Neurogenic dilatation and constriction of rat superior mesenteric artery in vitro: mechanisms and mediators

In the rat superior mesenteric arteries, the mechanical responses to perivascular nerve stimulation were characterized. The predominant response was contraction mediated by the release of norepinephrine, acting postjunctionally on alpha 1-adrenoceptors. These frequency-dependent contractions were unaffected by the alpha 2-selective adrenoceptor antagonist yohimbine, but were markedly attenuated by clonidine, the alpha 2-selective adrenoceptor agonist. In the presence of prazosin, the alpha 1-selective antagonist, a significant component of the nerve-mediated contraction was still present. At the concentrations used, prazosin, yohimbine, as well as clonidine acted as competitive antagonists of response to exogenous norepinephrine. This differential inhibition of norepinephrine- and nerve-mediated responses suggested the presence of distinct postjunctional adrenoceptors. The effects of clonidine and yohimbine are interpreted to arise from prejunctional modulation of norepinephrine release. In 30 of the 100 vessels studied, there was spontaneous myogenic tone. In these arteries, field stimulation caused frequency- and voltage-dependent relaxations. These responses were neural in origin, dependent on sympathetic nerve activity, but were nonadrenergic and noncholinergic in nature. Naloxone, indomethacin, and substance P inhibited these relaxations with no significant effect on the tone. The opioid agonist, 1-13 dynorphin relaxed these vessels and only naloxone inhibited this response. The effects of these agents were selective against field-stimulated responses since they did not alter the relaxation to the nonspecific agent sodium nitroprusside. These results provide circumstantial evidence for opioid-mediated vascular relaxation that is presynaptically modulated by prostanoids and substance P.     

Presynaptic beta(2)-adrenoceptors mediate nicotine-induced NOergic neurogenic dilation in porcine basilar arteries

We previously reported that nicotine-induced nitric oxide (NO)-mediated cerebral neurogenic vasodilation was dependent on intact sympathetic innervation. We hypothesized that nicotine acted on sympathetic nerve terminals to release norepinephrine (NE), which then acted on adrenoceptors located on the neighboring nitric oxidergic (NOergic) nerve terminals to release NO, resulting in vasodilation. The adrenoceptor subtype in mediating nicotine-induced vasodilation in isolated porcine basilar arterial rings denuded of endothelium was therefore examined pharmacologically and immunohistochemically. Results from using an in vitro tissue bath technique indicated that propranolol and preferential beta(2)-adrenoceptor antagonists (ICI-118,551 and butoxamine), in a concentration-dependent manner, blocked the relaxation induced by nicotine (100 microM) without affecting the relaxation elicited by transmural nerve stimulation (TNS, 8 Hz). In contrast, preferential beta(1)-adrenoceptor antagonists (atenolol and CGP-20712A) did not affect either nicotine- or TNS-induced relaxation. Results of double-labeling studies indicated that beta(2)-adrenoceptor immunoreactivities and NADPH diaphorase reactivities were colocalized in the same nerve fibers in basilar and middle cerebral arteries. These findings suggest that NE, which is released from sympathetic nerves upon application of nicotine, acts on presynaptic beta(2)-adrenoceptors located on the NOergic nerve terminals to release NO, resulting in vasodilation. In addition, nicotine-induced relaxation was enhanced by yohimbine, an alpha(2)-adrenoceptor antagonist, which, however, did not affect the relaxation elicited by TNS. Prazosin, an alpha(1)-adrenoceptor antagonist, on the other hand, did not have any effect on relaxation induced by either nicotine or TNS. The predominant facilitatory effect of beta(2)-adrenoceptors in releasing NO may be compromised by presynaptic alpha(2)-adrenoceptors.     

