Inhibition of nerve-mediated contractions in isolated guinea-pig ileum by 1-methylisoguanosine, a novel purine from a sponge

1-Methylisoguanosine, a novel purine isolated from the sponge Tedania digitata (Schmidt) selectively inhibited contractions produced by nerve stimulation in the guinea-pig ileum but was without effect on contractions produced by acetylcholine or histamine. The ED50 for inhibition of nicotine responses or responses to submaximal transmural stimulation was 1.1 mumoles/l. The inhibition of nerve-mediated contractions appeared to be due to inhibition of transmitter release from nerve endings in the ileum, as has been suggested for the action of adenosine. Theophylline antagonized the action of 1-methylisoguanosine and overall the results suggest that 1-methyl-isoguanosine acts at an adenosine receptor in the guinea-pig ileum, but is approximately ten times more potent than adenosine itself. A series of related purines which were resistant to the action of adenosine deaminase were also tested for their effect on the nerve-mediated contractions of guinea-pig ileum and the results compared with the in vivo effect on muscle relaxation in mice. All active purines tested produced results qualitatively similar to those of 1-methylisoguanosine itself.     

Pharmacological profile of the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146) in the cardiovascular system.

We investigated the cardiovascular effects of 2-octynyladenosine (YT-146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4 micrograms/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at h hypotensive doses. Orally given YT-146 (0.1 - 1 mg/kg) produced a potent and long-lasting antihypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadenosine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long-acting hypotensive agent having less cardiac depressant activity.     

1-Methylisoguanosine: interaction with central adenosine receptors and lack of antagonism of its in vivo effects by a benzodiazepine antagonist

1-Methylisoguanosine, a marine natural product analogue of adenosine, with moderate activity as a benzodiazepine receptor ligand, has previously been shown to have muscle-relaxant and hypothermic activity in mice in vivo. The present experiments showed that the benzodiazepine antagonist Ro15-1788 did not block the in vivo muscle-relaxant and hypothermic effects of 1-methylisoguanosine, suggesting that these particular actions are not due to interactions with benzodiazepine receptors. When applied by microiontophoresis near spontaneously-active neurones or neurones activated by ACh, DL-homocysteate or glutamate in the ventrobasal thalamus of anaesthetized rats, 1-methylisoguanosine had a depressant action; it was similar to adenosine in potency and in its ability to be antagonized by 8-(parasulphophenyl)theophylline. The depression was usually longer lasting than that caused by adenosine, consistent with previous neurochemical data showing it to be resistant to adenosine deaminase and a poor substrate for the uptake system for adenosine in the CNS. These results suggest that the major pharmacological/behavioural actions of 1-methylisoguanosine in vivo are more likely to be caused by an interaction with adenosine receptors, rather than with benzodiazepine sites.     

Evidence that a novel 8-phenyl-substituted xanthine derivative is a cardioselective adenosine receptor antagonist in vivo

The ability of caffeine, enprofylline (3-propylxanthine), 8-phenyltheophylline, 8-p-sulphophenyl-theophylline, 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine, and 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine-2-aminoethyl amide (XAC) to antagonize the effects of an adenosine analogue, N-5'-ethylcarboxamidoadenosine, on heart rate and blood pressure in anesthetized rats was examined. The first five xanthine derivatives were equally active in antagonizing the two responses. By contrast, XAC was approximately 20 times more potent in antagonizing the heart rate response than the blood pressure response. Measurements of the concentration of XAC in plasma and brain indicate that it penetrates the central nervous system poorly. It is concluded that XAC is a cardioselective adenosine antagonist, and since adenosine is supposed to reduce heart rate via an effect on A1-receptors, and the blood pressure via A2-receptors, XAC may be a selective A1-adenosine receptor antagonist in vivo.     

Pharmacological analyses of hydralazine-induced cardiac action in intact dogs and isolated, blood-perfused canine atria

The effects of hydralazine (HYD) on heart rate and blood pressure in the intact dog and on atrial rate and contractile force in the isolated atrium were investigated. HYD (0.1-1 mg) injected into the sinus node artery produced double peaked positive inotropic and negative chronotropic effects in a dose-related manner. The initial positive inotropic and negative chronotropic responses were not affected by propranolol and atropine, respectively. The second positive inotropic response was inhibited by propranolol or reserpine, but it was not suppressed by imipramine or tetrodotoxin. When HYD (0.1-1 mg/kg) was administered intravenously to the donor dog, an initial increase followed by a decrease in blood pressure and an increase in heart rate were observed. In the isolated atrium, an increase in contractile force was induced. The increases of blood pressure and heart rate in the donor dog and the positive inotropic effect in the isolated atrium after HYD treatment were suppressed by reserpine. These results suggest that HYD has direct positive inotropic and negative chronotropic effects and indirect cardiac stimulating effects caused by a release of catecholamines from sympathetic nerve terminals, and that HYD-induced catecholamine release is not mediated by a tyramine-like action or via nerve excitation.     

