Ontogeny of renal alpha-1 and alpha-2 adrenoceptors in the spontaneously hypertensive rat

Renal alpha-1 and alpha-2 adrenoceptors were characterized during the development of the spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats through Scatchard analysis of [3H]prazosin and [3H]yohimbine binding to kidney membrane preparations in an attempt to correlate biochemical changes with the reported functional changes occurring in hypertension development in the SHR. Renal alpha-1 and alpha-2 receptor density was higher in SHR than in Wistar-Kyoto rats at all ages tested. In contrast to Wistar-Kyoto rats, in which the number of alpha-1 and alpha-2 receptors remained relatively constant with age, the number of renal alpha-1 adrenoceptors in the SHR was lowest at the 4th week of age (61 fmol/mg) increasing transiently at 5 weeks and then again at 8 week reaching a plateau at that time. The maximum number of binding sites for [3H]yohimbine binding in the SHR was also age dependent. The number of renal alpha-2 adrenoceptors in the SHR was lowest at 4 weeks of age (125 fmol/mg) increasing to 220 fmol/mg at 5 weeks of age and to 260 fmol/mg at 8 weeks of age. Adult levels (308 fmol/mg) were reached by 18 weeks of age. Unlike receptor densities, affinity constants were not significantly altered during postnatal development. The changes in alpha-1 and alpha-2 adrenoceptors in the kidneys of SHR may suggest an important developmental role which is not yet understood.     

Studies that question the existence of alpha-2 adrenoceptors in tail arteries of normotensive Sprague-Dawley rats

Many pharmacological studies have demonstrated two distinct types of alpha adrenoceptor in the vasculature; these receptors have been named alpha-1 and alpha-2. In the present study, using isolated perfused tail arteries from normotensive Sprague-Dawley rats, we have demonstrated two types of alpha adrenoceptor but neither of these could be classified as an alpha-2 adrenoceptor. Dose-dependent contraction of rat tail arteries was produced by the following alpha adrenoceptor agonists or agonist-antagonist combination: phenylephrine (PE alpha-1), clonidine (alpha-1 and alpha-2), clonidine in the presence of 10(-7) M prazosin (alpha-2) and BHT-920 (alpha-2). The ED50 values for PE and clonidine were four orders of magnitude lower than those for clonidine plus prazosin and BHT-920. In addition, the action of PE was faster in onset than that of BHT-920, reached a higher maximum (5-fold) and attenuated more rapidly than that of BHT-920. The specific alpha-2 adrenoceptor antagonist yohimbine, in concentrations as high as 10(-6) M, did not antagonize arterial responses to BHT-920. However, responses to BHT-920 were antagonized by the alpha-1 adrenoceptor antagonist prazosin, in concentrations as low as 10(-10) M, and by the serotonin/alpha-1 adrenoceptor antagonist ketanserin (10(-7) M). These results suggest that the two alpha-adrenoceptor types in isolated rat tail arteries are both of the alpha-1 type. We also found that whereas responses to PE were stable and reproducible between 2 and 5 hr of arterial perfusion, responses to BHT-920 increased progressively over 5 hr. The latter effect probably resulted from a gradual disappearance of the arterial endothelium.     

Naloxone-induced bradycardia in pithed rats: evidence for an interaction with the peripheral sympathetic nervous system and alpha-2 adrenoceptors.