Nature of alpha 1 and postjunctional alpha 2 adrenoceptors in the pulmonary vascular bed

The subtypes of postjunctional alpha adrenoceptors in the feline pulmonary vascular bed were studied by using selective alpha-adrenoceptor agonists and antagonists. Under conditions of controlled pulmonary blood flow and constant left atrial pressure, intralobar injections of the alpha 1 agonists phenylephrine and methoxamine, and the alpha 2 agonists UK 14,304 and B-HT 933, increased lobar arterial pressure in a dose-related manner. Prazosin, an alpha 1-adrenoceptor antagonist, reduced responses to phenylephrine and methoxamine to a greater extent than responses to UK 14,304 and B-HT 933. Yohimbine, an alpha 2 blocker, decreased responses to UK 14,304 and B-HT 933 without altering responses to phenylephrine or methoxamine. The same pattern of blockade was observed in animals pretreated with 6-hydroxydopamine, an adrenergic neuronal blocking agent. However, in propranolol-treated animals, prazosin antagonized responses to phenylephrine and methoxamine without altering responses to UK 14,304 or B-HT 933, and the selectivity of the blocking effects of yohimbine were preserved. Responses to intralobar injections of norepinephrine (NE) were markedly decreased by prazosin, whereas yohimbine had only a small effect. These data suggest the presence of both postjunctional alpha 1 and alpha 2 adrenoceptors mediating vasoconstriction in the pulmonary vascular bed. These results also indicate that the vasoconstrictor responses to injected NE in the cat pulmonary vascular bed result mainly from activation of alpha 1 adrenoceptors.     

Norepinephrine induces apoptosis in skin melanophores by attenuating cAMP-PKA signals via alpha2-adrenoceptors in the medaka, Oryzias latipes

The density of skin melanophores in many teleost fish decreases during long-term adaptation to a white background. Using the medaka, Oryzias latipes, we previously reported that apoptosis is responsible for the decrease in melanophores, and that a sympathetic neurotransmitter, norepinephrine (NE), induces their apoptosis in skin tissue cultures. In this study, we show that NE-induced apoptosis of melanophores is mediated by the activation of alpha2-adrenoceptors. Clonidine, an alpha2-adrenoceptor agonist, induced apoptotic melanophore death in skin organ culture, while phenylephrine, an alpha1-adrenoceptor agonist, had no effect. NE-induced apoptosis was diminished by an alpha2-adrenoceptor antagonist, yohimbine, but an alpha1-adrenoceptor antagonist, prazosin, did not abrogate the effect of NE. Furthermore, forskolin inhibited NE-induced apoptosis, while an inhibitor of PKA, H-89, mimicked the effect of NE. These results suggest that NE induces apoptosis in melanophores by attenuating cAMP-PKA signaling via alpha2-adrenoceptors.     

Pharmacologic characterization of cirazoline-activated inositol phospholipid hydrolysis in rat brain cortical slices

Interaction of cirazoline, an imidazoline derivative, with alpha 1-adrenoceptor coupled inositol phospholipid hydrolysis was characterized in rat brain cortical slices. Norepinephrine, a full alpha 1-agonist, and phenylephrine, a partial alpha 1-agonist, on inositol phospholipid hydrolysis were included for comparison. Norepinephrine produced a fourfold stimulation of inositol phospholipid hydrolysis, whereas cirazoline and phenylephrine caused only submaximal responses (40-60%) when compared with norepinephrine. The stimulation of inositol phospholipid hydrolysis by cirazoline was completely blocked by the alpha 1-adrenoceptor antagonist prazosin, but not by selective alpha 2- or beta-adrenoceptor antagonists. Furthermore, the norepinephrine dose-response curve was shifted to the right in the presence of cirazoline, without affecting the maximal response. These results suggest that cirazoline behaves as a partial agonist at brain alpha 1-adrenoceptors linked to inositol phospholipid hydrolysis.     

Clonidine-induced coronary vasodilatation in isolated guinea pig heart is not mediated by endothelial alpha2 adrenoceptors.

