Effects of SK&F 85174, a DA-1/DA-2 receptor agonist, on pre- and postganglionic sympathetic neurotransmission to the heart

We have performed experiments to determine the effects of SK&F 85174, a mixed DA-1/DA-2 receptor agonist, on the tachycardia elicited during pre- and postganglionic stellate stimulation in anesthetized dogs in order to identify a possible action of this compound on the stellate ganglia. SK&F 85174 produced hypotension and caused significant impairment of positive chronotropic responses elicited during pre- and postganglionic stellate stimulation. Pharmacological analysis of SK&F 85174-induced inhibition of cardiac sympathetic function with selective DA-1 and DA-2 receptor antagonists revealed that prior treatment with either S-sulpiride or domperidone (DA-2 receptor antagonists) significantly attenuated the inhibitory effects of SK&F 85174 on responses to pre- and postganglionic stellate stimulation. R-sulpiride (DA-1 receptor antagonist) failed to antagonize SK&F 85174-induced inhibition of tachycardia elicited during preganglionic stellate stimulation. Pretreatment with SCH 23390 (DA-1 receptor antagonist) did not modify the inhibitory effect of SK&F 85174 on responses to postganglionic nerve stimulation. However, SCH 23390 was most effective in antagonizing the hypotensive effect of SK&F 85174. These results show that SK&F 85174 inhibits sympathetic neurotransmission to the heart by activating presynaptic and possibly ganglionic DA-2 receptors, whereas the hypotension produced by SK&F 85174 results predominantly from the activation of the vascular DA-1 receptors. SK&F 85174 does not seem to exert any effect on the ganglionic DA receptors which are reported to be activated by the selective DA-1 receptor agonist, fenoldopam.     

Effects of alpha 1- and alpha 2-adrenoceptor antagonists on venous tone in conscious rats

The dose-response effects of hexamethonium, prazosin and rauwolscine - a ganglionic blocker, alpha 1- and alpha 2-adrenoceptor antagonists, respectively - on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were examined in conscious and unrestrained rats. Prazosin and rauwolscine were also administered to rats after venous tone was elevated by drug-induced hypotension via the infusion of the vasodilator drug hydralazine. The effects of these drugs were compared with those of the vehicle, acidified glucose solution, administered to control rats. In intact rats, i.v. infusions of prazosin and rauwolscine dose dependently decreased MAP; the highest dose of rauwolscine, but not prazosin slightly reduced MCFP. The i.v. infusion of hexamethonium reduced MAP and caused a marked dose-dependent decrease in MCFP. After venous tone was raised by hydralazine, both prazosin and rauwolscine dose dependently decreased MCFP. The decrease in MCFP caused by rauwolscine was significantly greater than that caused by prazosin. Our results show that in the basal condition, the capacitance vessels are somewhat resistant to the effects of alpha-adrenoceptor antagonists in contrast to the effects of ganglionic blockers. After venous tone was raised by reflex mechanisms, both alpha-adrenoceptor antagonists were effective in lowering venous tone, however, the effect of alpha 2-adrenoceptor antagonist is significantly greater than that of alpha 1-adrenoceptor antagonist.     

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.     

Postsynaptic alpha 1-and alpha 2-adrenoceptor involvement in the vascular responses to neuronally released and exogenous noradrenaline in the hindlimb of the dog and cat

The contribution of postsynaptic alpha 1-and alpha 2-adrenoceptors to vascular responses was investigated in the blood perfused hindlimbs of pentobarbitone-anaesthetised dogs and chloralose-anaesthetised cats. Responses were obtained to sympathetic nerve stimulation, noradrenaline, phenylephrine and UK-14,304. In the dog and cat hindlimbs, the response to phenylephrine was reduced by the selective alpha 1-adrenoceptor antagonist, prazosin, while that to UK-14,304, in the dog, was reduced by the alpha 2-adrenoceptor antagonist, rauwolscine. Responses to noradrenaline and sympathetic nerve stimulation were only partially blocked by prazosin in both the dog and cat, but were further reduced by the addition of rauwolscine. These results suggest that the hindlimb vasculature of the dog and cat responds to neuronally released, as well as exogenous, noradrenaline by activation of both postsynaptic alpha 1- and alpha 2-adrenoceptors.     