Earlier experiments performed in this laboratory have demonstrated that naloxone infusion (1 mg/kg/min i.v.) into conscious rats results in a bradycardia that has a peripheral component, is dependent on a certain level of sympathetic activity and is sensitive to alpha adrenoceptor blockade (5 mg/kg of phentolamine i.v.). The main objective of this investigation was to examine the underlying mechanism(s) responsible for the peripherally mediated naloxone-induced bradycardia, and to test the hypothesis that naloxone interacts with peripheral inhibitory alpha adrenoceptors associated with depression of peripheral sympathetic activity. Naloxone infusion (1 mg/kg/min i.v.) in pithed rats, in the absence of sympathetic nerve activation, resulted in a bradycardia that could not be blocked by 1 mg/kg (i.v.) of atropine, 5 mg/kg (i.v.) of phentolamine, 0.1 mg/kg (i.v.) of prazosin or 0.5 mg/kg (i.v.) of rauwolscine. Isoproterenol or norepinephrine-induced tachycardia was not blocked by naloxone infusion, suggesting that naloxone does not antagonize the postjunctional activation of cardiac adrenoceptors to cause bradycardia. In the presence of sympathetic nerve activity, naloxone depresses neurogenic tachycardia. This effect was blocked completely by 5 mg/kg (i.v.) of phentolamine or 0.5 mg/kg (i.v.) of rauwolscine, but not 0.1 mg/kg (i.v.) of prazosin or 1 mg/kg (i.v.) of atropine. The results of this investigation suggest that the naloxone-induced bradycardia in pithed rats is mediated postjunctionally and prejunctionally, and that this prejunctional effect is dependent on sympathetic nerve activity and inhibitory alpha-2 adrenoceptors. Furthermore, these results confirm results obtained from conscious rats in an earlier investigation.     

Positive chronotropic activity of bradykinin in the pithed normotensive rat

Summary— The positive chronotropic effect of bradykinin was investigated in the pithed rat preparation. Cumulative treatment with bradykinin (0.20 nmol/kg-6.59 μmol/kg, intravenous [iv]) caused a dose-dependent increase in heart rate (HR) by a maximum of 80 ± 3.3 beats min^-1. In contrast, the active metabolite of bradykinin and selective bradykinin B₁- receptor agonist, [des-Arg⁹]-bradykinin did not influence the spontaneous frequency of beating. Propranolol alone reduced the bradykinin-induced increase in HR and a combination of propranolol with prazosin abolished the chronotropic effect of bradykinin. The selective bradykinin B₂ receptor antagonist, Hoe 140, dose-dependently shifted the dose-response curves of bradykinin to the right, whereas the bradykinin B1 receptor antagonist, des-Arg¹⁰-[Leu⁹]-kallidin proved ineffective. From our experiments it may be concluded that bradykinin induces tachycardia in the pithed rat primarily by stimulating the sympathetic ganglia leading to the release of noradrenaline, which subsequently activates cardiac β₁-adrenoceptors. The bradykinin-induced chronotropic effect is mediated by bradykinin B₂-receptors, whereas B₁-receptors appear not to be involved.     

Analysis of the presence of postjunctional alpha-2 adrenoceptors in the rat anococcygeus muscle

When the tone is raised by guanethidine, rat anococcygeus muscle produces inhibitory responses to field stimulation, whose mechanism is not understood properly. The present study is an attempt to investigate the role of alpha adrenoceptors in the field stimulation-induced relaxations in isolated rat anococcygeus muscle. When the tissues are contracted with clonidine, UK-14,304 and low doses of oxymetazoline, field stimulation produced relaxations at lower frequencies, but not in the tissues precontracted with phenylephrine and norepinephrine. Relaxations induced by low frequencies were blocked by idazoxan, but not by phentolamine, prazosin, indomethacin, N-methyl-hydroxylamine, ouabain or 3,4-diminopyridine. When the tone of the muscle is raised by norepinephrine, prazosin reversed the field stimulation-induced contractions to relaxation responses. The data of the present study suggested the possible involvement of alpha-2 adrenoceptors during the field stimulation-induced relaxations of the rat anococcygeus muscle. To analyze and quantitate the alpha-2 adrenoceptor antagonism in the rat anococgygeus muscle, Schild analyses of clonidine-induced contractions against idazoxan were conducted either for idazoxan alone or after partially alkylating the alpha-1 adrenoceptors with phenoxybenzamine and by pharmacologic resultant analysis by blocking the alpha-1 adrenoceptors with prazosin. The Schild regression for idazoxan and pharmacologic resultant analysis suggested that the rat anococcygeus muscle responds to alpha-2 agonists with alpha-1-mediated contractions and idazoxan competes with alpha-1 antagonists for the same site, i.e., alpha-1 adrenoceptor site. However, the atypical Schild regression of idazoxan after partial alkylation with phenoxybenzamine indicated the existence of a second alpha adrenoceptor site in the rat anococcygeus muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet alpha-2 adrenoceptors and the menstrual cycle

