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The selectivity of a number of agonists for peripheral α1- and α2- adrenoreceptors was determined and related to their cardiovascular effects in pentobarbitone-anaesthetized rats., In isolated tissues, presynaptic α2- and postsynaptic α1-adrenoreceptor activity was determined on the rat vas deferens and anococcygeus muscle respectively. Xylazine, guanabenz, guanoxabenz and guanfacin were more selective, whilst lofexidine, tiamenidine, naphazoline, oxymetazoline and St 91 were less selective than clonidine for presynaptic α2-adrenoreceptors., The anococcygeus muscle of the pithed rat was used to determine the α-adrenoreceptor selectivity of the compounds in vivo. The selectivities were similar to those obtained in vitro., Following intravenous administration to pentobarbitone-anaesthetized rats guanabenz and guanfacin caused small transient pressor responses and a prolonged secondary hypotension. In contrast oxymetazoline and St 91 produced marked initial pressor responses and the secondary reduction in blood pressure was absent. Clonidine and tiamenidine produced marked initial pressor responses followed by secondary hypotensive effects. All compounds reduced heart rate., Intracerebroventricular (i.c.v.) administration of clonidine, guanabenz and guanfacin elicited falls in blood pressure and heart rate. In contrast blood pressure was either unaffected or elevated following i.c.v. administration of St 91, oxymetazoline and tiamenidine., It is concluded that in the normotensive rat, central α2-adrenoreceptors play a major role in the hypotensive effects of clonidine and related compounds. [ABSTRACT FROM AUTHOR]

Abstract Background African Americans are disproportionately exposed to cigarette advertisements, particularly for menthol brands. Tobacco industry documents outline strategic efforts to promote menthol cigarettes to African Americans at the point of sale, and studies have observed more outdoor and retail menthol advertisements in neighborhoods with more African-American residents. Little research has been conducted to examine the effect of this target marketing on adolescents’ recognition of cigarette brand advertising and on smoking uptake. To our knowledge, this is the first study to examine racial differences in brand recognition and to assess the prospective relationship between brand recognition and smoking uptake. Methods School-based surveys assessing tobacco use and environmental and social influences to smoke were administered to 6th through 9th graders (ages 11 to 15) in an urban and racially diverse California school district. The primary outcome for the cross-sectional analysis (n = 2,589) was brand recognition, measured by students’ identification of masked tobacco advertisements from the point of sale. The primary outcome for the longitudinal analysis (n = 1,179) was progression from never to ever smoking within 12 months. Results At baseline, 52% of students recognized the Camel brand, 36% Marlboro, and 32% Newport. African-American students were three times more likely than others to recognize Newport (OR = 3.03, CI = 2.45, 3.74, p Conclusions The study findings illustrate that African-American youth are better able to recognize Newport cigarette advertisements, even after adjustment for exposure to smoking by parents and peers. In addition, recognition of Newport cigarette advertising predicted smoking initiation, regardless of race. This longitudinal study contributes to a growing body of evidence that supports a ban on menthol flavored cigarettes in the US as well as stronger regulation of tobacco advertising at the point of sale.

Asian American and Pacific Islanders are one of the fastest growing and most diverse groups in the United States. Yet, they are often aggregated as a single group, masking within-group differences in rates of disease and demographic characteristics commonly associated with elevated health risk. While more than four decades have passed since the Khmer Rouge genocide, Cambodians continue to experience trauma-related psychiatric disorders, including post-traumatic stress disorder and major depression. Funded by the California Department of Public Health Office of Health Equity, the Community Wellness Program (CWP) aimed to reduce mental health disparities among Cambodians in Long Beach and Santa Ana, California, using community-defined approaches. The 6-month program comprised community outreach, educational workshops, strengths-based case management, and social and spiritual activities. Our study aimed to examine the effects of the CWP on trauma symptoms. Program evaluation followed an incomplete stepped wedge waitlist design with two study arms. A linear mixed models analysis revealed that participants reported fewer trauma symptoms as a result of participation in the CWP and that participants experienced fewer symptoms over time. This is an especially important finding, as trauma can lead to long-term individual health effects and to social and health repercussions on an entire cultural group by way of intergenerational trauma. As the number of refugees and displaced individuals continues to grow, there is an urgent need for programs such as the CWP to prevent the lasting effects of trauma.

