Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA-salt hypertensive rats.
OBJECTIVE
This study was performed to examine whether hypertension affects the sympathetic transmission to resistance vessels of pithed rats via inhibitory presynaptic cannabinoid CB1 receptors and whether endocannabinoids are involved in this response.


METHODS
We compared uninephrectomised rats rendered hypertensive by high salt diet and deoxycorticosterone acetate (DOCA) injections with normotensive animals (uninephrectomy only). Experiments were performed on vagotomised and pithed animals. Increases in diastolic blood pressure (DBP) were induced four times (S1-S4) by electrical stimulation or phenylephrine injection.


RESULTS
Electrical stimulation (0.75Hz, 1ms, 50V, 5 impulses) of the preganglionic sympathetic nerve fibres innervating the blood vessels more strongly increased DBP in normotensive than in DOCA-salt rats. Phenylephrine (0.01μmol/kg) induced similar increases in DBP in both groups. The cannabinoid receptor agonist CP55940 (0.01-1μmol/kg) did not modify the rises in DBP induced by phenylephrine. However, it inhibited the electrically stimulated increases in DBP, more strongly in DOCA-salt than in normotensive animals (maximally by 50 and 30%, respectively). The effect of CP55940 was attenuated by the CB1 antagonist AM251 (3μmol/kg). AM251 enhanced the neurogenic vasopressor response during S4 by itself in hypertensive rats only. URB597 (3μmol/kg), which inhibits degradation of the endocannabinoid anandamide, did not modify the electrically stimulated increases in DBP.


CONCLUSIONS
The function of inhibitory presynaptic CB1 receptors on sympathetic nerves is enhanced in DOCA-salt hypertensive rats. Thus, the CB1 receptor-mediated inhibition of noradrenaline release from the sympathetic nerve fibres innervating the resistance vessels might play a protective role in hypertension.
Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicz Str. 2A, 15-222 Białystok, Poland.
Marek
M
Toczek
Department of Pharmacology and Toxicology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Eberhard
E
Schlicker
Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicz Str. 2A, 15-222 Białystok, Poland.
Emilia
E
Grzęda
Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicz Str. 2A, 15-222 Białystok, Poland. Electronic address: bmalin@umb.edu.pl.
Barbara
B
Malinowska
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D064791:Desoxycorticosterone Acetate; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009392:Nephrectomy; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D017661:Receptors, Presynaptic / Q000187:drug effects*; D012982:Sodium, Dietary / Q000009:adverse effects; D013564:Sympathetic Nervous System / Q000187:drug effects*
D001549:Benzamides; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D043884:Receptor, Cannabinoid, CB1; D017661:Receptors, Presynaptic; D012982:Sodium, Dietary; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D010656:Phenylephrine; D064791:Desoxycorticosterone Acetate
11-Deoxycorticosterone acetate (PubChem CID: 3001); AM251 (PubChem CID: 2125); CP55940; CP55940 (PubChem CID: 104895); Cannabinoid receptors; DOCA–salt hypertension; Phenylephrine hydrochloride (PubChem CID: 5284443); Pithed rat; Presynaptic receptors; Prostaglandin F(2α) (PubChem CID: 5282415); URB597 (PubChem CID: 1383884)