Functional role of endothelial alpha(2)-adrenoceptor in coronary circulation remains unclear. Clonidine, an agonist of alpha(2)-adrenoceptors, was reported to induce coronary vasodilatation via stimulation of endothelial alpha(2)-adrenoceptors or coronary vasoconstriction involving vascular smooth muscle alpha(2)-adrenoceptors. Moreover, H(2) receptor-dependent responses to clonidine were described. Here, we reassess the contribution of endothelial alpha(2)-adrenoceptor and H(2) receptors to coronary flow and contractility responses induced by clonidine in the isolated guinea pig heart. We found that clonidine (10(-9) - 10(-6) M) produced concentration-dependent coronary vasoconstriction without a significant change in contractility. This response was inhibited by the alpha(1)/alpha(2)-adrenoceptor antagonist - phentolamine (10(-5) M) and the selective alpha(2)-adrenoceptor antagonist yohimbine (10(-6) M), but it was not changed by the selective alpha(1)-adrenoceptor antagonist prazosin (10(-6) M). In the presence of nitric oxide synthase inhibitor, L-NAME (10(-4) M) the clonidine-induced vasoconstriction was potentiated. Clonidine at high concentrations of 10(-5) - 3 x 10(-5) M produced coronary vasodilatation, and an increase in myocardial contractility. These responses were abolished by a selective H(2)-receptor antagonist, ranitidine (10(-5) M), but not by phentolamine (10(-5) M). We conclude that in the isolated guinea pig heart, clonidine-induced vasoconstriction is mediated by activation of smooth muscle alpha(2)-adrenoceptors whereas clonidine-induced coronary vasodilatation is mediated by activation of vascular H(2) histaminergic receptors. Accordingly, endothelial alpha(2)-adrenoceptors does not seem to play a major role in coronary flow response induced by clonidine.     

Contractile responses to adrenergic nerve stimulation are enhanced with removal of endothelium in rat caudal artery

Removal of the endothelium from isolated perfused rat caudal arteries produced a two fold increase in the contractile response to transmural nerve stimulation. Pretreatment with 6-hydroxydopamine eliminated the contractile response to adrenergic nerve stimulation but failed to uncover any vasodilatory effect of electrical stimulation, either directly on smooth muscle or via non-adrenergic nerves. Endothelial removal also produced two and four fold enhancement of the contractile responses to the selective alpha 1- and alpha 2-adrenoceptor agonists methoxamine and B-HT 920. However, pKB values for prazosin and yohimbine versus both agonists indicate that both methoxamine and B-HT 920 are acting primarily at alpha 1-adrenoceptors in this tissue. These results provide evidence that endothelial factors released either at basal levels or by the stimulation of agonists play a significant physiological role in modifying the contractile responses of blood vessels.     

Prejunctional beta 1-adrenoceptors inhibit cholinergic transmission in canine bronchi

The aim of the present study was to determine in canine bronchi the effects produced by norepinephrine (released from adrenergic nerve terminals) on cholinergic neurotransmission. Electrical stimulation of canine bronchi activates cholinergic and adrenergic nerve fibers. The adrenergic neuronal blocker, bretylium tosylate, inhibited the increase in [3H]norepinephrine overflow evoked by electrical stimulation but did not prevent that caused by the indirect sympathomimetic tyramine. During blockade of the exocytotic release of norepinephrine with bretylium, the pharmacological displacement of the sympathetic neurotransmitter by tyramine significantly decreased the contractions evoked by electrical stimulation but did not affect contractions caused by exogenous acetylcholine. Metoprolol, a beta 1-adrenergic antagonist, abolished and propranolol significantly reduced the effect of tyramine during electrical stimulation. alpha 2-Adrenergic blockade, beta 2-adrenergic blockade, or removal of the epithelium did not significantly affect the response to tyramine. These results suggest that norepinephrine when released from sympathetic nerve endings can activate prejunctional inhibitory beta 1-adrenoceptors to depress cholinergic neurotransmission in the bronchial wall.     

Postsynaptic alpha-adrenoceptor characterization and Ca2+ channel antagonist and activator actions in rat tail arteries from normotensive and hypertensive animals