Lack of effect of 1-methylisoguanosine on sleep in rats

The dose-response effects of intracerebroventricular (i.c.v.) administration of 1-methylisoguanosine (MIG) on sleep in rats were examined. Not even the largest dose (100 nmol/rat) of 1-methylisoguanosine produced significant hypnotic effects, whereas doses of 10 and 100 nmol/rat suppressed rapid eye movement sleep in rats. The only statistically significant effect of 1-methylisoguanosine on sleep latencies was an increase in the latency of S2 after intracerebroventricular administration of 100 nmol/rat of the drug. These effects of 1-methylisoguanosine on sleep were unlike those of both adenosine and the benzodiazepines, suggesting that, contrary to earlier speculations, 1-methylisoguanosine does not interact with central adenosine or benzodiazepine receptors.     

Hemodynamic effects of inosine in combination with positive and negative inotropic drugs: studies on rats in vivo.

Inosine applied as a continuous i.v. infusion of 400 mg/kg/h for 20 min had a negative chronotropic and inotropic effect in closed-chest, anesthetized rats. In the presence of adenosine deaminase (ADA, 133 U/kg/h), the reduction in heart rate was abolished indicating that adenosine is responsible for that effect. However, the negative inotropic effect persisted. It was characterized by a 38 and 56% decrease in left ventricular systolic pressure (LVSP) and diastolic aortic pressure, respectively, a 24% decline in LV dp/dtmax and a 16% fall in cardiac output. Total peripheral resistance was diminished by 38%. Inosine in combination with ADA antagonized the noradrenaline-induced positive inotropic effect and the increase in cardiac output. On the other hand, i.v. bolus injection of noradrenaline in rats pretreated with inosine and ADA did not increase blood pressure and total peripheral resistance. Inosine administered in animals pretreated with the beta-receptor blocker metoprolol or with the calcium antagonist verapamil aggravated the negative inotropic effect. Inosine in combination with ADA caused a decline in cardiac output in metoprolol-pretreated rats that was more pronounced than that induced by inosine alone. However, in rats pretreated with verapamil, inosine did not cause a reduction in cardiac output.     

Adenosine on myocardial oxygen consumption.

1 A 3 min intracoronary infusion of adenosine (50 mug/min) produced a significant decrease in coronary artery perfusion pressure, left ventricular systolic pressure and myocardial O2 consumption in the isolated supported heart preparation of the dog perfused at a constant coronary blood flow. Heart rate was controlled at 150, 190 or 230 beats/minute. 2 Myocardial contractile force and maximal left ventricular dp/dt were not changed by adenosine infusion. 3 The absolute decrease in myocardial O2 consumption was greater at increasing heart rates whereas the decrease in coronary artery perfusion pressure and peak left ventricular systolic pressure were similar. 4 The results suggest that the reduction in myocardial O2 consumption produced by adenosine is not related to coronary vasodilatation or to a negative chronotropic or inotropic action, but may be due to a functional shunting of blood flow from high O2 extracting regions of the myocardium to low O2 extracting ones and/or important effects on myocardial substrate utilization.     

Lithium chloride-induced cardiovascular changes in rabbits are mediated by adenosine triphosphate-sensitive potassium channels.

The effect of lithium chloride on the mean arterial blood pressure, heart rate and heart contractility was evaluated in rabbits. The intravenous administration of 50 mg kg-1 lithium chloride as a bolus injection into rabbits produced a progressive decrease in the mean arterial blood pressure, heart rate and heart contractility during the 2-h period of investigation. Pretreatment of animals with 5 mg kg-1 glibenclamide, a potent inhibitor of adenosine triphosphate-sensitive potassium channels, markedly inhibited the cardiovascular changes induced by lithium chloride. Doubling the dose of glibenclamide nearly abolished these effects of lithium chloride. Similarly, lithium chloride produced a concentration- dependent relaxation of noradrenaline-induced contractions in isolated aortic strips of rabbits. This relaxant effect of lithium chloride was inhibited by pretreatment of the aortic strips with glibenclamide. Doubling the concentration of glibenclamide in the bathing fluid nearly abolished the effect of lithium. Diazoxide and verapamil potentiated the relaxant effect of lithium chloride on the isolated noradrenaline-contracted aortic strips. Pretreatment with glibenclamide markedly reversed the effect of diazoxide but not that of verapamil. The intravenous administration of lithium was also found to be capable of increasing the plasma potassium level and of decreasing the intracellular levels of adenosine triphosphate in cardiac and vascular tissues in a time-dependent manner. The plasma sodium and calcium levels were not changed. These results provide evidence that the hypotensive and cardiac depressant effects of lithium chloride are mediated by activation of adenosine triphosphate-sensitive potassium channels.     

