereoselective. Its Kd and Bmax were 4.2 +/- 0.3 nM and 181 +/- 11 fmol/2.5 X 10(6) PMNs, respectively. The stereoselectivity of the binding was suggested by the 600- and 1050-fold higher potency of the d-enantiomer with respect to l-52770 RP in displacing [3H]52770 RP or [3H]PAF, respectively. Several PAF analogs (e.g., lyso-PAF, 2-O-methyl-lyso-PAF), which are poorly active as PAF receptor agonists in functional tests, were weak displacers of [3H]PAF and [3H]52770 RP. Furthermore, for a series of 14 known PAF receptor agonists or antagonists belonging to different chemical families, there was an excellent correlation (r = 0.98) between their ability to displace [3H]PAF and [3H]52770 RP. Thus, [3H]52770 RP and [3H]PAF appear to interact with the same binding site on human PMNs which is proposed to be the PAF receptor mediating functional responses.(ABSTRACT TRUNCATED AT 250 WORDS)

1. In pentobarbitone-anaesthetized dogs, prazosin (2×1·3 µmol day—1 kg—1; 2×0·5 mg day—1 kg—1) administered orally for 3 days reduced resting aortic blood pressure as well as the pressor response to bilateral carotid occlusion. Prazosin neither affected resting heart rate nor the tachycardia induced by intravenous isoprenaline, noradrenaline and electrical stimulation of preganglionic and postganglionic sympathetic nerve fibres. Prazosin significantly attenuated the fall in perfusion pressure in a perfused hind leg resulting from the section of the ipsilateral sympathetic lumbar chain. Furthermore, the drug inhibited by about 50% the hind-leg pressor responses elicited by intra-arterial administration of a-adrenoreceptor agonists and by stimulation of the lumbar sympathetic chain, without altering the effects of angiotensin II. 2. Acute administration of prazosin into the innervated hind leg provoked a dose-related reduction in vascular resistance. However, after spinal anaesthesia no such an effect was observed even when vascular tone was increased by infusion of vasopressin. Under the same experimental conditions administration of papaverine induced a vasodilatation. 3. This study confirms that prazosin impairs the function of vascular a-adrenoreceptors, and strongly challenges the claim that this compound produces a directly mediated vasodilatation of the leg vascular bed.

High-affinity binding sites for platelet-activating-factor (PAF) have been identified in human polymorphonuclear leukocytes (PMNs). The aim of this investigation was to assess their functional relevance by characterizing PAF-induced elastase release, an enzyme present in azurophilic granules. At 37 degrees C, maximal release (measured with a spectrofluorimetric method) was achieved with 0.3 microM PAF. PAF analogs (e.g. lyso-PAF, 2-O-methyl-lyso-PAF) and enantio-PAF, which exhibit poor PAF-like activity in binding studies, were very weak releasers of elastase. The degranulation induced by PAF was fully and competitively inhibited by RP 59227, a potent, d-enantiomeric PAF antagonist. This effect was stereoselective and specific inasmuch as this compound was 500-fold more potent than its l-enantiomer and was devoid of effects on the degranulation promoted by N-formyl-l-methionyl-l-leucine-l-phenylalanine or [5S,12R]hydroxyeicosa-6,14-cis-8,10-trans-tetraenoic acid. The PAF-induced elastase extrusion was enhanced by physiological concentrations of CaCl2 and MgCl2. For instance, 1 mM Ca++ increased by 200% the release produced by 100 nM PAF. The mechanism of this effect is probably related to the capability of Ca++ and Mg++ to enhance the maximum number of [3H]PAF binding sites in whole or lysed PMNs without affecting the affinity (Kd) of the ligand. An additional possibility is that these ions intervene at the level of the signal transduction system leading to degranulation. For a series of 22 known PAF receptor antagonists, belonging to different chemical families, there was a strong correlation (r = 0.95) between their ability to displace [3H]PAF and to inhibit the PAF-evoked elastase release.(ABSTRACT TRUNCATED AT 250 WORDS)