The alpha 1- and alpha 2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat

An attempt has been made to characterise the alpha-adrenoceptor subtype (alpha 1 or alpha 2) mediating the hypotensive and bradycardic action of clonidine in conscious renal hypertensive cats. The relatively selective alpha 2-adrenoceptor agonists clonidine, UK-14,304, guanfacine and lofexidine caused significant hypotension and bradycardia when given intracerebroventricularly (i.c.v.). This suggests that alpha 2-adrenoceptors can mediate hypotension and bradycardia. However, both alpha 1- and alpha 2-adrenoceptor antagonists, prazosin, UK-33,274, corynanthine, yohimbine, rauwolscine and RS21361 blocked the hypotensive effect of clonidine. These results suggest an alpha 1-adrenoceptor may also mediate the central hypotensive action of clonidine, or possibly that the central alpha-adrenoceptors in which clonidine acts, may show pharmacological differences to peripheral alpha 1- and alpha 2-subtypes.     

Characterization of the alpha-adrenoceptors in the female rabbit urethra.

A radioligand binding technique was used to evaluate the proportions of alpha 1- and alpha 2-adrenoceptors in crude membrane preparations obtained from the female rabbit bladder base and urethra. In addition, urethral rings were studied in vitro in an attempt to determine if alpha 1- and/or alpha 2-adrenoceptors are located postjunctionally in the urethral smooth muscle. Studies of the inhibition of [3H]-dihydroergocryptine binding by the selective alpha 1-adrenoceptor antagonist prazosin or the selective alpha 2-adrenoceptor antagonist rauwolscine revealed the alpha-adrenoceptor population to consist of approximately 25% alpha 1-adrenoceptors and 75% alpha 2-adrenoceptors. These proportions were confirmed in saturation studies with [3H]-prazosin and [3H]-rauwolscine. The sum of alpha 1- and alpha 2-adrenoceptors labelled by these selective alpha 1- and alpha 2-adrenoceptor antagonists was about equal to the number labelled by the non-selective alpha-adrenoceptor antagonist [3H]-dihydroergocryptine. Noradrenaline, as well as the selective alpha 1-adrenoceptor agonist phenylephrine and the selective alpha 2-adrenoceptor agonist clonidine, induced contractions of urethral ring preparations. Prazosin blocked contractions induced by phenylephrine to a greater extent than contractions induced by clonidine. The opposite was true for the inhibitory effect of rauwolscine. In addition to showing that both alpha 1- and alpha 2-adrenoceptor binding sites exist in membrane preparations of the rabbit bladder base and urethra, the results reveal the presence of both adrenoceptor subtypes postjunctionally in the rabbit urethra; and both mediate contraction of the smooth muscle.     

Contribution of alpha 2-adrenoceptors to the central cardiovascular effects of clonidine and S 8350 in anaesthetized rats.

1. The alpha 2-adrenoceptor agonist clonidine elicits centrally mediated effects through an interaction with both alpha 2-adrenoceptors and imidazoline binding sites. 2. We selected a new oxazoline derivative, S 8350, which competes with [3H]-yohimbine for binding to cerebral alpha 2-adrenoceptors (IC50, 67 +/= 17 nmol/L) and displays a higher affinity (35-fold) for alpha 2- than for alpha 1-adrenoceptors. 3. As observed for clonidine, intravenous (i.v.) administration of S 8350 resulted in a brief pressor effect followed by a prolonged hypotension. When S 8350 was administered i.v. to spinally pithed rats, only a rise in blood pressure was observed. 4. In order to discriminate the cardiovascular effects related to the central imidazoline receptor or alpha 2-adrenoceptor activation, the effects of intracisternal (i.c.) administration of clonidine and S 8350 were investigated in the rat. 5. In the anaesthetized rat, both clonidine and S 8350 displayed a profound central (i.c. route) hypotensive effect associated with a bradycardia. 6. The cardiovascular effects of S 8350 were abolished by the central administration of the selective alpha 2-adrenoceptor antagonist rauwolscine. Conversely, rauwolscine completely prevented bradycardia but it induced only a partial reversion of the hypotension elicited by clonidine. 7. These results suggest that central alpha 2-adrenoceptors are responsible for hypotension and bradycardia while imidazoline binding sites do not apparently contribute to heart rate control.     