Effect of urethane on hydralazine-induced tachycardia in rats.

1. In conscious normotensive rats, hydralazine (5-10 mg kg-1 p.o.) produced a dose-related fall in systolic blood pressure, accompanied by a pronounced increase in heart rate. 2. The tachycardia induced by hydralazine (10 mg kg-1 p.o.) in conscious normotensive rats was strongly inhibited after anaesthesia with urethane (1.26 g kg-1 i.p.). 3. In anaesthetized normotensive rats, hydralazine (1 mg kg-1 i.v.) caused a fall in mean blood pressure, accompanied by irregular effects on the heart rate that consisted in a combination of initial tachycardia followed by bradycardia. 4. In pithed rats, hydralazine (1 mg kg-1 i.v.) did not affect mean arterial blood pressure but produced a significant decrease in heart rate. 5. In rat isolated atria, hydralazine (2 mM) produced a positive inotropic/negative chronotropic effect. 6. These results suggest that urethane inhibits the cardiovascular reflex that causes the tachycardia induced by hydralazine in conscious normotensive rats. For this reason, in anaesthetized normotensive rats appear the direct effect of the drug on the heart.     

The effects of central injections of adenosine analogs on blood pressure and heart rate in the rat

Rats were implanted with chronic indwelling cannulae into the lateral cerebral ventricle. After recovery from surgery, acute experiments on blood pressure were conducted under methoxyflurane/nitrous oxide anesthesia. Rats were injected intracerebroventricularly with two adenosine analogs, 5'-N-ethylcarboxaminidoadenosine (NECA) and (-)-N-(1-methyl-2-phenylethyl)adenosine(L-phenylisopropyladenosine) (L-PIA), and the effects on blood pressure and heart rate recorded. Both analogs produced dose-related reductions in blood pressure and heart rate with L-PIA producing a more potent depression of heart rate than NECA. These effects on blood pressure and heart rate were antagonized by parenteral injections of caffeine. In separate experiments, the responses of blood pressure and heart rate to microinjection of NECA into the brainstem of rats anaesthetized with methoxyflurane/nitrous oxide were also examined. Microinjection of 2.7 nmol/kg into the fourth ventricle in the region of the area postrema produced a profound and long-lasting depression of blood pressure and heart rate. These results show that central injections of analogs of adenosine can influence the areas of the central nervous system involved in the control of cardiovascular function.     

Pharmacological properties of the stereoisomers of prizidilol: their use in analysis of reflex tachycardia and blood pressure control in normotensive cats, rats, and dogs

Prizidilol, a combined vasodilator/beta-adrenoceptor antagonist, has two optical isomers. The pharmacological activities of these isomers have been established and heart rate/blood pressure responses to both isomers have been determined. Both the R and S isomers elicited similar blood pressure lowering and vasodilator activity in anaesthetised normotensive rats. S-Prizidilol was a substantially more potent beta-adrenoceptor antagonist in vitro and in vivo than R-prizidilol. Neither optical isomer showed any specificity for either beta 1- or beta 2-adrenoceptors. In conscious rats both isomers lowered blood pressure similarly with only marginal differences in heart rate. In conscious cats the importance of increased sympathetic drive in reflex tachycardia was emphasised by the incidence of tachycardia after R-prizidilol but not after S-prizidilol when administered at equieffective blood pressure lowering doses. In conscious dogs both isomers caused tachycardia although S-prizidilol tended to cause the greater fall in blood pressure.     