Objective: To review research on consumer use and understanding of nutrition labels, as well as the impact of labelling on dietary habits., Design: A systematic review was conducted by searching electronic databases. Relevant articles were screened by two reviewers and included if they met inclusion criteria, including eight methodological criteria. A total of 120 articles were included in the review, including cross-sectional surveys (n 96), experimental designs (n 17), 'natural experiments' (n 7) and longitudinal population-based surveys (n 2)., Setting: Articles covered seven jurisdictions: USA (n 88), Europe (n 12), Canada (n 9), Australia and New Zealand (n 4), Norway (n 2), Thailand (n 1) and Trinidad (n 1)., Subjects: Participants were from a wide range of age groups, socio-economic strata and geographical regions., Results: Nutrition labels on pre-packaged foods are among the most prominent sources of nutrition information. Nutrition labels are perceived as a highly credible source of information and many consumers use nutrition labels to guide their selection of food products. Evidence also shows a consistent link between the use of nutrition labels and healthier diets. However, the use of labels varies considerably across subgroups, with lower use among children, adolescents and older adults who are obese. Research also highlights challenges in terms of consumer understanding and appropriate use of labelling information., Conclusions: Nutrition labels on pre-packaged foods are a cost-effective population-level intervention with unparalleled reach. However, to capitalize on their potential, governments will need to explore new formats and different types of information content to ensure that nutrition information is accessible and understandable.

The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha 1- and alpha 2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens, (pA2 = 8.89) and the contractile effects of phenylephrine on the rat anococcygeus muscle (pA2 = 6.03). Efaroxan had a selectivity ratio (alpha 2/alpha 1) of 724 compared to a value of 182 for idazoxan. In pithed rats, the i.v. doses of efaroxan (mumol/kg) producing 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac alpha 2-adrenoceptors and postjunctional vascular alpha 2-adrenoceptors, and for cirazoline at postjunctional vascular alpha 1-adrenoceptors, were 0.05, 0.13 and 2.96, respectively. In conscious fasted rats, prazosin (5 mg/kg p.o.) increased resting glucose levels and exacerbated the hyperglycaemic effects of UK-14,304 and adrenaline. In contrast, efaroxan (1-5 mg/kg p.o.) had little effect on resting plasma glucose but markedly antagonised the hyperglycaemic actions of UK-14,304 and adrenaline. Efaroxan increased resting plasma insulin levels and markedly potentiated the rise in insulin levels produced by adrenaline; this latter effect was prevented by the co-administration of propranolol. These results demonstrate that efaroxan is a potent and selective alpha 2-adrenoceptor antagonist and provide further support for the involvement of alpha 2-adrenoceptors in glucose homeostasis.

The effect of efaroxan (1 and 5 mg/kg p.o.; a selective alpha 2-adrenoceptor antagonist) was compared to glibenclamide (1 and 5 mg/kg p.o.; a standard sulphonylurea) on basal plasma glucose levels of fed and fasted rats. In addition, the effect of efaroxan (5 mg/kg p.o.) and glibenclamide (2 or 5 mg/kg p.o.), alone and in combination, on the hyperglycaemia and hyperinsulinaemia induced by glucose challenges, were investigated. An intra-arterial (250 mg/kg i.a.) and a subcutaneous (1 g/kg s.c.) glucose challenge were used to stimulate the fast and slow release phases of insulin secretion. Efaroxan increased plasma insulin levels in both conscious fed and fasted rats without greatly affecting plasma glucose levels. Glibenclamide also elevated insulin levels, but was associated with marked hypoglycaemia. Efaroxan and glibenclamide potentiated the slow and fast release of insulin secretion, but glibenclamide had a tendency to produce hypoglycaemia in these test situations, a property not shared by efaroxan. A combination of efaroxan and glibenclamide produced a greater elevation in the slow and fast insulin release phases than either compound alone, but did not enhance the hypoglycaemia seen with glibenclamide alone. These results provide further evidence that pancreatic alpha 2-adrenoceptors are involved in the regulation of insulin secretion.

