Adrenoceptor-mediated Vasoconstriction Research Articles

ET B Receptor Mediated Increases in Vasomotor Sympathetic Activity

Dysfunctional autonomic balance is a hallmark of many forms of hypertension. Endothelin B receptors (ETB-Rs) are present throughout the autonomic nervous system, but their role in modulating autonomic balance remains unclear. We have previously demonstrated that acute activation of ETB-Rs on sympathetic nerves increases blood pressure via a-1 adrenoceptor-mediated vasoconstriction. ETB-R deficient (ETB-def) rats lack functional ETB-Rs except on adrenergic tissues where functional ETB-Rs are expressed via transgene and have elevated vasomotor sympathetic tone compared to transgenic control (TG) rats, which express functional ETB-Rs and possess the transgene. We hypothesized that selective ETB-R blockade lowers blood pressure and sympathetic tone in ETB-def rats but raises blood pressure and sympathetic tone in TG controls. We anticipated that ETB-R blockade would create an intermediate blood pressure and sympathetic tone phenotype where ETB-def and TG controls would meet in the middle. We implanted male and female ETB-def rats and controls with telemetry to monitor freely-moving, conscious blood pressure, heart rate, and frequency domain parameters. Following baseline recordings, we implanted osmotic minipumps to deliver 10 mg/kg/d of A-192621, a selective ETB-R antagonist. We also injected 1.0 mg/kg chlorisondamine to directly measure vasomotor sympathetic tone both during baseline and drug infusion periods. All statistical comparisons were evaluated by 2-way RM ANOVA followed by Sidak's post hoc test. Following 3-4 days of A-192621 treatment, systolic blood pressure (SBP) did not change from baseline in ETB-def rats (+ 0.1 ± 3.2 mmHg; p = 0.99); however, SBP rose dramatically in TG controls (+ 18.0 ± 1.4 mmHg; p < 0.001). During A-192621 infusion, SBP in ETB-def and TG controls were similar (150.1 ± 2.7 vs 148.5 ± 2.3 mmHg, respectively, p = 0.85). In essence, TG controls became like ETB-def rats following ETB-R antagonism. At baseline, ETB-def exhibited higher vasomotor sympathetic tone as demonstrated by a greater decline in SBP following ganglionic blockade from chlorisondamine relative to TG controls (-61.0 ± 2.7 vs. -47.1 ± 2.1 mmHg, respectively; p = 0.01). A-192621 did not alter this response in ETB-def rats (- 64.6 ± 3.3 mmHg; p = 0.61 vs. baseline) but increased vasomotor tone in TG controls (- 56.8 ± 3.0; p = 0.03 vs. baseline). Frequency domain analysis also indicated that TG controls had increased sympathetic to parasympathetic vasomotor balance following A-192621 as measured by the low frequency to high frequency ratio (LF/HF) of SBP variability (+ 0.43 ± 0.11 LF/HF; p = 0.02) whereas ETB-def did not have a significant difference between baseline and treatment periods (-0.04 ± 0.18 LF/HF; p = 0.96). Taken together, these results indicate that selective ETB-R antagonism had no effect on blood pressure or vasomotor sympathetic tone in ETB-def animals but increased both parameters in TG controls to levels comparable to ETB-def. Contrary to our hypothesis, these results suggest that ETB-Rs on efferent sympathetic nerves may not influence blood pressure of vasomotor autonomic tone under normal physiological conditions; however, blockade or absence of ETB-Rs on sensory pathways may be responsible for the elevation of sympathetic tone and blood pressure.

Activation of α1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of α1 -adrenoceptors has been reported in different vessels. We investigated the involvement of each α1 -adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process. Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72weeks-old, were used to evaluate the desensitization process. Expression of α1 -adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients with a wide age range. Repeated application of phenylephrine decreased subsequent α1 -adrenoceptor-mediated vasoconstriction by increasing nNOS protein expression in aorta, but not in tail or mesenteric resistance arteries, where mRNA levels of nNOS were undetectable. This desensitization process disappeared in the absence of endothelium or in the presence of L-NAME (100μM), nNOS inhibitors, SMTC (1μM) and TRIM (100μM), and 5-methylurapidil (100nM, α1A -antagonist), but not BMY7378 (10nM, α1D -antagonist). The α1A /nNOS-mediated desensitization was absent in aged SHR and Wistar animals, where the expression of α1A -adrenoceptors was reduced in aorta and LV. In human LV, a negative correlation was found between age and α1A -adrenoceptor expression. The α1A -adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological 'brake' against the detrimental effects of excessive α1 -adrenoceptor-mediated vasoconstriction. Reduced α1A -adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity.

TRPM4 inhibitor 9-phenanthrol activates endothelial cell intermediate conductance calcium-activated potassium channels in rat isolated mesenteric artery.

Smooth muscle transient receptor potential melastatin 4 (TRPM4) channels play a fundamental role in the development of the myogenic arterial constriction that is necessary for blood flow autoregulation. As TRPM4 channels are present throughout the vasculature, we investigated their potential role in non-myogenic resistance arteries using the TRPM4 inhibitor 9-phenanthrol. Pressure and wire myography were used to assess the reactivity of rat arteries, the latter in combination with measurements of smooth muscle membrane potential. Immunohistochemistry (IHC) and endothelial cell (EC) calcium changes were assessed in pressurized vessels and patch clamp measurements made in isolated ECs. The TRPM4 inhibitor 9-phenanthrol reversibly hyperpolarized mesenteric arteries to circa EK and blocked α1 -adrenoceptor-mediated vasoconstriction. Hyperpolarization was abolished and vasoconstriction re-established by damaging the endothelium. In mesenteric and cerebral artery smooth muscle, 9-phenanthrol hyperpolarization was effectively blocked by the KCa 3.1 inhibitor TRAM-34. 9-Phenanthrol did not increase mesenteric EC [Ca(2+)]i , and Na(+) substitution with N-methyl-D-glucamine only increased the muscle resting potential by 10 mV. Immunolabelling for TRPM4 was restricted to the endothelium and perivascular tissue. These data reveal a previously unrecognized action of the TRPM4 inhibitor 9-phenanthrol - the ability to act as an activator of EC KCa 3.1 channels. They do not indicate a functionally important role for TRPM4 channels in the reactivity of non-myogenic mesenteric arteries.