Postsynaptic alpha-adrenoceptors in the rat tail artery have been examined by determining the pA2 values for antagonists against several alpha-adrenoceptor agonists. In this tissue the alpha-adrenoceptor agonists all produce concentration-dependent mechanical responses with the following rank order of potency: clonidine greater than norepinephrine greater than phenylephrine greater than UK 14304 greater than B-HT 920. Antagonism by prazosin and yohimbine of phenylephrine, norepinephrine, and clonidine responses does not reveal the anticipated discrimination between alpha 1- and alpha 2-adrenoceptors. Thus, pA2 values for prazosin (9.1-9.5), yohimbine (7.2-7.4), and corynanthine (7.0-7.1) and idazoxan (7.6) do not show large differences between these receptor agonists and suggests the predominance of alpha 1-adrenoceptor mediated contractile responses in this preparation. Significant differences between antagonist activities (pA2 values) in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) artery preparations have not been observed. The sensitivity sequence of alpha-adrenoceptor agonist-induced responses to nifedipine and D 600 is B-HT 920 greater than clonidine greater than phenylephrine greater than norepinephrine. Dependence of agonist response upon extracellular Ca2+ parallels the sensitivity to Ca2+ channel antagonists. Sensitivity to D 600 of phenylephrine responses increased with decreasing concentration of phenylephrine or with receptor blockade by phenoxybenzamine: sensitivity of responses to B-HT 920 was not affected by these procedures. Tail artery strips from WKY and SHR do not exhibit major differences in sensitivity to D 600 or to Ca2+ depletion. Bay k 8644, a Ca2+ channel activator, produces concentration-dependent mechanical responses in the tail artery in the presence of modestly elevated K+ concentrations (10-15 mM): these actions of elevated K+ can be mimicked by both alpha 1- and alpha 2-adrenoceptor agonists including methoxamine, St 587, UK 14304, and clonidine. These studies do not provide clear evidence for the existence of discrete postsynaptic alpha 1- and alpha 2-adrenoceptor populations in rat tail artery as indicated by pA2 values or Ca2+ dependence of response.     

Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of alpha1- and alpha2-adrenoceptors on renal sensory nerve fibers

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating alpha-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49 degrees C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 +/- 900 and 4,870 +/- 670%.s (area under the curve ARNA vs. time). Renal pelvic perfusion with norepinephrine increased ARNA 1,870 +/- 210%.s. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8 +/- 1 to 16 +/- 1 pg/min, and PGE(2) release, from 77 +/- 11 to 161 +/- 23 pg/min, suggesting a role for PGE(2) in the norepinephrine-induced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE(2). PGE(2) enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Interaction between ERSNA and ARNA is modulated by norepinephrine, which increases and decreases the activation of the renal sensory nerves by stimulating alpha(1)- and alpha(2)-adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE(2).     

Modulation of neurotransmitter release by NO is altered in mesenteric arterial bed of spontaneously hypertensive rats

Nitric oxide (NO) reacts with catecholamines resulting in their deactivation. In the present study with the use of the perfused mesenteric arterial bed as a model of the sympathetic neuroeffector junction, the NO synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) resulted in the enhancement of the periarterial nerve stimulation-induced increase in perfusion pressure and norepinephrine overflow while decreasing neuropeptide Y (NPY) overflow. These changes were prevented by l-arginine, demonstrating that the effects of l-NAME were specific to the inhibition of NOS. From the fact that norepinephrine acts on prejunctional alpha(2)-adrenoceptors to inhibit the evoked release of sympathetic cotransmitters, we carried out experiments in the presence of the alpha(2)-adrenergic receptor antagonist yohimbine to investigate the possibility that the decrease in NPY observed in the presence of l-NAME was due to the increase in bioactive norepinephrine acting on its autoreceptor. Periarterial nerve stimulation in the presence of both l-NAME and yohimbine prevented the previously observed decrease in NPY, indicating that the cause of this decrease was, as predicted, due to alpha(2)-adrenoceptor activation. The periarterial nerve stimulation-induced increase of norepinephrine overflow was greater in the spontaneously hypertensive rat compared with normotensive rats. In contrast to what was observed in the isolated perfused mesenteric arterial bed obtained from normotensive animals, inhibition of NOS did not result in a further increase in the overflow of norepinephrine or in a subsequent decrease in NPY. These results demonstrate that, in addition to being a direct vasodilator, NO, by deactivating norepinephrine, can modulate sympathetic neurotransmission and that this modulation is altered in the spontaneously hypertensive rat.     