An investigation has been made of the effects of the selective alpha 2-adrenoceptor antagonist, idazoxan, on the plasma immunoreactive insulin and glucose responses following a glucose stimulus in conscious euglycaemic rats. UK 14304 (100 micrograms/kg), a selective alpha 2-adrenoceptor agonist, reduced the insulin response and potentiated the hyperglycaemia elicited by an intra-arterial glucose load (0.25 g/kg), thereby confirming previous findings that alpha 2-adrenoceptors can influence pancreatic insulin secretion and glycaemia. The effects of UK 14304 were totally abolished by idazoxan (1.0 mg/kg), indicating that idazoxan, at the dose studied, effectively antagonized alpha 2-adrenoceptor-mediated responses. However, idazoxan (1.0 mg/kg) by itself did not significantly affect the plasma glucose and insulin responses to glucose challenge. The data indicate that selective alpha 2-adrenoceptor blockade per se does not potentiate glucose-evoked insulin secretion.

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1). 7. The results indicate that adrenoceptors do not appear to be involved in regulating basal plasma glucose and IRI concentrations in the fasted rat. However, the effects of catecholamines on these parameters are mediated by alpha 2- and beta 2-adrenoceptors, whereas alpha,- or beta l-adrenoceptors do not appear to be involved.

1. The spinal sympathetic outflow to the eyelid, heart, splanchnic blood vessels, vas deferens and anococcygeus muscle was stimulated in pithed rats. 2. Clonidine inhibited sympathetic outflow to all of the tissues studied. The inhibitory effects of clonidine on cardiac nerves and hypogastric nerves were antagonized by phentolamine. 3. Clonidine produced a postsynaptic alpha-adrenoceptor agonist action on the eyelid, splanchnic blood vessels and the anococcygeus muscle. These effects were also antagonized by phentolamine. 4. The effects of clonidine, naphazoline and oxymetazoline on pre- and postsynaptic alpha-adrenoceptors were determined. 5. The presynaptic alpha-adrenoceptors employed were situated in either the sympathetic cardiac or hypogastric nerve terminals. Increases in diastolic blood pressure were used to assess concurrent postsynaptic alpha-adrenoceptor agonist activity. 6. The presynaptic alpha-adrenoceptor agonist potencies of clonidine, naphazoline and oxymetazoline were very similar on cardiac nerve terminals whereas on the hypogastric nerve terminals oxymetazoline was about 6 times more potent than either naphazoline or clonidine. 7. The results support the view that presynaptic alpha-adrenoceptors regulate transmitter release in sympathetic nerves. There appear to be subtle differences between the presynaptic alpha-adrenoceptors of different sympathetic nerve endings.

Some 2-aryl-5-guanidino-(or N-substituted guanidino)-1,3,4-thiadiazoles and closely related analogues were found to lower blood pressure in metacorticoid (DOCA) hypertensive rats. In the unsubstituted guanidines that exhibited low toxicity, optimum activity resulted when the aryl group was a 2-methylphenyl ring (11). Modifications to the guanidine group did not increase antihypertensive activity, but, in the 2-methylphenyl series, the N-n-butyl- and N-(2-methoxyethyl)guanidines (63 and 78) and the related iminoimidazolidine 93 were of comparable activity to that of the unsubstituted guanidine 11. The iminoimidazolidine 93 showed a somewhat longer duration of action than the guanidine derivatives. Preliminary studies in a pithed rat preparation indicated that these thiadiazole derivatives (11, 63, and 93) lowered blood pressure by a direct relaxant effect on vascular smooth muscle.

Some 2-aryl-5-hydrazino-1,3,4-thiadiazoles have been synthesized and screened for antihypertensive activity. In general, compounds with a 2-substituted phenyl ring had higher activity than their 3- or 4-substituted counterparts or those containing heteroaryl groups. The 2-methylphenyl and 2-ethylphenyl derivatives 7 and 18 were the most potent members of the series. Preliminary studies indicated that the hypotensive action of these compounds was due to a direct relaxant effect on vascular smooth muscle.

