Postsynaptic Α-adrenoceptors Research Articles

α1 AND α2 MEDIATED RENAL VASOCONSTRICTION IN FETAL (F) AND ADULT (A) SHEEP: ONTOGENY OF POST-JUNCTIONAL α ADRENOCEPTORS

It has been suggested by others that renal hemodynamic response to a adrenoceptor stimulation is greater in newborns than adults (Am J Physiol 226:796, 1974). To further characterize the development of a adrenoceptors, the renal vascular response to specific α1 and α2 adrenoceptor stimulation using Phenylephrine (Phe) (α1) and Guanabenz (Gb) (α2) was determined in chronically catheterized F (132-140 days gestation; term 145 days) and A. Phe (4.5×10−8M to 3.6×10−7M) or Gb (6.2× 10−7M to 5×10−8M) was infused intrarenally and % changes in renal blood flow (%ΔRBF) were measured using a Doppler flow probe. α2 mediated renal vasoconstriction was of smaller magnitude in F than A (p<.001 ANOVA); ED50F/ED50A 5.3:1. However, α1 mediated vasoconstriction was different only at the highest dose of Phe tested. (*p<0.01, F vs. A, Newman-Keuls) In conclusion: 1) this study does not confirm previous observations of increased α-adrenoceptor activity during development, 2) post-synaptic α2 adrenoceptors are functional in F, and 3) the F response to α2 stimulation is less than A while α1 response tends to be similar, suggesting a difference in the ontogeny of α1 and α2 adrenoceptors.

Alpha 2-adrenoceptor antagonists as antidepressants: the search for selectivity.

Tricyclic antidepressants and monoamine oxidase inhibitors are presumed to act rapidly to elevate synaptic levels of norepinephrine (NE) and serotonin (5-HT) by inhibiting uptake and metabolism, respectively. Synaptic levels of NE, how-ever, are not controlled entirely by reuptake and metabolic processes, but are under the additional influence of a negative feedback inhibition mediated by an agonist action of NE itself upon α2-adrenoceptors located presynaptically on the noradrenergic nerve terminal (Timmermans and van Zwieten 1982). Antagonism of these so-called autoreceptors leads to enhancement of the release of NE from its storage sites in the nerve terminal and thereby to a situation akin to that following uptake inhibition. α2-Autoreceptors have been demonstrated to exist at almost all noradrenergic axons where postsynaptic α-adrenoceptors are known to occur, and they are widely distributed in the brain, particularly in the cortex. The possibility that α2-autoreceptor antagonism might lead to antidepressant properties has stimulated the development of a number of putative therapeutic agents, which vary widely in their potency and selectivity (Pinder 1985 a, b).

O-202 - Pharmacological and electrophysiological characteristics of postsynaptic α1 and α2 adrenoceptors of vascular smooth muscle

O-202 - Pharmacological and electrophysiological characteristics of postsynaptic α1 and α2 adrenoceptors of vascular smooth muscle

Effects of Selective α1- and α2-Adrenoceptor Agonists on the Physiologic Properties of Rat Left Atria

Summary: The effects of the selective α1-adrenoceptor agonist, phenylephrine, and the α2-adrenoceptor agonist, B-HT933, on the contractility, excitability, automaticity, and functional refractory period in the isolated rat left atria were investigated. For the depletion of catecholamine in rat left atria and the blockade of intra- and extraneuronal uptake of catecholamine, reserpine (10 mg/kg, i.p.) was given to rat 16-18 h before the experiment; cocaine (30 μM) and hydrocortisone (30 μM) were continuously present in the bath. The positive inotropic effect of phenylephrine was competitively antagonized by prazosin with a pA2 value of 9.29. The excitability of rat left atria was not affected by phenylephrine, whereas the automaticity of left atria induced by adrenaline was enhanced and the functional refractory period of left atria was prolonged by phenylephrine. The prolongation of functional refractory period caused by phenylephrine was competitively inhibited by prazosin with a pA2 value of 8.15. B-HT933 was not able to induce any change in the contractility, excitability, automaticity, and functional refractory period of rat left atria under the same conditions. The results indicated that the cardiophysiological effects on rat left atria caused by stimulation of postsynaptic α-adrenoceptor was mediated by α1-type receptors while postsynaptic α2-type receptors are not of functional importance on rat left atria.