Studies on the functional role of alpha-adrenoceptors in the cardiac sympathetic ganglia of the dog.

Inhibitory alpha-adrenoceptors were studied in cardiac ganglia of pentobarbital-anesthetized dogs. Blockade of alpha 1- or alpha 2-adrenoceptors augmented preganglionic nerve stimulation induced tachycardia without altering the response to postganglionic nerve stimulation. The effect produced by blockade of ganglionic alpha 1-adrenoceptors with terazosin had different frequency-response characteristics from, was of smaller magnitude than, and was additive with the effect produced by blockade of ganglionic alpha 2-adrenoceptors with rauwolscine. The response to activation of ganglionic nicotinic cholinergic receptors in the absence of electrical stimulation of the preganglionic nerve was not affected by blockade of either alpha 1- or alpha 2-adrenoceptors. The response to nicotinic cholinergic receptor activation during periods of continuous preganglionic nerve stimulation was augmented following blockade of alpha 2-adrenoceptors but unaffected by alpha 1-adrenoceptor blockade. These results suggest that there are two different inhibitory pathways involving alpha-adrenoceptors in mammalian sympathetic ganglia and provide evidence that these inhibitory pathways are operative under the experimental conditions of ganglionic transmission.     

Presynaptic alpha-adrenoceptors in median preoptic nucleus modulate inhibitory neurotransmission from subfornical organ and organum vasculosum lamina terminalis

The median preoptic nucleus (MnPO) in the lamina terminalis receives a prominent catecholaminergic innervation from the dorsomedial and ventrolateral medulla. The present investigation used whole cell patch-clamp recordings in rat brain slice preparations to evaluate the hypothesis that presynaptic adrenoceptors could modulate GABAergic inputs to MnPO neurons. Bath applications of norepinephrine (NE; 20-50 microM) induced a prolonged and reversible suppression of inhibitory postsynaptic currents (IPSCs) and reduced paired-pulse depression evoked by stimulation in the subfornical organ and organum vasculosum lamina terminalis. These events were not correlated with any observed changes in membrane conductance arising from NE activity at postsynaptic alpha(1)- or alpha(2)-adrenoceptors. Consistent with a role for presynaptic alpha(2)-adrenoceptors, responses were selectively mimicked by an alpha(2)-adrenoceptor agonist (UK-14304) and blockable with an alpha(2)-adrenoceptor antagonist (idazoxan). Although the alpha(1)-adrenoceptor agonist cirazoline and the alpha(1)-adrenoceptor antagonist prazosin were without effect on these evoked IPSCs, NE was noted to increase (via alpha(1)-adrenoceptors) or decrease (via alpha(2)-adrenoceptors) the frequency of spontaneous and tetrodotoxin-resistant miniature IPSCs. Collectively, these observations imply that both presynaptic and postsynaptic alpha(1)- and alpha(2)-adrenoceptors in MnPO are capable of selective modulation of rapid GABA(A) receptor-mediated inhibitory synaptic transmission along the lamina terminalis and therefore likely to exert a prominent influence in regulating cell excitability within the MnPO.     

Evaluation of isomers of octopamine for in vitro alpha-adrenergic stimulation of the aortic smooth muscle from spontaneously hypertensive rats

Isomers of octopamine were tested for in vitro alpha-adrenergic stimulation of aortic smooth muscle of spontaneously hypertensive rats (SHR). In order to test the response of alpha 1-adrenoceptors to meta-, para-, and ortho-octopamine, alpha 2-adrenoceptors were blocked with 10(-7) M yohimbine, and to measure the response of alpha 2-adrenoceptors the alpha 1-adrenoceptors were blocked with 10(-7) M prazosin. The contractile response of aortic smooth muscle of SHR to stimulation by phenylephrine, m-, p-, and o-isomers of octopamine in the presence of yohimbine was not appreciably altered. However, administration of prazosin severely attenuated the response of muscles of these compounds indicating that like phenylephrine, the isomers of octopamine stimulate mainly alpha 1-adrenoceptors. The attenuation of contractile response to isomers of octopamine in the presence of prazosin was not as pronounced as in the case of phenylephrine. The comparative potencies of phenylephrine, m-, p-, and o-octopamine in the presence of 10(-7) M prazosin were 1:1.2:2.5:0.75, respectively. Thus, it appears that the isomers of octopamine, especially para- and meta-octopamine, play a much more important role in the physiology of vascular smooth muscle than has been thus far perceived.     

