Central muscarinic M2 cholinoceptors involved in cholinergic hypertension

Özkutlu, Uǧur; Onat, Filiz; Aslan, Alaattin; Oktay, Şule

doi:10.1016/0014-2999(93)90020-i

Cited by 20 publications

(7 citation statements)

References 22 publications

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“…The ID 50 value obtained with the M 3 receptor antagonist was also increased in the hypertensive strain, but according to the high doses of p‐F‐HHSiD necessary to inhibit the physostigmine‐induced pressor response in both strains (ID 50 for WKY: 60.52±2.38; ID 50 for SHR: 139.5±2.82) and to the relative selectivity of this antagonist, it is difficult to suggest that the M 3 receptor subtype is indeed involved in the physostigmine‐induced pressor response. In spite of conflicting opinions ( Brezenoff et al ., 1988 ; Xiao & Brezenoff, 1988 ; Martin, 1992 ; Flores et al ., 1996 ), our results are in agreement with previously published reports in the rat ( Sundaram et al ., 1988 ; 1989 ; Özkutlu et al ., 1993 ; Lazartigues et al ., 1998 ) or the cat ( Ally et al ., 1993 ; 1995 ) excluding the involvement of M 3 muscarinic cholinoceptors in this pressor response.…”

Section: Discussionmentioning

confidence: 99%

“…In the last decade, ®ve muscarinic receptor genes (m1 ± 5) encoding distinct muscarinic cholinoceptors have been cloned. Some authors have suggested the involvement of M 1 (Hori et al, 1995), M 2 (O È zkutlu et al, 1993;Ally et al, 1995) or M 3 (Martin, 1992) receptors in the central pressor response to cholinomimetics. However, the relative importance of the dierent muscarinic cholinoceptor subtypes remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Spontaneously hypertensive rats cholinergic hyper‐responsiveness: central and peripheral pharmacological mechanisms

Lazartigues

Brefel‐Courbon

Tran

et al. 1999

British J Pharmacology

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1 The mechanisms and the subtypes of muscarinic receptors implicated in the cardiovascular eects of physostigmine were investigated in conscious normotensive and spontaneously hypertensive rats. 2 Intravenous (i.v.) physostigmine (50 mg kg 71) induced in both strains a long pressor response, accompanied by a bradycardia. This pressor response was larger in spontaneously hypertensive (+41+6 mmHg) than in Wistar-Kyoto (+25+2 mmHg) rats (P50.05). 3 Pretreatment with atropine sulphate (0.4 mg kg 71 i.v.), completely abolished the physostigmineinduced pressor response in both normotensive and hypertensive rats. In both strains, the physostigmine pressor response was signi®cantly reduced by the systemic administration of either an a 1 -adrenoceptor antagonist (prazosin, 1 mg kg 71 ) or a V 1A -vasopressin receptor antagonist (AVPX, 20 mg kg 71 ). This physostigmine pressor eect was completely abolished in both strains when both antagonists were administered concomitantly. 4 In WKY rats, the pressor response to physostigmine (50 mg kg 71 i.v.) was inhibited in a dosedependent manner by i.c.v. administration of atropine (ID 50 =3.70 nmoles), the M 1 receptor antagonist pirenzepine (ID 50 =10.71 nmoles), the M 2 receptor antagonist methoctramine (ID 50 =4.31 nmoles), the M 3 receptor antagonist p-F-HHSiD (ID 50 =60.52 nmoles) and the M 4 receptor antagonist tropicamide (ID 50 =214.20 nmoles). In the hypertensive strain, the ID 50 were found to be signi®cantly higher for atropine (7.34 nmoles), pirenzepine (21.60 nmoles) and p-FHHSiD (139.50 nmoles) (P50.05). 5 The present results indicate that physostigmine acts in normotensive and spontaneously hypertensive rats, through stimulation of both central M 2 and M 1 cholinoceptors to induce a rise in blood pressure mediated by an increase in plasma vasopressin and sympathetic out¯ow. Moreover, our results suggest that some modi®cations of the M 1 receptor subtypes in terms of expression or anity could be responsible for the hyper-responsiveness of the hypertensive strain to cholinomimetic agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spontaneously hypertensive rats cholinergic hyper‐responsiveness: central and peripheral pharmacological mechanisms