Pharmacological and Electrophysiological Discrimination of Contractile Responses to Selective α1- and α1-Adrenoceptor Agonists in Rat Tail Artery

Pharmacological and electrophysiological properties of postsynaptic α-adrenoceptor subtypes in rat tail artery were compared using selective α1- and adrenoceptor agonists. Five α-adrenoceptor agonists contracted the tail artery with the following order of maximal effects: norepinephrine (α1 and α1)>methoxamine (α1)=phenylephrine (α1)≫clonidine (α2)>UK-14,304 (α2). Phenoxyben-zamine greatly diminished contractions induced by methoxamine and phenylephrine, but had little effect on responses to UK-14,304. Idazoxan antagonized more potently against UK-14,304 than against methoxamine. These results suggest the heterogeneity of postsynaptic α-adrenoceptors in the rat tail artery. Furthermore, responses to methoxamine and phenylephrine 1) had faster onsets and 2) were more resistant to Ca2+ entry blockers, nicardipine and diltiazem, and a promotor, Bay K 8644, or decreasing of extracellular Ca2+ and 3) were more sensitive to a calmodulin antagonist, W-7, than the responses to UK-14,304 and clonidine. Both methoxamine and UK-14,304 depolarized the membrane but methoxamine produced stronger depolarization than UK-14,304. Therefore, the high sensitivity of α2-adrenoceptor agonists-induced responses to Ca2+ entry blockers and promotors cannot be accounted for solely by membrane depolarization. These results may indicate the differences in the Ca2+ movement for the contractions produced by α1 -and α2-adrenoceptor agonists.

Distribution and function of peripheral α-adrenoceptors in the cardiovascular system

α-Adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic α-adrenoceptors are generally of the α 2-subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic α-adrenoceptors are usually of the α 1-subtype and mediate the response of the effector organ. Although this “anatomical” subclassification is generally applicable, many exceptions exist. A more useful classification of α-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Peripheral α-adrenoceptors are critical in the regulation of the cardiovascular system. Postsynaptic α-adrenoceptors in arteries and veins represent a mixed population of α 1/ α 2-adrenoceptors, with both subtypes mediating vasoconstriction. In the peripheral arterial circulation, postsynaptic vascular α 1-adrenoceptors are found in the adrenergic neuroeffector junction, whereas postsynaptic vascular α 2-adrenoceptors are located extrajunctionally. In the venous circulation, it appears that α 2-adrenoceptors may be predominantly junctional, whereas α 1-adrenoceptors may be predominantly extrajunctional. It has been proposed that junctional α-adrenoceptors will respond predominantly to norepinephrine liberated from sympathetic neurons, whereas extrajunctional α-adrenoceptors likely respond to circulating catecholamines. The functional role of extrajunctional α-adrenoceptors may be more important in disease states such as hypertension and congestive heart failure where circulating levels of catecholamines may be high and contribute to the maintenance of elevated vascular resistance. α 2-Adrenoceptors are also associated with the intima and may play a role in the release of an endogenous relaxing factor from the endothelium. In the heart, postsynaptic α 1-adrenoceptors mediate an increase in the contractile state of the myocardium with little or no change in heart rate. It appears that the inotropic effects of dobutamine may be mediated, at least in part, through stimulation of postsynaptic myocardial α 1-adrenoceptors. Both α 2-adrenoceptors have been identified in the kidney, and their functions are just beginning to be understood. Renal α 1-adrenoceptors may regulate renal blood flow and gluconeogenesis. Renal α 2-adrenoceptors may also regulate renal blood flow as well as inhibit renin secretion.