The profiles of 2-(3,4-dimethoxyphenylamino)-imidazoline HCl (RX 77171) and 2-[6-(1,4-benzodioxanylamino)]imidazoline maleate (RX 801074) were compared with that of clonidine in isolated tissues and pithed rats. RX 77171 consistently displayed prejunctional alpha 2-adrenoceptor antagonist and postjunctional agonist properties. In contrast, RX 801074 had a complex profile which showed considerable variability between tissues. This variability is highlighted by comparing its effects at the prejunctional alpha 2-adrenoceptors of the isolated vas deferens and guinea-pig ileum; in the former RX 801074 was an agonist whereas only antagonist properties were apparent in the ileum.

1 The selectivity of a number of agonists for peripheral alpha 1- and alpha 2- adrenoreceptors was determined and related to their cardiovascular effects in pentobarbitone-anaesthetized rats. 2 In isolated tissues, presynaptic alpha 2- and postsynaptic alpha 1-adrenoreceptor activity was determined on the rat vas deferens and anococcygeus muscle respectively. Xylazine, guanabenz, guanoxabenz and guanfacin were more selective, whilst lofexidine, tiamenidine, naphazoline, oxymetazoline and St 91 were less selective than clonidine for presynaptic alpha 2-adrenoreceptors. 3 The anococcygeus muscle of the pithed rat was used to determine the alpha-adrenoreceptor selectivity of the compounds in vivo. The selectivities were similar to those obtained in vitro. 4 Following intravenous administration to pentobarbitone-anaesthetized rats guanabenz and guanfacin caused small transient pressor responses and a prolonged secondary hypotension. In contrast oxymetazoline and St 91 produced marked initial pressor responses and the secondary reduction in blood pressure was absent. Clonidine and tiamenidine produced marked initial pressor responses followed by secondary hypotensive effects. All compounds reduced heart rate. 5 Intracerebroventricular (i.c.v.) administration of clonidine, guanabenz and guanfacin elicited falls in blood pressure and heart rate. In contrast blood pressure was either unaffected or elevated following i.c.v. administration of St 91, oxymetazoline and tiamenidine. 6 It is concluded that in the normotensive rat, central alpha 2-adrenoreceptors play a major role in the hypotensive effects of clonidine and related compounds.

The profiles of four analogues of idazoxan have been examined at alpha-adrenoceptors and the results compared to those obtained with idazoxan and yohimbine. The compounds possessed either a methyl (RX 801079), ethyl (RX 811033), n-propyl (RX 811054) or isopropenyl (RX 811005) group at the two position of idazoxan. The rank order of antagonist potency against UK-14,304 at prejunctional alpha 2-adrenoceptors of the rat isolated vas deferens was RX 811054 greater than RX 811033 greater than idazoxan greater than RX 811005 greater than yohimbine = RX 801079. All compounds were competitive antagonists. The rank order of antagonist potency against noradrenaline at postjunctional alpha 1-adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine greater than RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of alpha-adrenoceptor selectivity (alpha 2/alpha 1) was RX 811005 greater than RX 801079 greater than RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine. In pithed rats, intravenous administration of all compounds fully reversed the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. In pithed rats the rank order of antagonist potency against UK-14,304 at cardiac prejunctional alpha 2-adrenoceptors was RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine greater than RX 811005 greater than RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional alpha 1-adrenoceptors) was RX 811054 greater than RX 811033 greater than yohimbine greater than idazoxan greater than RX 811005 greater than RX 801079. The rank order of alpha 2-adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 greater than RX 811054 greater than idazoxan greater than yohimbine. Although idazoxan produced contractions of the anococcygeus muscle and increased blood pressure in pithed rats, three of the analogues (RX 811005, RX 801079 and RX 811033) were inactive. In conclusion, alkyl substitution in the 2-position of idazoxan can enhance either alpha 2-adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial alpha 1-adrenoceptor agonist properties of idazoxan can be removed.