Effects of chronic alpha 2-adrenoceptor blockade on platelet and lymphocyte adrenoceptor binding in normal volunteers.

Platelet and lymphocyte adrenoceptor binding was measured in 12 healthy male volunteers before and after 22 days treatment with the alpha 2-adrenoceptor antagonist idazoxan 40 mg tds. Platelet alpha 2-adrenoceptor number assessed by the agonist 3H-UK 14304 [correction of UK 14303] was significantly increased following idazoxan, with a smaller increase in antagonist binding (3H-rauwolscine). Lymphocyte beta-adrenoceptor number was unaltered by idazoxan, although the variance within the sample was significantly increased. Plasma MHPG levels were significantly reduced by chronic idazoxan. These data indicate upregulation of the platelet alpha 2-adrenoceptor in response to chronic blockade and suggest that this may reflect a similar change in presynaptic alpha 2-adrenoceptors which regulate norepinephrine release.     

Potential involvement of a propranolol-insensitive atypical beta-adrenoceptor the vasodilator effect of cyanopindolol in the human pulmonary artery.

The aim of our study was to examine whether non beta(1)-/beta(2)-adrenoceptors participate in the relaxation of the human pulmonary artery. For this purpose the vasodilatory effect of the non-conventional partial beta-adrenoceptor agonist cyanopindolol was examined. Cyanopindolol (1-300 microM), studied in the presence of the beta(1)-/beta(2)-adrenoceptor antagonist propranolol, relaxed the human pulmonary artery preconstricted with serotonin 1 microM in a concentration-dependent manner (maximally by about 80%). This effect was diminished by bupranolol 10 microM (an antagonist of beta(1)-beta(3)-adrenoceptors and the low affinity state of the beta(1)-adrenoceptor) and CGP 20712 10 microM (known to antagonize the low-affinity state of the beta(1)-adrenoceptor at high concentrations). In further experiments, the effect of beta-adrenoceptor ligands on the serotonin-induced vasoconstriction was examined. The concentration-response curve for serotonin was not affected by cyanopindolol 30 microM, bupranolol 10 microM and CGP 20712 10 microM but shifted to the right by cyanopindolol 100 and 300 microM; the serotonin 5-HT(2A) receptor antagonist ketanserin 0.3 microM abolished the maximum contraction elicited by serotonin. In conclusion, the present study reveals that the vasodilatory effect of cyanopindolol in the human pulmonary artery consists of two components, i.e. activation of a propranolol-insensitive atypical beta-adrenoceptor and antagonism against 5-HT(2A) receptors.     

The alpha adrenoceptors on endothelial cells

Endothelial cells release a powerful factor (endothelium-derived relaxing factor [EDRF]) that relaxes smooth muscle cells in response to some vasodilating agents such as acetylcholine. Contraction curves to norepinephrine (NE) in greyhound, mongrel dog, and pig coronary artery rings were studied in vitro in the presence of propranolol. Removal of endothelium increased the sensitivity and maximum contraction in response to NE. In other experiments pig coronary rings were precontracted with a thromboxane mimetic U 46619 in the presence of propranolol. NE relaxed these arteries only if endothelium was present. Methoxamine was without effect but the relaxation response to NE was antagonized by phentolamine, idazoxan, and yohimbine, which suggests that there are alpha 2 adrenoceptors on endothelial cells that mediate the release of EDRF. Greyhound and mongrel dog large coronary arteries relaxed to NE only if prazosin was present, which suggests that alpha 1-adrenoceptor stimulation on the vascular smooth muscle can override the relaxation response to EDRF. Comparison of NE responses in carotid, mesenteric, renal, and femoral large arteries of the pig, greyhound, and mongrel dog indicate the nonuniformity of distribution of alpha 2 adrenoceptors on endothelium and alpha 1 and alpha 2 adrenoceptors on vascular smooth muscle. The integrity of the endothelium must now be considered in interpreting the vascular responses to alpha-adrenoceptor agonists.     