Sympathetic control of nasal blood flow in the rat mediated by alpha(1)-adrenoceptors

Experiments were undertaken, using laser-Doppler flowmetry, to determine the nature of adrenoceptors mediating sympathetic nerve evoked nasal vasoconstrictor responses in anesthetized rats. Presence of sympathetic tone was confirmed by a large (330%) increase of nasal blood flow following section of the ipsilateral preganglionic cervical sympathetic nerve. Electrical nerve stimulation produced reproducible, frequency-related nasal vasoconstrictor responses with near maximal response, observed at less than 10 Hz. Evoked nasal vasoconstrictor responses were largely blocked with intravenous treatment with the non-selective alpha-adrenoceptor antagonists, phentolamine (5 mg kg(-1)) and phenoxybenzamine (2 mg kg(-1)), as well as with the selective alpha(1)-adrenoceptor antagonist, prazosin (300 microg kg(-1)). alpha(2)-Adrenoceptor antagonism with rauwolscine (500 microg kg(-1)) potentiated neurally evoked nasal vasoconstriction. Neither atropine (1 mg kg(-1)) nor propranolol (1 mg kg(-1)) altered the evoked responses. Rats with intact cervical sympathetic nerves responded to rauwolscine with a modest constriction. Subsequent prazosin administration produced an increase of nasal blood flow of approximately 275%. These results suggest that the nasal vasculature of the rat is under intense sympathetic tone and that the resulting neurogenic vasoconstriction is mediated exclusively by activation of alpha(1)-adrenoceptors.     

Dopamine receptors in the stellate ganglion of the dog

Effects of fenoldopam, a selective DA1 dopamine receptor agonist, and dipropyl dopamine and propylphenethyl dopamine, preferential DA2 dopamine receptor agonists, on ganglion transmission were studied in pentobarbital-anesthetized, open-chest dogs. Tachycardia induced by electrical stimulation (supramaximal voltage, 0.5 ms duration, 1-2 Hz) of the preganglionic cardio-accelerator nerves was monitored as a measure of ganglionic transmission. Drugs were injected into the costocervical artery (i.a.) close to the arterial supply of the ganglion. Doses required to produce 30-40% inhibition of ganglionic transmission by the i.a. route were 2-8 micrograms for dipropyl dopamine, 4-16 micrograms for propylphenethyl dopamine, and 100 micrograms for fenoldopam. At these doses none of the agonists affected tachycardia induced by electrical stimulation of the postganglionic nerve. Domperidone (5 micrograms/kg i.v.), a selective DA2 dopamine receptor antagonist, markedly antagonized the effects of dipropyl dopamine and propylphenethyl dopamine, but had only minor (and statistically insignificant) effects on the inhibitory effect of fenoldopam. SCH 23390 (5 micrograms/kg i.v.), a selective and potent DA1 antagonist, failed to modify the effects of any of the agonists. In a separate series, infusion of fenoldopam, 20 micrograms/kg per min i.v. for 5-7 min, facilitated postganglionic nerve stimulation and blocked the inhibitory effect of UK 14,304, an alpha 2-adrenoceptor agonist, on the postganglionic nerve. These results confirm and support the presence of DA2 but do not support the presence of the prototypal DA1 dopamine receptor in the mammalian ganglia. Furthermore, the alpha 2-adrenoceptor blocking property of fenoldopam points to the complication of using i.v. administration for studying its ganglionic actions while monitoring the target tissue effects in response to preganglionic nerve stimulation.     

Effects of dopamine receptor and alpha 2-adrenoceptor agonists and antagonists on muscarinic receptor stimulation in cardiac sympathetic ganglia of the dog.