Pharmacologic and Therapeutic Significance of ??-Adrenoceptor Subtypes

The concept that neurotransmitters can modulate their own release through presynaptic inhibitory autoreceptors is well established. The presynaptic inhibitory autoreceptors involved in a negative feedback mechanism that modulates the release of norepinephrine are of the alpha 2-subtype. Stimulation of central alpha 2-adrenoceptors by drugs like clonidine, guanfacine, and guanabenz produces an antihypertensive and bradycardiac effect through a decrease in sympathetic tone. In vascular smooth muscle, the alpha 1-adrenoceptor subtype predominates and mediates vasoconstriction although alpha 2-adrenoceptors mediating vasoconstriction are also present in some vascular beds. Phenylephrine preferentially stimulates alpha 1-adrenoceptors and guanabenz preferentially stimulates alpha 2-adrenoceptors in vascular smooth muscle, whereas norepinephrine is an agonist at both alpha 1- and alpha 2-subtypes. The pressor response to phenylephrine was markedly reduced by prazosin. In contrast, the response to norepinephrine was relatively resistant to blockade, and that to guanabenz, totally resistant to blockade by prazosin. Inhibition of neuronal uptake by cocaine or desipramine and pretreatment of cats with 6-hydroxydopamine increased the effectiveness of prazosin in blocking the pressor responses to norepinephrine, but not to guanabenz or phenylephrine. These results support the proposal that postsynaptic alpha 1-adrenoceptors are preferentially innervated (i.e., within the neuroeffector junction), while the postsynaptic alpha 2-adrenoceptors are in extrasynaptic locations. The subclassification of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes opens the possibility of designing selective drugs to act as agonists or antagonists on these receptor subtypes. These compounds have useful therapeutic applications, and in the case of selective alpha 2-adrenoceptor antagonists, novel potential uses may exist, both at the level of the central nervous system and in the periphery.

(Imidazolinyl-2)-2-Benzodioxane 1–4 (Idazoxan) and Its Stereoisomers, New α2-Antagonists

Since (+/-) idazoxan is well known as alpha 2-antagonist, the present report described some results on the alpha-adrenoceptor blocking properties of the stereoisomers of idazoxan. At peripheral sites, (+) idazoxan revealed to be equipotent for blocking postsynaptic alpha 1- and alpha 2-adrenoceptors of the rat. On the other hand, it revealed to be a full antagonist of the inhibitory effects of clonidine on presynaptic alpha 2-adrenoceptors of rats. However, in vitro investigations have shown (+) idazoxan to be less selective than (-) idazoxan for alpha 2-adrenoceptors. (-) Idazoxan was selective for postsynaptic alpha 2-adrenoceptors and antagonized presynaptic alpha 2-adrenoceptors of the rat. Results obtained in central investigations revealed species differences between chickens and mice. The present results led to the conclusion that (+) idazoxan was equipotent on alpha 1- and alpha 2-adrenoceptors whereas (-) idazoxan was selective for alpha 2-adrenoceptors. On the other hand, they suggested a stereoselectivity of peripheral and central alpha 2-adrenoceptors for alpha-antagonists.

Beta-adrenergic activation of the renin-angiotensin system following alpha 2-, alpha 1-, or nonselective alpha-blockade in conscious dogs: no relation to the changes in blood pressure.