To clarify further the suggested influence of menstrual cycle phase on platelet alpha 2-adrenoceptors, we carried out cross-sectional studies in 77 subjects in a clinical trial of weight control strategies. Blood samples were drawn at baseline and after 6 weeks of diet, behavior modification, and exercise, a program that resulted in a mean weight loss of 4.5 kg. For the analyses, 42 premenopausal women were divided into four groups according to the week of menstrual cycle at the time of blood sampling. At baseline, there was no significant difference in mean platelet alpha 2-adrenoceptor numbers among the four groups. At week 6 accompanying the weight loss, there was a significant increase in the platelet alpha 2-adrenoceptor number for all groups. Despite the fact that the women were at a different phase of the menstrual cycle than at baseline, there was again no significant difference in mean platelet alpha 2-adrenoceptor number. Mean baseline platelet alpha 2-adrenoceptor number in the premenopausal women (113.7 +/- 5.5 fmol/mg protein) did not differ from values in 12 postmenopausal women (113.7 +/- 12.0 fmol/mg protein), four women with hysterectomies (105.9 +/- 8.9 fmol/mg protein), or 19 men (101.8 +/- 6.2 fmol/mg protein). Numbers at 6 weeks also did not differ. We conclude that the menstrual cycle has minimal effects on platelet alpha 2-adrenoceptor number and should not confound clinical studies of platelet alpha 2-adrenoceptors.     

Determination of molecular size of alpha-1 and alpha-2 adrenoceptors in rat mesenteric artery by radiation inactivation

Radiation inactivation of alpha-1 and alpha-2 adrenoceptors in the purified plasma membranes of rat mesenteric artery has been performed with high energy electrons at -45 to -55 degrees C. Alpha-1 and alpha-2 adrenoceptor inactivation was monitored with [3H] prazosin and [3H]yohimbine binding, respectively. Internal endogenous and external standards of known molecular weight were used in these studies to determine the molecular size. The average value of D37 for the [3H]prazosin binding site was 6.75 +/- 0.62 Mrad (n = 4) with an estimated molecular size of 122,921 +/- 11,329 Daltons. However, the average value of D37 for the [3H] yohimbine binding site was higher (D37 = 10.05 +/- 0.91 Mrad) and accordingly the molecular size of this binding site was less than the [3H]prazosin binding sites (molecular weight = 82,540 +/- 7478 Daltons; n = 4). Irradiation did not change the dissociation constant of either radioligand, suggesting that the loss of the radioligand binding sites after radiation is due to receptor protein inactivation. These results confirm our earlier finding that [3H]prazosin and [3H]yohimbine bind to two distinct sites in the plasma membranes of rat mesenteric artery. Whether both of these sites are the subunits of a common macromolecule of alpha adrenoceptor on vascular smooth muscle in rat mesenteric artery cannot be concluded from these results. This report is the first one in the literature on the molecular size of alpha-1 and alpha-2 binding sites in vascular smooth muscle.     

Inhibitory effect of alpha-1 adrenoceptor stimulation on cardiac sympathetic neurotransmission in pithed normotensive rats