The effects of dopamine (DA)-receptor and alpha 2-adrenoceptor agonists and antagonists on ganglionic muscarinic stimulation were examined in anesthetized dogs. All drugs were injected or infused intra-arterially into the blood supply of the cardiac sympathetic ganglia. The muscarinic agonists McN-A-343 (10, 20, and 30 micrograms) and muscarine (1, 2, and 3 micrograms) increased heart rate. The muscarinic receptor stimulation elicited by McN-A-343 or muscarine was significantly inhibited by infusion of the DA2-receptor agonist quinpirole (3 and 10 micrograms/min) but not by the DA1-receptor agonist SK&F 38393 (10 and 30 micrograms/min). The alpha 2-adrenoceptor agonist BHT 933 (3 and 10 micrograms/min) also inhibited muscarinic receptor stimulation. The DA2-receptor antagonist domperidone (10 micrograms/min) and the alpha 2-adrenoceptor antagonist yohimbine (1 micrograms/min) had no effects on muscarinic receptor stimulation, but they antagonized the inhibitory effects of quinpirole and BHT 933, respectively. The nicotinic transmission elicited by preganglionic cardiac sympathetic nerve stimulation (1 and 2 Hz) was also inhibited by DA-receptor and alpha 2-adrenoceptor agonists and antagonists. These results suggest that DA2-receptors and alpha 2-adrenoceptors suppress muscarinic transmission as well as nicotinic transmission in the cardiac sympathetic ganglia of the dog.     

Respective contributions of alpha-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs

The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central alpha2-adrenoceptors (alpha2ARs). However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. This work aims (i) to check whether imidazoline-like drugs with no alpha2-adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an alpha2ARs agonist alpha-methylnoradrenaline (alpha-MNA). We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at alpha2ARs but with high affinities for non-adrenergic imidazoline binding sites (IBS). S23515 decreased BP dose-dependently (-27+/-5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 microg kg(-1) i.c.) was prevented by S23757 (1 mg kg(-1) i.c.) and efaroxan (10 microg kg(-1) i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of alpha-MNA (3 and 30 microg kg(-1) i.c.). Moreover, the alpha2ARs antagonist rauwolscine (3 microg kg(-1) i.c.) did not prevent the effect of S23515. Finally, whilst 3 microg kg(-1) of S23515 or 0.5 microg kg(-1) of alpha-MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (-23+/-2%). These results indicate that an imidazoline-like drug with no alpha2-adrenergic properties lowers BP and interacts synergistically with an alpha(ARs agonist.     

Adenosine-mediated hypotension in in vivo guinea-pig: receptors involved and role of NO

1. Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic effect at the highest doses. The first phase hypotensive response was significantly reduced by the nitric oxide (NO) synthase inhibitor L-NAME. 2. The A(2a)/A(2b) agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not significantly modified by the A(2b) antagonist enprofylline. 3. The A(2a) agonist CGS 21680 did not significantly influence basal HR while induced a hypotensive response antagonized by the A(2a) selective antagonist ZM 241385, and reduced by both L-NAME and the guanylate cyclase inhibitor methylene blue. 4. The A(1) agonist R-PIA showed a dose-dependent decrease in BP with a drastic decrease in HR at the highest doses. The A(1) selective antagonist DPCPX significantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones. 5. The A(1)/A(3) agonist APNEA, in the presence of the xanthinic non-selective antagonist 8-pSPT, maintained a significant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine. 6. The selective A(3) agonist IB-MECA revealed a weak hypotensive and bradycardic effect, but only at the highest doses. 7. In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A(2a)- and NO-mediated hypotension, and a bradycardic effect with a consequent hypotension, via atypical A(1) receptors. Finally, an 8-pSPT-resistant hypotensive response not attributable to A(3) receptor-stimulation or to release of histamine by mastocytes or other immune cells was observed.     