We analyzed the role of the renin-angiotensin system following alpha 2-, alpha 1-, or nonselective alpha-blockade in an intact organism in which both postsynaptic alpha-adrenoceptor types contribute to adrenergic vasoconstriction. In conscious dogs, alpha 2-blockade (0.3 mg/kg rauwolscine, n = 10) increased mean arterial pressure by 40 mm Hg, while hypotension by 8 mm Hg occurred following nonselective alpha-blockade (1.5 mg/kg phentolamine, n = 9) and by 20 mm Hg following alpha 1-blockade (1.2 mg/kg prazosin, n = 10). Plasma angiotensin II (pg/ml) rose by 103 +/- 28 (SEM), 143 +/- 48, and 58 +/- 15 following alpha 2-, nonselective alpha-, or alpha 1-blockade, respectively. While alpha 2- or nonselective alpha-blockade induced tachycardia and substantial elevations of plasma catecholamines, alpha 1-blockade did not. Beta-Blockade (2 mg/kg nadolol) attenuated the elevations of angiotensin following alpha 2- or nonselective alpha-blockade by 100 and 88%, respectively, without affecting the alpha 1-blockade-induced elevation, which is mainly mediated by the hypotension. Pretreatment with 3 mg/kg captopril reduced the pressure increase induced by alpha 2-blockade from 40 to 13 +/- 10 mm Hg and aggravated the decline in blood pressure induced by nonselective alpha-blockade from 8 to greater than 50 mm Hg. In anesthetized, spinalized dogs, both types of alpha-blockade competitively antagonized the pressor effect of the alpha 2-agonist azepexole by the same degree. It is concluded that, in the intact animal, the central and peripheral presynaptic augmentation of sympathoexcitation induced by alpha 2- or nonselective alpha-blockade leads to a strong beta-adrenergic activation of the renin-angiotensin system, independent of the concomitant changes in blood pressure. The constrictive action of the activation contributes substantially to the compensation of the vascular adrenoceptor blockade induced by nonselective or alpha 2-selective blockade in the intact organism.

Postjunctional alpha-adrenoceptors. Alpha 1 and alpha 2 subtypes in rat vasculature in vitro and in vivo.

The postsynaptic alpha-adrenoceptors in rat aorta and in pithed rat were investigated according to their sensitivity to nine alpha-adrenergic agonists and to the selective antagonists yohimbine (alpha 2) and prazosin (alpha 1) and the nonselective one, phentolamine. In addition, in radioligand binding studies, the affinity and selectivity of the drugs were determined on rat cerebral cortex using [3H] yohimbine and [3H] prazosin. On rat aorta, prazosin is 1,000 times more potent than yohimbine against each alpha-adrenoceptor agonist, whether alpha 1- or alpha 2-selective. Rat aorta probably contains only alpha 1-adrenoceptors. Pressor effects in pithed rats are mediated by post-junctional alpha 1- and alpha 2-adrenoceptors. The dose-response curve for alpha-methylnorepinephrine in the presence of prazosin, using Hofstee's plots, revealed alpha 1- and alpha 2-adrenoceptors, respective proportions being 80.5 and 19.5%.

Effects of chemical sympathectomy by 6-hydroxydopamine on alpha-adrenoceptor-mediated pressor responses in pithed rat.

The effects of 6-hydroxydopamine (6-OHDA) treatment of neonatal and adult rats on vasopressor responses to postsynaptic alpha-adrenoceptor activation were studied in adult pithed rats. The pressor response to electrical stimulation of the thoracosympathetic outflow (T7-T9) was markedly reduced after neonatal or adult 6-OHDA treatment, indicating a functional destruction of the sympathetic input to the vasculature. Pressor response curves to injected noradrenaline (a nonselective alpha-agonist) and phenylephrine (a selective alpha 1-agonist) were shifted to the left in all 6-OHDA-treated animals. However, the pressor response to the selective alpha 2-agonist M-7 (5,6-hydroxy-2-dimethylamino tetralin) was unaltered in all the 6-OHDA-treated animals. It is concluded that functional destruction of peripheral sympathetic nerve endings in vascular smooth muscle by treatment of neonatal or adult rats with 6-OHDA produces an increased pressor response to alpha 1-adrenoceptor agonists, but not to alpha 2-adrenoceptor agonists in the pithed rat.