Vasodilation by medroxalol mediated by beta 2-adrenergic receptor stimulation

A contribution by active vasodilation to the hypotensive effect of medroxalol was investigated in anesthetized dogs and reserpinized pithed rats. In anesthetized dogs, intravenous doses of medroxalol, which decreased blood pressure and heart rate, also produced a dose-related vasodilation in the isolated perfused gracilis muscle in situ. This vasodilator effect of medroxalol was completely blocked by propranolol; the hypotensive effect of medroxalol was inhibited 50% by propranolol but not at all by practolol. In reserpinized pithed rats with angiotensin-supported blood pressure, intravenous doses of medroxalol also produced propranolol-sensitive decreases in diastolic blood pressure and did not alter heart rate. Labetalol produced similar effects but was significantly less potent. Comparatively, equivalent amounts of isoproterenol and pindolol decreased diastolic blood pressure but increased heart rate. In the isolated guinea pig trachea, medroxalol produced a propranolol-sensitive relaxation at concentrations that antagonized the relaxant effects of salbutamol. Identical concentrations of medroxalol did not increase rate of isolated guinea pig atria. It is concluded that a substantial portion of the hypotensive effect of medroxalol is due to a beta 2-adrenergic-receptor-mediated vasodilation.     

Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine

Modification of clonidine-induced cardiovascular effects by endothelin-1 (ET-1) was studied in male Sprague-Dawley rats. A dose-dependent decrease in blood pressure and heart rate was produced by clonidine (100, 250 and 500 μg/kg i.v.). Lower doses produced only a fall in blood pressure (through central -adrenoceptors) while higher doses of clonidine produced an initial hypertensive response (through peripheral -adrenoceptors) and subsequent longer lasting hypotension and bradycardia. The hypotension and bradycardia induced by 100 and 250 μg/kg i.v. dose of clonidine were completely blocked by ET-1 (100 ng/kg i.v.) pretreatment. Conversely, the hypertensive response induced by high dose of clonidine (500 μg/kg i.v.) was significantly potentiated by ET-1 pretreatment. In cervical sectioned rats, i.v. administered clonidine failed to produce any hypotensive effect, indicating lack of central effect of clonidine. ET-1 significantly (P< 0.0005) potentiated the hypertensive response of a low dose (50μg/kg i.v.) of clonidine in cervical-sectioned rats. I.c.v administration of clodinine (1, 2, 4 and 6 μg) produced a dose-dependent decrease in blood pressure and heart rate. ET-1 pretreatment (25 ng i.c.v. transietly blocked the clonidine-induced decrease in blood pressure and heart rate for about 10 min but the hypotension and bradycardia was observed subsequently. Since the major site of action of clonidine is the ventral surface of medulla, clonidine was applied directly to the ventral surface of medulla and produced a decrease in blood pressure and heart rate. ET-1 pretreatment at the ventral surface of medulla blocked the clonidine-induced decrease in blood pressure and heart rate initially but the fall in blood pressure and heart rate was observed subsequently. To explore the possibility that transient antagonism of clonidine-induced effects is due to vasoconstriction, studies were performed with angiotensin II, a powerful vasoconstrictor. Angiotensin II (5 μg i.c.v.) pretreatment like ET-1 blocked the hypotensive and bradycardic effect of i.c.v. or i.v. administered clonidine. It is concluded that ET-1 blocks the hypotensive and potentiates the hypertensive effect of clonidine, possible mechanisms have been discussed.     

Species differences in renal vascular effects of dipyridamole and in the potentiation of adenosine action by dipyridamole

The effects of dipyridamole and adenosine on the renal vasculature and on the enhancement by dipyridamole of the action of adenosine were studied in pigs, dogs, rabbits, and rats. Intravenous adenosine in doses of 10-300 micrograms/kg produced dose-dependent decreases in heart rate and blood pressure of rabbits and rats. Potentiation of adenosine action by intravenous infusion of dipyridamole occurred only in rabbits. When administered into the renal artery of pigs, dogs, rabbits, and rats, adenosine caused dose-dependent vasoconstriction in all species, whereas dipyridamole produced vasoconstriction in rabbits and vasodilation in pigs and rats. In dogs, the renal vascular response to dipyridamole depended on the perfusion method used. In kidneys perfused at a fixed flow rate with a pump, intrarenal dipyridamole elicited vasoconstriction, but in kidneys perfused by their own systemic blood pressure without the use of a pump, it caused vasodilation. The adenosine-induced renal vasoconstriction was enhanced by dipyridamole in pigs, dogs, and rabbits, but not in rats. Species differences and the perfusion method used are important for the renal vascular effects of dipyridamole. Dipyridamole appears to possess not only an indirect action on blood vessels which is related to adenosine, but also a direct vasodilator effect.     