In the present study we investigated the inhibitory effect of the selective alpha-1 adrenoceptor agonists cirazoline, amidephrine and St 587 on the cardiac sympathetic neurotransmission in pithed normotensive rats. Increases in heart rate were elicited by electrical stimulation of the cardiac sympathetic nerves or by i.v. administration of norepinephrine, isoproterenol or tyramine. Intravenous pretreatment of the animals with cirazoline, amidephrine or St 587 diminished the heart rate response to sympathetic stimulation significantly. However, the tachycardia produced by norepinephrine, isoproterenol or tyramine was also inhibited significantly by the selective alpha-1 adrenoceptor agonists. The selective alpha-1 antagonist prazosin blocked the sympathoinhibitory effect to alpha-1 adrenoceptor stimulation significantly. However, the inhibitory effect of cirazoline and St 587 was not suppressed completely by a maximally effective dose of prazosin. In contrast, the sympathoinhibitory action of amidephrine was antagonized completely by prazosin. However, the selective alpha-2 antagonist rauwolscine also produced a significant, albeit modest, attenuation of the sympathoinhibitory effect to amidephrine. The results of the present study indicate that alpha-1 adrenoceptor agonists, at relatively high doses, inhibit the sympathetic neurotransmission in rat heart. This sympathoinhibitory effect is mediated largely by alpha-1 adrenoceptors which are localized postjunctionally rather than prejunctionally.     

Urethane inhibits cardiovascular responses mediated by the stimulation of alpha-2 adrenoceptors in the rat

Clonidine and oxymetazoline (4.0 microgram/kg i.v. or i.a.) evoked a marked bradycardia in either methylatropine-pretreated conscious or pentobarbital-anesthetized (55 mg/kg i.p.), vagotomized rats. Urethane (1.2 g/kg i.p.) inhibited by more than 50% this effect which is mediated through the stimulation of peripheral and/or central neuronal alpha-2 adrenoceptors. However, in adrenalectomized rats only the inhibition of oxymetazoline by urethane was significantly less pronounced. In pithed rats in which the adrenal glands were either left untouched or surgically removed, urethane significantly attenuated the clonidine or oxymetazoline-induced decreases in experimental neural sympathetic tachycardia although it neither changed the base-line nor the experimentally elevated heart rate. Urethane, in contrast to pentobarbital, increased plasma epinephrine concentrations in intact but not in adrenalectomized or in pithed rats. Elevation of plasma epinephrine did not result from the low arterial pressure level associated with urethane anesthesia since the increase of this parameter with vasopressin did not abolish the effect of urethane. Furthermore, guanethidine-pretreated rats, when anesthetized with urethane, exhibited a higher heart rate and plasma adrenaline value than those anesthetized with pentobarbital. The elevated heart rate was decreased by either propranolol or adrenalectomy. The bradycardia produced by injecting clonidine into the lateral cerebral ventricles of either intact or adrenalectomized rats was markedly less in urethane- than in pentobarbital-anesthetized animals. Whereas in pentobarbital-anesthetized rats the peak heart rate effects of i.v. or i.c.v. clonidine were similar, in urethane-anesthetized animals the effects of clonidine were more inhibited when it was given centrally than when it was given peripherally. In pithed rats, the cumulative dose-pressor response curves elicited by the relatively selective alpha-2 adrenoceptor agonists, B-HT 930 and M-7, were depressed by urethane significantly more than those produced by the relatively selective alpha-1 adrenoceptor agonists, phenylephrine and cirazoline, or by angiotensin II. Urethane also decreased the pressor responses evoked by clonidine, oxymetazoline and norepinephrine which stimulate both alpha-1 and alpha-2 adrenoceptors. However, the extent of this inhibition was less than that of B-HT 920 and M-7 but greater than that of cirazoline and phenylephrine. These results show that urethane inhibits cardiovascular responses that are mediated by peripheral and central alpha-2 adrenoceptors. Furthermore, urethane increases the central drive to the adrenal medulla and this leads to the secretion of epinephrine. This may be partly responsible for the inhibitory activity of urethane on oxymetazoline-induced bradycardia. Although the basic mechanism by which urethane impairs responses mediated by alpha-2 adrenoceptors remains to be determined, it is advised that urethane anesthesia should be avoided, particularly for cardiovascular studies.     