α-Adrenoceptors: Recent development and some comparative aspects

1. On anatomical and functional bases, α-adrenoceptors have been divided into pre- and postsynaptic α-adrenoceptors. 2. Recently, α-adrenoceptors have been classified as α 1 and α 2 according to their pharmacological responses, irrespective of their anatomical location. 3. The presynaptic α-adrenoceptors, which have been recognized as α 2, determine the frequency of the nerve impulses travelling along the axon and also the amount of transmitter released per nerve impulse from the varicose terminal. 4. Postsynaptic α-adrenoceptors have been recognized in various tissues including smooth muscle, pancreatic islets, fat cells, platelets and other tissues. Both α 1- and α 2-adrenoceptors have been located postsynaptically. 5. α-Adrenoceptors have been found also in the central nervous system. Generally, they fall into the same categories ( α 1 and α 2) as the peripheral α-adrenoceptors. 6. A new class of drugs, the so called calcium blockers, inhibit the postsynaptic response to α 2 stimulation but not the α 1-mediated response, indicating that the α 2-adrenoceptors are dependent on Ca 2+ ions for their function. 7. In the most primitive group of vertebrates, the fishes, α-adrenoceptors seem to be different in as much as they do not respond to many of the classical drugs employed to distinguish between α-adrenoceptors in mammals. 8. In reptiles and amphibians α 2-adrenoceptors have been shown to exist. These receptors are involved in the regulation of melanocytes. In the most advanced non-mammalian vertebrates (birds) both peripheral and central α-adrenoceptors seem to be qualitatively similar to the mammalian types.

Effects of 2-[(5-chloro-2-methoxyphenyl)azo]-1H-imidazole (M6434), a new alpha-adrenoceptor agonist, on pre- and postsynaptic alpha-adrenoceptors in canine mesenteric artery.

Post- and presynaptic alpha-adrenoceptors in the canine mesenteric artery show distinct features of alpha 1 and alpha 2 types, respectively. The effects of a newly synthesized pressor agent, 2-[(5-chloro-2-methoxyphenyl)azo]-1H-imidazole (M6434), on the pre- and postsynaptic alpha-adrenoceptors of the canine mesenteric artery were examined pharmacologically. M6434 produced a contractile response in the mesenteric artery. The EC50 value of M6434 was 1.1 X 10(-7) M, that was almost the same as that of norepinephrine but significantly lower than the value seen with methoxamine. The maximum amplitude of contraction developed by M6434 was approximately 81% of that induced by norepinephrine. The contractile response to M6434 was competitively inhibited by prazosin (pA2 = 9.23 +/- 0.08) and yohimbine (pA2 = 7.85 +/- 0.09). M6434 also reduced the 3H-efflux evoked by electrical transmural stimulation in the arterial tissues preincubated with 3H-norepinephrine, and the maximum inhibition corresponded to about 60% of the case of norepinephrine. This presynaptic effect was inhibited by yohimbine but not by prazosin. The results show that M6434 is almost a full agonist for alpha 1-adrenoceptor with partial alpha 2-effect.

P-194) - Characterization of postsynaptic α-adrenoceptor population in the vascular system of autoperfused rat mesentery

P-194) - Characterization of postsynaptic α-adrenoceptor population in the vascular system of autoperfused rat mesentery

An examination of age-related changes in pre- and postsynaptic α-adrenoceptors in the rat isolated vas deferens

Age-related changes in pre- and postsynaptic α-adrenoceptors were investigated in prostatic and epididymal portions of vasa deferentia from young adult (2–3 month) and 24 month old Sprague-Dawley rats, using the selective α 1-agonist amidephrine and the selective α 2-agonist xylazine. Effects of agonists were assessed against the isometric contraction to single pulse field stimulation. There was no change in the pre- or postsynaptic potency of amidephrine, but the presynaptic inhibitory potency of xylazine was significantly reduced in old rats. Therefore, in old rats there is a reduced sensitivity of presynaptic α 2- but no change in pre- or postsynaptic α 1-adrenoceptors and this may result in increased peripheral sympathetic neurotransmission.