Pharmacological characterization of the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arteries and veins

Summary This investigation was undertaken to characterize the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arterial and venous preparations. Contractile responses to cumulative additions of phenylephrine (selective alpha, -adrenoceptor agonist), UK-14,304 (selective alpha₂-adrenoceptor agonist), noradrenaline (non-selective alpha-adrenoceptor agonist), and dopamine (non-selective alpha-adrenoceptor agonist) were measured in the presence and absence of rauwolscine, a selective alpha₂-antagonist, and terazosin, a selective alpha₁-antagonist. Phenylephrine was a more potent agonist in the mesenteric artery than in the mesenteric vein; UK-14,304 exhibited the opposite profile of activity. Terazosin was a more potent antagonist than rauwolscine against each of the agonists, except dopamine, in the mesenteric artery but rauwolscine was more potent than terazosin in the vein. Terazosin and rauwolscine were equipotent in inhibiting the contractile responses to dopamine in the artery while rauwolscine was more potent than terazosin in the vein. The pA₂ values measured in both vessels failed, however, to demonstrate a high selectivity for either alpha-adrenoceptor antagonist. These results suggest that the alpha-adrenoceptors in the canine mesenteric artery and vein exhibit pharmacological characteristics typical of both alpha,- and alpha₂-adrenoceptor subtypes.This work was supported by NIH grants HL-00872 and GM-22220, and the Searle Clinical Pharmacology ProgramDr. Rajfer is the recipient of a Clinical Investigator Award (HL-00872) from the National Institutes of Health Send offprint requests to S. I. Rajfer at the above address     

Competitive antagonism of alpha 1-adrenoceptor mediated pressor responses in the rat mesenteric artery

(-)-Noradrenaline-mediated pressor responses in the rat mesenteric artery preparation are blocked by alpha 1-adrenoceptor antagonists, BE2254 and prazosin with pA2 values of 8.59 and 8.52 respectively. The alpha 2-adrenoceptor selective antagonist rauwolscine, does not influence responses to (-)-noradrenaline in concentrations up to 10 microM. This rank order is consistent with an alpha 1-adrenoceptor mediated effect. Shifts in the (-)-noradrenaline dose-response curve produced by BE2254 and prazosin were parallel and there was no significant effect on the observed maximal response. Slope values from Schild plots were not significantly different from unity indicating that these antagonists were behaving as classical competitive antagonists.     

An examination of pre- and postsynaptic alpha-adrenoceptors in the autoperfused rabbit hindlimb

Pre- and postsynaptic alpha-adrenoceptors in autoperfused rabbit hindlimbs were examined employing the yohimbine diastereomers rauwolscine and corynanthine, as well as other drugs with varying selectivities for alpha 1-and alpha 2-adrenoceptors. Vasoconstrictor responses were elicited by sympathetic nerve stimulation and by intraarterial injection of agonists. The alpha 2-selective antagonist rauwolscine (10(-7) and 10(-6) M) reduced responses to injected noradrenaline (mixed alpha 1- and alpha 2-agonist) but not to injected phenylephrine (alpha 1-selective agonist); rauwolscine (10(-6) M) actually enhanced nerve-mediated responses. Corynanthine (alpha 1-selective antagonist) was about equipotent against agonist- and nerve-mediated responses. In another series of experiments, rauwolscine (10(-6) M) strongly antagonized the response to xylazine (alpha 2-selective agonist), antagonized the responses to alpha-methylnoradrenaline and noradrenaline (mixed agonists) less strongly, and did not affect the response to phenylephrine, Conversely, prazosin (alpha 1-selective antagonist, 10(-8) M) strongly antagonized phenylephrine, antagonized noradrenaline and alpha-methylnoradrenaline less strongly, and did not antagonize xylazine. Potentiation of neuroeffector responses by rauwolscine demonstrates the operation of an endogenous autoinhibition of noradrenaline release mediated by presynaptic alpha 2-adrenoceptors. However, in comparison with previous in vitro results on rabbit pulmonary artery, the potentiation was small due to the presence of postsynaptic alpha 2-adrenoceptors.     

Characterization of alpha-adrenoceptors participating in the central hypotensive and sedative effects of clonidine using yohimbine, rauwolscine and corynanthine