Effects of temperature on alpha adrenoceptors in limb veins: role of receptor reserve

In cutaneous veins of the dog, cooling augments the response to sympathetic nerve stimulation and exogenous norepinephrine (NE). The postjunctional alpha adrenoceptors in this blood vessel belong to both the alpha 1 and alpha 2 subtypes. Cooling augments alpha 2-adrenergic responses (presumably because of an increased receptor affinity), but depresses alpha 1-adrenergic responses (presumably because of a direct inhibitory effect on the contractile process). When agonists of high efficacy such as NE or phenylephrine are used, an alpha 1-adrenoceptor reserve is present that buffers the response from the inhibitory effect of cooling. This allows the potentiating effect of cold on the alpha 2-adrenergic component of the response to catecholamines to predominate, and the contractile response to exogenous NE and sympathetic nerve stimulation is augmented. By contrast, in deep veins of the limb, cold reduces the contractions evoked by alpha 1- and alpha 2-adrenergic activation. This can be explained best by the absence of a receptor reserve for alpha 1-adrenergic agonists of high efficacy, combined with a reduced density of postjunctional alpha 2 adrenoceptors.     

Modulation by beta-adrenoceptors and angiotensin II receptors of splanchnic nerve evoked catecholamine release from the adrenal medulla.

In the present study, we have evaluated the effect of both facilitatory beta 2-adrenoceptor and angiotensin II receptor on the release of adrenal catecholamines induced by electrical stimulation of the splanchnic nerve in anaesthetized and vagotomized dog. In these experiments, individual or combined treatments with the beta 2-adrenoceptor antagonist ICI 118551 (0.3 mg/kg i.v.), the converting enzyme inhibitor captopril (2 mg/kg i.v.), or the angiotensin II receptor antagonist saralasin (2 micrograms.kg-1.min-1 i.v.) were found to significantly decrease the release of adrenal catecholamines during splanchnic nerve stimulation (5-V pulses of 2 ms duration for 3 min at 1 Hz) whatever the order of administration of the drugs. On the other hand, the infusion of angiotensin II (20 ng.kg-1.min-1) was shown to potentiate the release of adrenal catecholamines in response to electrical stimulation, and this effect was totally blocked by treatment with saralasin (4 micrograms.kg-1.min-1 i.v.). This facilitating angiotensin mechanism differed from beta-adrenoceptor facilitating mechanism, since following beta-blockade with ICI 118551, angiotensin II infusion still significantly potentiated the release of catecholamines during splanchnic nerve stimulation. These observations thus suggest that both facilitating beta 2-adrenoceptors and angiotensin II receptors can independently modulate the release of adrenal catecholamines.     

Nisoldipine inhibits vasoconstrictor responses in the cat pulmonary vascular bed

The influence of nisoldipine, a dihydropyridine calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the feline pulmonary vascular bed under conditions of controlled blood flow. The calcium channel blocking agent caused a small reduction in lobar vascular resistance and blocked pulmonary vasoconstrictor responses to BAY K 8644, an agent which promotes calcium entry. The calcium entry blocking agent also reduced pulmonary vasoconstrictor responses to methoxamine and to BHT 933, alpha 1- and alpha 2-adrenoceptor agonists, and to U 46619, an agent which mimics the actions of thromboxane A2. Although there was a marked difference in vasoconstrictor potency in the pulmonary vascular bed, responses to the thromboxane mimic and to the alpha 1- and alpha 2-adrenoceptor agonists were reduced by approximately the same extent. The increases in systemic arterial pressure in response to BAY K 8644, methoxamine, and BHT 933 were also reduced by nisoldipine, and the calcium entry antagonist reduced systemic arterial pressure and systemic vascular resistance. The results of the present study suggest that an extracellular source of calcium is required for the maintenance of vascular tone and for the expression of vasoconstrictor responses, resulting from activation of alpha 1- and postjunctional alpha 2-adrenoceptors and thromboxane receptors in the feline pulmonary vascular bed.