Chronic caffeine treatment causes changes in cardiac adenosine receptor function in rats

Caffeine exerts a number of cardiovascular effects via antagonism of adenosine A1 and A2a receptors, and chronic caffeine intake has been suggested to be a preventable risk factor for cardiovascular disease. We attempted, therefore, to determine the effects of chronic caffeine treatment on adenosine receptor function and the heart rate and blood pressure of anaesthetized rats. Rats were given two weeks of drinking water containing either caffeine (0.2%) or tap water alone. Rats were then anaesthetized and blood pressure and heart rate was assessed, as well as cardiovascular responses to adenosine receptor agonists and antagonists. Following 2 weeks caffeine treatment, both the resting blood pressure and heart rate of the treated rats were significantly increased compared to the non-caffeine treated (147 +/- 5 compared to 161 +/- 3 mm Hg). Negative chronotropic responses to A1 receptor agonist N6 cyclopentyladenosine occurred at lower concentrations in caffeine-treated rats than control (2.5-fold decrease in the ED50 of bradycardic responses to N6 cyclopentyladenosine), whilst vasodilator and reflex tachycardic responses to A2a receptor agonist CGS 21680 were unchanged. A shorter duration of caffeine- treatment resulted in moderate increases in heart rate and bradycardic responses to N6 cyclopentyladenosine. In summary, we found changes in resting heart rate and blood pressure in caffeine-treated rats which were concurrent with changes in adenosine receptor function.     

Aortic baroreceptors exert a tonically active restraining influence on centrally mediated depressor responses.

This study tested the hypothesis that aortic baroreceptors exert a central restraining influence on centrally mediated depressor responses and that this mechanism is tonically active and is independent of their modulation of basal arterial pressure. The effects of short-term (48-72 h) aortic baroreceptor deafferentation (ABD) on the acute hemodynamic (peripherally mediated pressor and centrally mediated depressor) effects of clonidine were investigated in conscious and anesthetized normotensive rats. ABD caused an immediate increase in basal arterial pressure and heart rate and a significant attenuation of the baroreceptor reflex control of heart rate. Since only arterial pressure subsided to control levels by 48-72 h, the data suggest that central reorganizational changes were potent enough to overcome the tonically active restraining influence of aortic baroreceptors on basal arterial pressure but not heart rate. Clonidine produced a similar pressor effect in conscious ABD and sham rats but its depressor effect was significantly greater in ABD rats whose baroreceptor reflex control of heart rate was significantly attenuated. Intracisternal (i.c.) administration of 0.1 microgram of clonidine, a dose that had no effect when administered i.v., produced a near-maximal depressor effect in conscious ABD rats vs. no effect in sham rats (-16.7 +/- 4.1 vs. -0.3 +/- 2 mm Hg; p less than 0.001). The depressor effect of clonidine was also enhanced in chloralose-anesthetized rats and coincided with an anesthesia-induced attenuation of the baroreceptor reflex control of heart rate. It is concluded that aortic baroreceptors exert a potent restraining influence on the centrally mediated depressor effect of clonidine. Since ABD had no significant effect on the depressor response to nitroprusside, but enhanced the depressor response to ganglion blockade by hexamethonium, the data suggest that a higher peripheral sympathetic neural activity existed in ABD rats. The reorganizational changes that occurred within 48-72 h after ABD were potent enough to overcome the tonically active restraining influence of aortic baroreceptors on basal arterial pressure but not on the centrally mediated depressor responses. Thus, the buffering influence of aortic baroreceptors and their central projections on centrally mediated depressor responses seems to be tonically involved in blood pressure control.     

NORMOTENSIVE WISTAR RATS DIFFER FROM SPONTANEOUSLY HYPERTENSIVE AND RENAL HYPERTENSIVE RATS IN THEIR CARDIOVASCULAR RESPONSES TO OPIOID AGONISTS

1. The effects of three opioid receptor agonists on the blood pressure and heart rate of anaesthetized normotensive, spontaneously hypertensive and renal hypertensive rats were measured. 2. Mu agonist morphiceptin i.c.v. induced a pressor response and increase in heart rate in hypertensive rats, but hypotension in normotensive rats. After intravenous (i.v.) injection, morphiceptin produced a hypotensive response in all three groups of rats. 3. In contrast, the delta agonist DTLET i.c.v. decreased blood pressure and heart rate in hypertensive rats, but increased both pressure and beat rate in normotensive rats. After i.v. injections DTLET produced a hypertensive response and increase in heart rate in all groups of rats. 4. Kappa agonist U-50, 488H given i.c.v. induced effects similar to morphiceptin: an increase in blood pressure and heart rate in hypertensive and a decrease in normotensive rats. After i.v. injections U-50, 488H produced decreases in blood pressure and heart rate in all treated groups of rats. 5. Pretreatment with naloxone antagonized the activity of morphiceptin but prevented only the stimulating effect of DTLET in normotensive rats. Cardiovascular actions of U-50, 488H were not blocked by naloxone. 6. The results suggest that opioid agonists exert similar changes in cardiovascular function at central and peripheral sites in both models of experimental hypertension and these effects are different in normotensive rats.     