The central alpha-adrenoceptors responsible for mediating the clonidine-induced central hypotension in anaesthetized cats and sedation in mice have been characterized according to their sensitivities to the alpha-adrenoceptor antagonist yohimbine and its two diastereomeric congeners rauwolscine and corynanthine. Yohimbine and rauwolscine (1-10 microgram/kg) dose-dependently antagonized the central hypotensive response to clonidine (1 microgram/kg) applied 15 min later. Greater amounts of corynanthine (30-100 micrograms/kg) had to be administered to diminish the central depressor effect of clonidine. In these studies the drugs were infused via the left vertebral artery. The prolongation of the hexobarbitone-induced loss of the righting reflex in mice by clonidine (0.3 mg/kg, i.p.) was inhibited by previous treatment with yohimbine and rauwolscine (0.04-5 mg/kg, i.p.) in a dose-dependent manner, but not by corynanthine. Binding experiments with rat isolated cerebral membranes demonstrated the higher affinity of yohimbine and rauwolscine for the [3H] clonidine- than for the [3H]prazosin-specific binding sites. The reverse was found for corynanthine. The relative potencies of yohimbine, rauwolscine and corynanthine in inhibiting these central effects of clonidine are comparable to their order of efficacies in blocking peripheral alpha 2-adrenoceptors. Accordingly, clonidine-induced central hypotension and sedation are mediated by alpha 2-adrenoceptors.     

Investigation of the haemodynamic effects of Phoneutria nigriventer venom in anaesthetised rabbits.

The haemodynamic alterations induced by the central and peripheral administration of the armed spider (Phoneutria nigriventer) venom (PNV) were investigated in anaesthetised rabbits. The intracerebroventricular injection of increasing doses of PNV (30 and 100 microg/kg) elicited a biphasic cardiovascular response characterised by a brief hypotension (1-3 min) followed by a marked and sustained (more than 30 min) increase in mean arterial pressure (61 +/- 5 and 61 +/- 10%, respectively) and in systemic vascular resistance (135 +/- 21 and 161 +/- 37%) accompanied by mild increases in cardiac contractility. Systemic alterations such as salivation and muscular fasciculation were also observed. At the opposite, the dose of 100 microg/kg of PNV injected intravenously produced only a hypotensive effect (29 +/- 4% decrease in mean arterial pressure) and a decrease in vascular resistance (38 +/- 5%). Nevertheless, a much higher dose of PNV (1 mg/kg) injected intravenously produced a hypertensive response analogous to the one observed upon central administration. The central hypertensive response induced by PNV was not affected by preteating the animals with selective antagonists of receptors of different neurotransmitters or endogenous mediators such as: acethylcoline muscarinic, bradykinin B2, angiotensin II AT1 receptors and also antagonists of the excitatory amino acid receptors of the central nervous system. Nevertheless, the intravenous pretreatment with the selective alpha1-adrenergic receptor antagonist prazosin significantly blunted the excitatory cardiovascular response evoked by the central injection of PNV. It is concluded that PNV can induce central as well as peripheral haemodynamic effects. The central component seems to be mediated by the activation of cardiovascular centres which in turn lead to an increase in the sympathetic outflow to the periphery, whereas the peripheral component can be accounted for either by direct activation of the vascular alpha1-adrenergic receptors or by catecholamine release from the sympathetic nerve endings.     

In vivo evidence that isoproterenol may increase heart rate in the rat by mechanisms in addition to activation of cardiac beta(1)- or beta(2)-adrenoceptors

This study demonstrates that the tachycardia produced by systemic injections of the beta-adrenoceptor agonist, isoproterenol (10 microg/kg, i.v.), in conscious rats were not reduced after injection of the selective beta(1)-adrenoceptor antagonist, atenolol (1 mg/kg, i.v.), or after subsequent injection of the beta(1,2)-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.). The hypotensive responses produced by isoproterenol were slightly diminished by atenolol and markedly diminished by propranolol. The tachycardia produced by catecholamines released for cardiac sympathetic nerve terminals were blocked by atenolol. These results suggest that the hypotensive actions of a 10 microg/kg dose of isoproterenol are mediated by activation of beta(1,2)-adrenoceptors whereas the increases in heart rate may be due to activation of another type of beta-adrenoceptor in cardiac pacemaker cells.     