Adrenoceptor-mediated effects of optically active catecholimidazolines in pithed rat.

Adrenoceptor-mediated effects of the enantiomers of the optically active imidazoline, 2-(3,4,α-trihydroxybenzyl)imidazoline, and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, have been investigated in the pithed rat. The enantiomers and desoxy derivative were potent pressor agents with a direct action mediated predominantly via postsynaptic vascular α2-adrenoceptor. These compounds were significantly less potent at presynaptic α2-adrenoceptor in rat heart. The rank order of potency for the two enantiomers and desoxy derivative at postsynaptic vascular α1- and presynaptic cardiac α2-adrenoceptor in pithed rat were: desoxy≥R(−) >(+), consistent with our previous findings in vitro. This order of potency is not in agreement with the rank order of R(−)>S(+)=desoxy which is predicted by the Easson-Stedman Hypothesis. The β-adrenoceptor-mediated chronotropic and β-adrenoceptor-mediated vasodepressor effects of these imidazolines were also investigated in pithed rat and found to be weaker than either the α1- or α2-adrenoceptor-mediated effects. However, the rank order of potency of the enantiomers and corresponding desoxy derivative for β1- and β2-adrenoceptor-mediated effects was found to be similar to that order predicted by the Easson-Stedman Hypothesis. Studies with these optically active imidazoline enantiomers and corresponding desoxy derivativative indicate that quantitative as well as qualitative differences exist in the stereochemical requirements of α- and β-adrenoceptor. The results also support our previous observations which suggest that phenethylamines and imidazolines may interact differently with α-adrenoceptor since the former adhere strictly to the Easson-Stedman Hypothesis whereas the latter do not.

Differential interactions of clonidine and methoxamine with the postsynaptic alpha-adrenoceptor of rabbit main pulmonary artery.

We investigated the dependence upon extracellular Ca2+ of contractile responses of the isolated rabbit main pulmonary artery to the alpha-adrenoceptor subtype-selective agonists clonidine (alpha 2) and methoxamine (alpha 1). The calcium-entry blocker verapamil caused a weak, surmountable antagonism of contractile responses to methoxamine, whereas the concentration-response curve of clonidine was antagonized in a noncompetitive manner with a marked depression of maximal responses. Withdrawal of Ca2+ from the physiological saline solution virtually abolished contractile responses to clonidine, without significantly affecting methoxamine-induced responses. We, therefore, determined if clonidine and methoxamine were interacting with the same population of vascular postsynaptic alpha-adrenoceptors. We found that the alpha 1-antagonist prazosin and the alpha 2-antagonist yohimbine caused competitive blockade of contractile responses to both agonists. However, the potency of both antagonists was significantly greater against clonidine than methoxamine. This may reflect a heterogeneity in the population of postsynaptic alpha-adrenoceptors of the rabbit main pulmonary artery. On the other hand, the difference in extracellular Ca2+ sensitivity of clonidine- and methoxamine-induced contractions may be explained as a differential mode of stimulation of the postsynaptic alpha 1-adrenoceptor, possibly through separate, interacting recognition sites for both agonists.