The effects of the selective alpha 2-adrenoreceptor antagonist idazoxan on diurnal variations in plasma growth hormone levels were studied in acromegalic patients. Seven patients entered the study; six patients had been unsuccessfully treated with either pituitary adenotomy, bromocriptine or other drug therapy or a combination of the two procedures. Plasma growth hormone levels were measured at hourly intervals over a period of 24 h under control conditions and following 4 days treatment with either placebo or idazoxan (20 mg po, three times a day); the comparison of idazoxan with placebo was a double blind cross-over study. Except in one patient, the diurnal growth hormone plasma profiles were virtually superimposable under control conditions and following either placebo or idazoxan; each patient had a characteristic profile. Four patients had impressive nocturnal elevations ranging from about 40 to 200 per cent above average daytime levels. Only one had definite paradoxical early postprandial peaks. These observations are contrary to accepted views on growth hormone levels in acromegalic patients. The majority of our patients thus had profiles reminiscent of the normal diurnal plasma growth hormone pattern albeit at a higher level indicating some preserved central drive. The rather high prevalence in the present study of patients having relapses after adenomectomy may indicate that a selection had been made of cases with hypothalamic aetiology. Administration of the selective alpha 2-adrenoreceptor antagonist idazoxan did not modify plasma growth hormone profiles in these patients.

The effects of alpha-adrenoceptor agonists and antagonists and of antidepressant drugs were studied on pre- and postsynaptic alpha-adrenoceptors. The rat vas deferens, stimulated at low frequency (0.1 Hz) was used for presynaptic studies. The rat anococcygeus muscle was used in postsynaptic studies. In the agonist studies clonidine and guanfacine were selective for presynaptic alpha-adrenoceptors, methoxamine and phenylephrine were selective for postsynaptic alpha-adrenoceptors and noradrenaline and alpha-methylnoradrenaline were equipotent at pre- and post-synaptic alpha-adrenoceptors. In the antagonist studies piperoxane and yohimbine were selective for presynaptic alpha-adrenoceptors, phentolamine was equipotent at pre- and postsynaptic alpha-adrenoceptors and prazosin was a selective postsynaptic alpha-adrenoceptor antagonist. In the series of antidepressants studied, mianserin was the most potent antagonist at presynaptic alpha-adrenoceptors, followed by trazodone, amitriptyline and nortriptyline in descending order of potency. Mianserin was approximately two hundred times less potent than piperoxane as a presynaptic alpha-adrenoceptor antagonist. Viloxazine and desipramine were inactive. With the exception of viloxazine all of the antidepressants examined possessed postsynaptic alpha-adrenoceptor antagonist properties.

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX 781094 was also a competitive antagonist at the postjunctional alpha 1-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha 1-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of alpha 2/alpha 1-adrenoceptor selectivities for the antagonists studied was RX 781094 greater than RS 21361 greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4101 greater than prazosin. 5 RX 781094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. 7 In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX 781094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 21361 greater than WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha 1-adrenoceptors. 9 RX 781094 had little effect on the cardiovascular responses to 5-hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. 10 These results demonstrate that RX 781094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.

Modification of the 1,4-benzodioxan ring present in RX 781094 has not previously been considered. This paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives. The dihydrobenzofuranylimidazoline compound 7 is the only analogue possessing presynaptic antagonist potency potency and selectivity comparable to that of 1. In view of this result, a number of derivatives was prepared to determine the structure-activity relationships within this series. Many derivatives, as well as the parent compound 7, were found to possess presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties. Two of the selective presynaptic antagonists, 13 and 14 possess greater potency and selectivity than that possessed by 1. The 5-chloro derivative 25 is twice as potent as after oral administration but only about half as potent when given intravenously.

The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.

A series of phthalazinyl- and quinoxalinylguanidines has been synthesized and evaluated for potential antihypertensive activity. Unsubstituted guanidines were prepared by treating the appropriate intermediate chloro compounds with guanidine free base. Substituted guanidines were prepared by treating the cyanamides 9 and 16 with the appropriate amine; with hydrazines, cyanamide 9 gave the triazoles 14 and 15. Moderate falls in blood pressure were observed with compounds 10, 11, 14, and 15. The triazole 15 caused a 25% fall in heart rate. Some of the compounds (10, 11, 13, and 18) displayed weak alpha-adrenoceptor antagonist properties in vitro, and this activity was confirmed in the pithed rat (in vivo).