Characterization of alpha-adrenoceptors in the vasculature of the canine nasal mucosa.

alpha-Adrenoceptors present in the vasculature of the nasal mucosa in beta-adrenoceptor blocked dogs have been characterized pharmacologically using selective alpha 1- and alpha 2-adrenoceptor agonists and antagonists. In pentobarbitone-anaesthetized dogs, intra-arterial (i.a.) administration of the selective alpha 1-agonists cirazoline and phenylephrine, the selective alpha 2-agonist UK-14,304 and the mixed alpha 1/alpha 2-agonists adrenaline, noradrenaline and oxymetazoline produced dose-related nasal vasoconstrictor responses (as measured by decreases in nasal cavity pressure). The rank order of agonist potency was adrenaline greater than oxymetazoline = UK-14,304 greater than noradrenaline greater than cirazoline greater than phenylephrine. The nasal response to cirazoline was inhibited by the selective alpha 1-adrenoceptor antagonist prazosin but not by the new, potent selective alpha 2-adrenoceptor antagonist RX811059. In contrast, UK-14,304 was inhibited only by RX811059. Either prazosin or RX811059 reduced the effect of the mixed agonist adrenaline. In spinal dogs, the noradrenaline-evoked fall in nasal cavity pressure was reduced by either prazosin or RX811059. Prazosin attenuated markedly the nasal vasoconstrictor response to electrical stimulation of postganglionic fibres emerging from the superior cervical ganglion (SNS) whereas RX811059 was ineffective. Administration of the neuronal re-uptake inhibitor cocaine potentiated the effect of i.a. noradrenaline but reduced marginally the maximal response to SNS. After cocaine, RX811059 enhanced the effect of SNS and attenuated the response to noradrenaline. Prazosin reduced effectively the responses to both SNS and noradrenaline after cocaine. Pretreatment with the alpha 2-agonist UK-14,304 did not affect the response to noradrenaline in the nasal cavity but evoked a persistent (up to 2 h) reduction in the response to SNS. RX811059 antagonized the inhibitory effect of UK-14,304. These results demonstrate that both postjunctional alpha 1- and alpha 2-adrenoceptors mediating vasoconstriction are present in the canine nasal mucosa. In addition, sympathetic neurones innervating the nasal mucosa are characterized by a very efficient re-uptake process and contain prejunctional alpha 2-adrenoceptors.     

Site-dependent inhibition of neuronal c-jun in the brainstem elicited by imidazoline I1 receptor activation: role in rilmenidine-evoked hypotension

Clonidine (a mixed alpha2-adrenoceptor and imidazoline I1 receptor agonist)-evoked hypotension was associated with dissimilar reductions in c-jun gene expression in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS) in normotensive rats. In the present study, we investigated the relative contribution of the alpha2-adrenoceptor vs. the imidazoline I1 receptor to the reduction in c-jun gene expression in these two brainstem areas. In conscious spontaneously hypertensive rats (SHRs), equihypotensive doses of three centrally acting hypotensive drugs with different selectivity for the two receptors were administered intracisternally (4 microl) to limit their actions to the brain. As a control, a similar hypotensive response was elicited by i.v. hydralazine. Clonidine (0.5 microg), or alpha-methylnorepinephrine (alpha-MNE, 4 microg), a highly selective alpha2-adrenoceptor agonist, similarly reduced c-jun mRNA expression in the NTS and rostral ventrolateral medulla. In contrast, a similar hypotensive response (-37+/-3.5 mm Hg) caused by the selective imidazoline I1 receptor agonist rilmenidine (25 microg) was associated with reduction in c-jun mRNA expression in the rostral ventrolateral medulla, but not in the NTS. Further, intra-rostral ventrolateral medulla rilmenidine (40 nmol) reduced c-Jun protein expression in rostral ventrolateral medulla and blood pressure and both responses were antagonized by selective imidazoline I1 receptor (efaroxan, 4 nmol), but not alpha2-adrenoceptor (SK&F 86466, 10 nmol) blockade. These results suggest: (1) the c-jun containing neurons in the brainstem are involved in the centrally mediated hypotension elicited by centrally acting antihypertensive agents, and (2) the alpha2-adrenoceptor modulates c-jun gene expression in the NTS and rostral ventrolateral medulla implicated in centrally mediated hypotension, and (3) the imidazoline I1 receptor mediated inhibition of c-jun gene expression in the rostral ventrolateral medulla, but not in the NTS, contributes to the centrally mediated hypotension by the second generation drugs.