Studies on several pyrrolo[2,3-d]pyrimidine analogues of adenosine which lack significant agonist activity at A1 and A2 receptors but have potent pharmacological activity in vivo

5'-Deoxy-5-iodotubercidin was previously reported to cause potent muscle relaxation and hypothermia when injected i.p. into mice. In normotensive rats, i.v. injection reduced blood pressure and heart rate. 5-Iodotubercidin possessed the same in vivo activities whereas tubercidin was pharmacologically almost inactive. None of these compounds interacted significantly with Al adenosine receptors, as determined by their ability to displace 3H-N6-phenylisopropyladenosine or 3H-5'-N-ethylcarboxamidoadenosine bound to rat brain membranes. Furthermore these compounds were much weaker than adenosine as agonists of adenosine-stimulated adenylate cyclase in guinea-pig brain slices (A2 receptors). A previous report showed that 5'-deoxy-5-iodotubercidin and 5-iodotubercidin were very potent inhibitors of adenosine kinase from rat or guinea-pig brain and were potent inhibitors of 3H-adenosine uptake into brain slices; relative to the halogenated derivatives, tubercidin was quite weak as an inhibitor of adenosine kinase and of adenosine uptake. We therefore propose that a significant part of the in vivo activity of the two halogenated tubercidin analogues may not be due to a direct agonist action at A1 and/or A2 adenosine sites (as proposed for a number of other metabolically-stable analogues of adenosine) but may result from an inhibition of reuptake of endogenously-released adenosine; the increased extracellular levels of adenosine resulting from this action could then interact directly with membrane receptors. Consistent with this, low concentrations of 5'-deoxy-5-iodotubercidin were shown to significantly potentiate the effects of exogenous adenosine on blood pressure and heart rate in anaesthetized rats and on adenosine-stimulated cAMP generation in guinea-pig brain slices. None of these compounds interacted with central benzodiazepine receptors. The cardiovascular and behavioural effects of 5'-deoxy-5-iodotubercidin and 5-iodotubercidin were blocked by theophylline; results from the cardiovascular studies suggest there may be different adenosine receptors in heart and blood vessels.     

Effects of guanabenz on the cardiovascular system, in comparison with clonidine and guanethidine

Cardiovascular actions of guanabenz, a new antihypertensive agent, were studied in comparison with those of clonidine and guanethidine. Guanabenz, administered intravenously, produced a rise of blood pressure which was followed by a prolonged fall in anesthetized dogs. Guanabenz also decreased the heart rate, inhibited the respiration, and produced an alteration in T wave and a prolongation of PQ or TP interval in the ECG of the dog. Such effects of guanabenz on blood pressure and heart rate were observed in the cat, rabbit and rat, but there was a slight species-difference in the effects. Clonidine, but not guanethidine, produced responses similar to those of guanabenz. The potency of guanabenz to produce hypotension and bradycardia was approximately 1/10 that of clonidine and 10 times higher than that of guanethidine. The depressor effect of guanabenz was not observed in the spinal cats; thus, the blood pressure rose after the administration. When guanabenz was administered intracerebroventricularly or into the nucleus tractus solitarius of rats, the initial pressor response was not produced, and the depressor and bradycardiac responses were observed. Guanabenz, administered intravenously or intra-arterially, produced an inhibition of cardiac functions, decreased the blood flow of common carotid and femoral arteries, and elevated the perfusion-pressure of the hindlimb in the dog. In the isolated rabbit and guinea-pig atria, guanabenz produced negative inotropic and chronotropic effects and attenuated the rate of rise of the action potential. The contractile responses to serotonin and histamine in the isolated rabbit thoracic aorta were noncompetitively inhibited by guanabenz. From these results, it is suggested that the hypotensive and bradycardiac actions of guanabenz are mediated via central actions, as well as those of clonidine. Furthermore, in addition to the central actions, it was found that guanabenz acts directly on cardiovascular tissues and attenuates the responsiveness.