1. Low frequency (0.1 Hz) electrical stimulation of the rat isolated vas deferens produced regular contractions that were inhibited by low concentrations of clonidine. 2. The inhibition of the vas deferens produced by clonidine was presynaptic in origin and involved alpha-adrenoceptors. 3. Presynaptic alpha-adrenoceptor antagonist activity was assessed by studying the effects of increasing concentrations of the antagonists on cumulative clonidine dose-response curves on the stimulated vas deferens. 4. Postsynaptic alpha-adrenoceptor antagonist activity was assessed by comparison of control cumulative noradrenaline dose-response curves with those in the presence of increasing concentrations of antagonists in the rat anococcygeus muscle. 5. The results indicate that yohimbine and phentolamine are more potent in blocking presynaptic than postsynaptic alpha-adrenoceptors. Phenoxybenzamine and prazosin block postsynaptic alpha-adrenoceptors preferentially. 6. The findings support the view that presynaptic and postsynaptic alpha-adrenoceptors differ in their sensitivity to alpha-adrenoceptor antagonists.

Studies with phentolamine, an alpha-adrenergic antagonist, in normal subjects and diabetic patients have indicated that insulin secretion may be inhibited by tonic alpha-adrenergic stimulation of pancreatic B-cells. We evaluated, with the use of the highly selective alpha 2-adrenoceptor antagonist idazoxan, the role of alpha 2-adrenergic receptors in the regulation of glucose-induced insulin secretion. A glucose infusion test (GIT) was performed after the administration of idazoxan or placebo in normal men (n = 15) and men with noninsulin-dependent diabetes mellitus (n = 6). The normal men were divided into two groups on the basis of high (n = 8) and low (n = 7) insulin responses to prior GITs. The blood glucose and plasma insulin and C-peptide responses to the GIT were similar after idazoxan (40 mg, orally) or placebo treatment in all three groups, although the responses differed among the groups. In the diabetic group iv administration of idazoxan 20 min before the GIT did not alter the insulin response to the GIT. We conclude that alpha 2-adrenergic blockade does not affect glucose-induced insulin secretion in normal men, nor does it improve the impaired first phase of insulin secretion in low insulin responders and noninsulin-dependent diabetes mellitus patients. Phentolamine probably stimulates insulin secretion by a mechanism not involving alpha 2-adrenergic receptors directly.

In the pithed rat electrically induced contractions of the anococcygeus muscle were inhibited by clonidine (0.1--3.0 microgram/kg, i.v.), mecamylamine (1 mg/kg, i.v.) and guanethidine (1 mg/kg, i.v.). Only the inhibition produced by clonidine was antagonised by yohimbine (0.3 mg/kg, i.v.). At higher concentrations (10 microgram/kg, i.v.) clonidine increased the resting tension of the tissue; this effect was antagonised by phentolamine (1 mg/kg, i.v.). The anococcygeus muscle of the pithed rat was used to simultaneously assess pre- and postsynaptic alpha-adrenoceptor agonist activity. Guanfacin was more selective and tiamenidine less selective than clonidine for presynaptic alpha-adrenoceptors. Naphazoline and oxymetazoline were selective postsynaptic alpha-adrenoceptor agonists.

Seven alpha 2-adrenoceptor antagonists with diverse chemical structures have been examined for their effects at alpha 2-adrenoceptors in the vas deferens and central nervous system of the rat. Antagonist potency assessed against the presynaptic alpha 2-adrenoceptor agonist action of clonidine in the isolated vas deferens (RX 781094 greater than Wy 26703 greater than yohimbine greater than rauwolscine greater than piperoxan greater than mianserin greater than RS 21361) was highly correlated with the ability of these drugs to displace saturable [3H]-RX 781094 binding from cerebral cortex membranes. Similarly, antagonist potency in the vas deferens was highly correlated with antagonist activity in reversing the centrally-mediated mydriasis induced by the selective alpha 2-adrenoceptor agonist, guanoxabenz, in pentobarbitone-anaesthetized rats. The results indicate that the presynaptic alpha 2-adrenoceptors in the vas deferens are pharmacologically similar to characterized these alpha 2-adrenoceptors in the central nervous system of the rat.