Lazartigues

Brefel‐Courbon

Tran

et al. 1999

British J Pharmacology

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“…Thus, cholinergic function in regard to BP and heart rate (HR) of SART-stressed rats was investigated using muscarinic antagonists, especially AF-DX 116, a specific muscarinic M2 antagonist, in this study. AF-DX 116 has already been reported to increase BP and HR in rats and dogs (21,22). The effects of AF-DX 116 on BP and HR in SART-stressed rats were compared with those of other muscarinic antagonists, pirenzepine, an M1 specific antagonist, and atropine, a nonselective muscarinic antagonist.…”

mentioning

confidence: 99%

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Hata

Itoh

Funakami

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Rats exposed to SART (specific alternation of rhythm in temperature) stress, which are ideal animal models for vagotonia-type dysautonomia, show various changes in cardiac and circulatory systems. In this study, attention was directed to cholinergic function in the SART-stressed rat heart and the effects of AF-DX 116, a specific muscarinic M 2 antagonist, on blood pressure and heart rate. The results were compared with those obtained for atropine and pirenzepine. In SART-stressed rats, systolic and diastolic blood pressures (SBP and DBP) were lower than in unstressed rats. Oral AF-DX 116 resulted in greater elevation of DBP than SBP in unstressed rats. In stressed rats, greater and more prolonged elevation of SBP than in unstressed rats was noted, particularly at higher doses. A dose-dependent SBP change in stressed rats, caused by intravenous AF-DX 116, was shifted upward in parallel with that in unstressed groups, unlike with oral administration. The positive chronotropic effect of this drug was smaller in stressed rats than in unstressed rats, in contrast to the pressor effect. SART-stressed rats may thus have an enhanced sympathetic tone in the heart, as well as changes in muscarinic M2 receptors at sympathetic nerve endings and at the heart muscle. The effects of AF-DX 116 on blood pressure and heart rate thus may arise from peripheral action and AF-DX 116 may be useful for treating hypotension related to autonomic imbalance of the vagotonia type.Keywords: Stress, Blood pressure, AF-DX 116, Hypotension, M2 antagonist Blood pressure (BP) is related to sympathetic tone and physical and/ or psychological stress (1 -7). In general, stress is thought to induce hypertension in humans and experimental animals. Rats subjected to SART (specific alternation of rhythm in environmental temperature) stress (8) showed hypotension (9) in a manner different from hypertension in animals subjected to other types of stress such as cold and restraint (10 -12).SART stress is induced through sudden drops in environmental temperature and is a type of repeated or intermittent cold stress in rodents. Experimental animals subjected to SART stress are accepted as animal models of vagotoniatype dysautonomia in consideration of the results of Aschner and Mecholyl tests (13). The stressed animals exhibit pathophysiological abnormalities such as an abnormal galvanic skin response (GSR) (8) and electroencephalogram (EEG) (14), hyperalgesia (15), thrombocytopenia (16), as well as hypotension (9). In cardiac and circulatory systems, the animals show tachycardia, short PQ and long QRS intervals and high voltage in R waves on electrocardiograms (ECG) (17), and blood flow either increases or decreases in the arteries (9, 18). In the cholinergic system, a decrease in acetylcholine (ACh) content and an elevation of the synthesis and hydrolysis of ACh in the brain (19) were noted in addition to an increase in ACh content, a decrease in ACh-esterase activity and the number of muscarinic ACh receptors in the small intestine (20).SART-stres...

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“…* P<0.05 vs basal value. ** P<0.01 vs basal value body of evidence that intracerebral acetylcholine injection induces pressor effects via enhancement of the sympathetic tone (Caputi and Brezenoff 1980;Özkutlu et al 1993). Acetylcholine microinjection (137 nmol/rat) into the dorsolateral PAG area of anaesthetized Long Evans rats induced a significant blood pressure increase; such an effect appeared in 20±5 s and lasted for 20±4 min.…”

Section: Resultsmentioning

confidence: 99%

Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area

Pizzirusso

Oliva

Maione

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of 1-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2+/-1 mmHg to 16+/-3 mmHg; glutamate in Long Evans rats: from +16+/-2 mmHg to +36+/-4 mmHg; NMDA in Brattleboro rats: from +5+/-2 mmHg to +34 +/-8 mmHg; NMDA in Long Evans rats: from +18+/-7 mmHg to 80+/-9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15+/-3 mmHg vs +24+/-4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25+/-3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation.

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Central muscarinic M2 cholinoceptors involved in cholinergic hypertension

Cited by 20 publications

References 22 publications

Spontaneously hypertensive rats cholinergic hyper‐responsiveness: central and peripheral pharmacological mechanisms

Spontaneously hypertensive rats cholinergic hyper‐responsiveness: central and peripheral pharmacological mechanisms

Blood Pressure and Heart Rate Are Increased by AF-DX 116, a Selective M2 Antagonist, in Autonomic Imbalanced and Hypotensive Rats Caused by Repeated Cold Stress

Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area

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