Postjunctional alpha-1 and alpha-2 adrenoceptors in the coronaries of the perfused guinea-pig heart

Prazosin and yohimbine were used to differentiate postjunctional alpha adrenoceptors in the coronaries of the perfused guinea-pig heart. Two postjunctional alpha adrenoceptor subtypes were distinguished by the affinities of the receptor for yohimbine and prazosin. The pA2 for yohimbine were 8.74 against alpha-methylnorepinephrine and 8.98 against BHT-920, and the pA2 for prazosin was 9.84 against phenylephrine. Yohimbine was not very active against the alpha-1 selective agonist as was prazosin against the alpha-2 selective agonists. Alpha-1 and alpha-2 postjunctional adrenoceptors mediate vasoconstriction in the whole coronary bed of the perfused guinea-pig heart.     

Effect of pertussis toxin treatment on postjunctional alpha-1 and alpha-2 adrenoceptor function in the cardiovascular system of the pithed rat

The role of pertussis toxin sensitive guanine nucleotide regulatory proteins (G-proteins) in the signal transduction processes involved in postjunctional vascular alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction has been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 micrograms/kg i.v., 3 days before experimentation) produced a marked inhibition of the alpha-2 adrenoceptor-mediated pressor response to B-HT 933. In contrast, pertussis toxin treatment had only a small effect on the alpha-1 adrenoceptor-mediated pressor response to cirazoline. However, after elimination of the alpha-1 adrenoceptor reserve for cirazoline with phenoxybenzamine (0.1 mg/kg i.v.), the pressor response to this agonist became highly sensitive to inhibition by pertussis toxin treatment. This pattern of inhibition of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by pertussis toxin is identical to that produced by inhibition of extracellular calcium influx by a high dose of the calcium channel antagonist, nifedipine (1.5 mg/kg i.a.), suggesting that those components of the alpha-1 and alpha-2 adrenoceptor-mediated vasoconstrictor processes that are dependent upon the translocation of extracellular calcium may involve a pertussis toxin sensitive G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue.

The role of alpha-2 adrenoceptors in lipid mobilization and blood flow was investigated in situ using microdialysis of subcutaneous adipose tissue in nonobese healthy subjects. The alpha-2 agonist clonidine caused dose-dependent biphasic response with increased glycerol levels at low clonidine concentrations and decreased glycerol levels at concentrations > 10(-7) mol/liter. Similar results were observed with epinephrine plus propranolol. Clonidine action was unaffected in the presence of labetalol (beta-/alpha-1 antagonist) but completely blunted by the presence of yohimbine (alpha-2 antagonist). The pseudolipolytic effect of clonidine was significantly more pronounced in gluteal as compared with abdominal adipose tissue. When clonidine was added together with the vasodilating agents nitroprusside or hydralazine, the pseudolipolytic effect was abolished and a dose-dependent decrease in dialysate glycerol was observed at all clonidine concentrations (10(-10)-10(-4) mol/liter). When ethanol was added to the perfusate to monitor blood flow, the escape of alcohol from the dialysate was accelerated by 30% with hydralazine or nitroprusside (P < 0.01) and 30% retarded (P < 0.05) by clonidine (10(-10) mol/liter). Thus, the results demonstrate an important role of blood flow for regulating lipid mobilization from adipose tissue in vivo. Alpha-2 adrenoceptor activation causes marked retention of lipids in adipose tissue due to vasoconstriction in combination with antilipoiysis.     

Evidence for the involvement of presynaptic alpha-2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain

In an attempt to evaluate the possible functional role of alpha-2 adrenoceptors located on noradrenergic nerve endings in the regulation of cerebral norepinephrine metabolism, we have measured the effects of clonidine and idazoxan on cerebral free 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (an index of norepinephrine turnover) in the rat after surgical and experimental manipulations that allow an exclusive interaction of the alpha-2 adrenergic agents with presynaptic alpha-2 autoreceptors. The possible contribution of distant (to cell bodies) transsynaptic feedback mechanisms triggered by stimulation of postsynaptic alpha-2 adrenoceptors and of somatodendritic alpha-2 autoreceptor-mediated regulatory mechanisms was eliminated by a local infusion of tetrodotoxin (50 ng) into the ascending noradrenergic bundle followed by electrical stimulation (at a frequency of 8 Hz) of this pathway distally to the neurotoxin injection site in chloral hydrate-anesthetized rats. Under these conditions, systemic injection of idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.) provoked an increase and a decrease, respectively, in free DOPEG levels in the hypothalamus, cerebral cortex and medial septum which were similar to those measured in naive rats. Moreover, in these animals the effect of idazoxan (1 mg/kg i.p.) was surmounted by a large dose of clonidine (0.3 mg/kg i.p.). The possible contribution of feedback mechanisms triggered by activation of postsynaptic alpha-2 adrenoceptors and mediated via local (to terminals) circuits (or a putative humoral agent released postsynaptically) was eliminated subsequently by a local injection of ibotenic acid in noradrenergic projection areas. Systemic administration of idazoxan (20 mg/kg i.p.) to ibotenate-lesioned rats elicited an increase in septal- and hypothalamic-free DOPEG levels comparable to that found in sham-operated rats. The effectiveness of the lesion was attested by a massive neuronal depopulation in the lesioned areas. Finally, ibotenic acid-induced destruction of noradrenergic target cells and local infusion of tetrodotoxin into followed by electrical stimulation of the ascending noradrenergic pathways were combined. Under these conditions, idazoxan still increased hypothalamic- and septal-free DOPEG levels, the extent of this alteration being similar to that found in normal rats. Altogether, these results suggest that irrespective of their low density, presynaptic alpha-2 autoreceptors play a cardinal role in the regulation of central nervous system norepinephrine metabolism.     

Differential inhibiton of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses in pithed rats

The relative potencies of alpha adrenoceptor antagonists at pre- and postsynaptic receptors were assessed by comparing their effects on increments in plasma norepinephrine levels and blood pressure during stimulation of the sympathetic outflow from the spinal cord of pithed rats. Since increments in blood pressure are related to the logarithms of increases in plasma norepinephrine, the latter appear to reflect levels of the catecholamine at vascular alpha receptors. Phenoxybenzamine, dibenamine and chlorpromazine were found to block preferentially postsynaptic alpha receptors, phentolamine and tolazoline were nearly equipotent at pre- and postsynaptic receptors and mianserin and piperoxan were more potent inhibitors of presynaptic alpha receptors. Phenoxybenzamine and dibenamine were much more effective in blocking the pressor responses to sympathetic stimulation than administered norepinephrine. The opposite was true of mianserin and piperoxan, whereas phentolamine appeared to be about equipotent in blocking the pressor response to stimulation and norepinephrine. These results suggest that the pressor effects of administered norepinephrine is mediated by different receptors (alpha-2-type) than is the pressor response to stimulation of the sympathetic outflow which appears to be mediated by alpha-1-type adrenoceptors.     

Role of alpha-1 and alpha-2 adrenoceptors in the sympathetic control of the proximal urethra

In the pithed rat, postjunctional alpha-1 and alpha-2 adrenoceptors mediate increases in proximal urethral perfusion pressure (UPP). The present study examined the role of alpha-1 and alpha-2 adrenoceptors in sympathetic control of the isolated in situ proximal urethra of the rat. An endogenous alpha adrenergic constriction was demonstrated in the proximal urethra by eliciting dose-related and phentolamine-sensitive increases in UPP after the systemic administration of tyramine. Transient dose-related and hexamethonium-sensitive increases in UPP were also elicited by ganglionic stimulation with 1,1-dimethyl-4-phenylpiperazinium (DMPP). Based on the relative sensitivity of the DMPP response to standard autonomic blockers, it was determined that constriction is the predominant autonomic response in the proximal urethra and this response is mediated by alpha adrenoceptor mechanisms. Prazosin, a selective alpha-1 adrenoceptor antagonist, substantially reduced (72%) the steady-state increases in UPP elicited by discrete low frequency electrical stimulation of the spinal hypogastric outflow. In contrast, selective alpha-2 adrenoceptor blockade with rauwolscine significantly increased (28%) the UPP response to hypogastric stimulation. Prazosin also abolished the increase in urethral tone elicited by tyramine, whereas rauwolscine had no effect on the tyramine. A different response profile was observed for prazosin and rauwolscine when the steady-state increase in UPP was evoked by simultaneously stimulating the midthoracic and hypogastric spinal outflow. Under these conditions of sympathoadrenal activation, UPP was reduced by both prazosin and rauwolscine (63 and 50%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog

Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.     

Alpha adrenoceptor-mediated vasoconstriction in rat hindlimb: innervated alpha-2 adrenoceptors in the saphenous arterial bed

The alpha adrenoceptor subtypes mediating vasoconstriction to exogenous agonists and to spinal sympathetic nerve stimulation have been characterized in the autoperfused (constant flow) femoral (predominantly skeletal musculature) and saphenous (predominantly cutaneous) vascular beds of the pithed rat. Intra-arterial infusion of the alpha-1 adrenoceptor agonist, methoxamine, increased perfusion pressure in both vascular beds over the same range of infusion rates, and the maximum responses were similar. The selective alpha-2 adrenoceptor agonist, B-HT 933, also increased perfusion pressure in both beds, although the maximum response to B-HT 933 in the saphenous bed was approximately twice that observed in the femoral bed. Responses to methoxamine were blocked by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg), but not the alpha-2 adrenoceptor antagonist, rauwolscine (1 mg/kg), or by the selective postjunctional alpha-2 adrenoceptor antagonist, SK&F 104078 (1 mg/kg). Conversely, responses to B-HT 933 were blocked by rauwolscine and by SK&F 104078, but not by prazosin. Vasopressor responses to B-HT 933 in both vascular beds of the rat hindlimb also were reduced markedly by the calcium channel blocker, nifedipine (1 mg/kg), whereas responses to methoxamine were relatively resistant to inhibition by nifedipine. In the femoral bed, as in the systemic arterial circulation, responses to sympathetic nerve stimulation were strongly inhibited by prazosin, were potentiated by rauwolscine and were unaffected by SK&F 104078. In contrast, in the saphenous arterial bed, the responses to sympathetic nerve stimulation were inhibited by all three antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human postjunctional alpha-1 and alpha-2 adrenoceptors: differential distribution in arteries of the limbs

Experiments were performed in order to characterize the post-junctional alpha adrenoceptors that mediate contraction in arteries of human limbs. Blood vessels were obtained from patients undergoing amputation of an extremity for reasons other than vascular disease. Proximal (dorsalis pedis and arcuate arteries of the foot, superficial palmer arch of the hand) and distal (digital arteries of the foot and hand) blood vessels were studied from each limb. The blood vessels were removed within 60 min of amputation and were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution. In proximal and distal arteries, alpha-1 adrenergic blockade with prazosin produced a nonparallel shift in the concentration-effect curve to high compared to low concentrations of the agonist. In contrast, alpha-2 adrenergic blockade with rauwolscine was more effective against responses evoked by low concentrations of norepinephrine. This suggests that the alpha-2 adrenergic component of the response to norepinephrine is a low-maximum effect compared to the alpha-1 adrenergic component. Prazosin was less potent and rauwolscine more potent in distal arteries, compared to proximal arteries which might indicate an increased alpha-2 adrenergic response in distal arteries. The selective alpha-1 adrenergic agonist, phenylephrine, produced similar responses in proximal and distal arteries. However, the selective alpha-2 adrenergic agonist, B-HT 920, caused greater contractile responses in distal arteries compared to proximal arteries. The results suggest that alpha-1 and alpha-2 adrenoceptors are present on the vascular smooth muscle of arteries of human limbs, and that alpha-2 adrenoceptors are more prominent on distal arteries. This may be related to an increased contribution of the distal arteries to thermoregulation.