α1-Adrenoceptor subtype mediating contraction in the urinary bladder of rabbits

Postsynaptic α-adrenoceptor subtypes were investigated using rabbit urinary bladder base and body in vitro. The drugs used in this investigation were phenylephrine and methoxamine (α1-selective), norepinephrine (nonselective) and Clonidine (α2-selective) as agonists and prazosin and YM-12617, 5-[2-[ [2-(o-ethoxyphenoxy)ethyl]amino]-2-methylethyl]-2-methoxybenzenesulfonamide HCl.(α2-selective) and yohimbine (α1-selective) as antagonists. All of the agonists caused concentration-dependent contraction in the base and body. The EDcq values for phenylephrine, methoxamine and Clonidine were significantly greater than that for norepinephrine. Norepinephrine, phenylephrine and methoxamine were full agonists,but only Clonidine was a partial agonist of low potency. In the base, YM-12617, prazosin and yohimbine competitively antagonized the contraction induced by either norepinephrine, phenylephrine, methoxamine or Clonidine. The mean pA2 values of YM-12617 (pA2= 9.81), prazosin (pA2= 8.28) and yohimbine (pA2= 6.36) were independent of the α-adrenoceptor agonists. YM-12617 (pA2= 9.75), prazosin (pA2= 8.13) and yohimbine (pA2= 6.44) against methoxamine in the body were almost the same as those obtained in the base. The pA2values of three antagonists in the rabbit urinary bladder base and body were clearly coincident with those appearing in the literature for these compounds in the tissues containing a]-adrenoceptors. Thus, the results suggest that α-adrenoceptor subtype mediating the contraction is α1 but not α2 in the rabbit urinary bladder base and body.

Postsynaptic αAl-Adrenoceptors in the Hypertensive Rat: Studies on Vascular ReactivityIn Vivoand Receptor BindingIn Vitro

An increase in vascular responsiveness (increase in diastolic blood pressure) to phenylephrine (PE), noradrenaline (NA) or angiotensin (AII) was seen in pithed SHR when compared with normotensive controls (WKY). This increase in vasoconstrictor effect was not seen with the postsynaptic α2-adrenoceptor agonists BHT 933 or TL 99. In SHR and DOCA-salt hypertensive rats prazosin was significantly more potent as an antagonist of α1-receptor mediated vasoconstriction (PE, or the endogenous release of NA by electrical stimulation of the spinal cord), and was also more potent against NA administered by i.v. injection, compared with normotensive controls. The potency of yohimbine against the postsynaptic α2-receptor mediated pressor responses to TL 99 was not significantly different in SHR or normotensive rats. Although these results indicate an apparent shift in the ratio of postsynaptic α1/α2-receptor mediated effects in hypertension in vivo, these effects were not correlated with any changes in α-receptor densi...

Effect of converting enzyme inhibition and angiotensin receptor blockade on the vasoconstriction mediated by alpha 1-and alpha 2-adrenoceptor stimulation in pithed normotensive rats.

The effect of functional impairment of the renin-angiotensin system on the vasoconstriction mediated by postsynaptic α1 and α2-adrenoceptors in pithed normotensive rats was studied. Selective α1-adrenoceptor stimulation was induced by intravenously administered cirazoline, whereas B-HT 920 was used as a selective agonists at α2-adrenoceptors. The angiotensin converting enzyme was inhibited by intravenous treatment of the pithed rats with captopril, teprotide or enalapril. Blockade of angiotensin receptors was produced by intravenously applied [Sar1 Ala8]angiotensin II (saralasin). Pretreatment with angiotensin converting enzyme inhibitors or with saralasin in doses which produced a maximal reduction in basal diastolic blood pressure, only slightly attenuated the hypertensive response to cirazoline. In contrast, these drugs provoked a most significant reduction of the α2-adrenoceptor mediated vasoconstriction. Restoration of the basal diastolic blood pressure by intravenous infusion with angiotensin II or with vasopressin completely reversed the inhibitory effect of captopril on the vasopressor response to B-HT 920. One hour after bilateral nephrectomy, captopril still reduced the α2-adrenoceptor mediated vasoconstriction. However, 18–24 h after bilateral nephrectomy, captopril had no additional inhibitory effect on the vasopressor response to selective α2-adrenoceptor stimulation. It is concluded that in pithed normotensive rats the pressor response to α2-adrenoceptor stimulation is significantly potentiated by endogenous angiotensin II, even at low circulating levels of the octapeptide. The modulatory action of angiotensin II on the α-adrenoceptor mediated vasoconstriction probably represents an effect on the basal arteriolar muscular tone rather than a specific interaction.