Differential involvement of .ALPHA.1-adrenoceptors in vasoconstrictor responses to cooling in mouse plantar arteries in vitro and in vivo

Cooling-induced reduction of skin blood flow results from a reflex increase in sympathetic output and an enhanced vasoconstrictor activity of skin vessels. The latter has been proposed to be mediated by increased reactivity of alpha(2C)-adrenoceptors during cooling in studies with isolated cutaneous vessels in vitro. We have previously shown in studies with tetrodotoxin-treated mice in vivo that reduction of plantar skin blood flow (PSBF) induced by local cooling results primarily from increased reactivity of alpha(2C)-adrenoceptors. In addition, we showed that part of the cooling-induced response was also mediated by alpha(1)-adrenoceptors. However, the mechanisms involved in the cooling-induced responses mediated by alpha(1)-adrenoceptors have not been elucidated. The present study is an investigation seeking to clarify the mechanisms involving alpha(1)-adrenoceptors. Medial plantar arteries were isolated from male ddY mice and changes in vessel diameter were measured in vitro using pressurized arteriography. In vivo measurements of PSBF were performed on artificially ventilated tetrodotoxin treated mice, anaesthetized with pentobarbital sodium, using laser Doppler flowmetry, with the probe positioned above the medial plantar artery. In the in vitro studies with isolated plantar arteries, cooling from 37 to 28 degrees C did not affect the constrictor potency of phenylephrine, an alpha(1)-adrenoceptor agonist, and the threshold concentration to evoke constriction was rather higher at 28 degrees C than it was at 37 degrees C. The cooling also suppressed the constrictor efficacy of UK14,304, an alpha(2)-adrenoceptor agonist. In contrast, cooling the air temperature around the foot from 25 to 10 degrees C in vivo decreased PSBF, which was significantly inhibited by phentolamine, an alpha-adrenoceptor antagonist, although MK-912, an alpha(2C)-adrenoceptor antagonist, had no effect on it. These results suggest that although alpha(1)-adrenoceptors are involved in cooling-induced reduction of PSBF in mice, the response is unlikely to result from an enhancement of alpha(1)-adrenoceptor-mediated vasoconstriction of plantar arteries during cooling.

Altered role of smooth muscle endothelin receptors in coronary endothelin-1 and α1-adrenoceptor-mediated vasoconstriction in Type 2 diabetes

Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ET(A)) and type B (ET(B)) receptors that have been implicated in cross talk with alpha(1)-adrenoceptors (alpha(1)-AR). ET(A) and ET(B) receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary alpha(1)-AR function has not been examined. Therefore, we examined the effect of ET(A) and ET(B) receptor inhibition on coronary vasoconstriction to ET-1 and alpha(1)-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/6J mice. Responses to ET-1 and the selective alpha(1)-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) alone or in combination with selective ET(A) or ET(B) receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ET(B), but not ET(A), receptor blockade reduced basal coronary tone in T2D hearts. In the presence of l-NAME, ET(A) receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ET(B) inhibition abolished this response only in control hearts. In addition, ET(A) inhibition enhanced alpha(1)-AR-mediated vasoconstriction in T2D, but not control, hearts following l-NAME treatment. Therefore, in this model, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ET(B) receptors, whereas the interaction with alpha(1)-ARs is mediated solely through the ET(A) receptor subtype.

Ageing affects nitric oxide synthase, cyclooxygenase and oxidative stress enzymes expression differently in mesenteric resistance arteries

1 Our aim was to study the role of nitric oxide (NO) and arachidonic acid pathways in the alpha(1)-adrenoceptor-mediated vasoconstriction in mesenteric resistance arteries from 3--4 and 22 to 23-month-old Sprague-Dawley rats. 2 The expression of NO synthase (NOS), cyclooxygenase (COX) isoforms, soluble guanylate cyclase, superoxide dismutase and the NAD(P)H oxidase subunits p22(phox) and p 47(phox) were determined. 3 The N(G)-nitro-l-arginine methyl ester, a non-selective NOS inhibitor, shifted to the left but indomethacin and NS 398, non-selective and selective COX-2 inhibitors, shifted to the right the concentration-response curve for the vasoconstriction by phenylephrine in both age groups. 4 Ageing up-regulated endothelial NOS and p22(phox) expression but did not modify COX, soluble guanylate cyclase, superoxide dismutase and p 47(phox) expression. 5 These data suggest that the observed enhancement of eNOS protein expression could constitute a compensatory mechanism to counter-regulate a chronic loss of NO possibly through increased superoxide anion production from NAD(P)H oxidase induced by age.

Reduced α‐adrenoceptor responsiveness and enhanced baroreflex sensitivity in Cry‐deficient mice lacking a biological clock

To reveal the role of clock genes in generating the circadian rhythm of baroreflexes, we continuously measured mean arterial pressure and baroreflex sensitivity in free-moving normal wild-type mice, and in Cry-deficient mice which lack a circadian rhythm, in constant darkness for 24 h. In wild-type mice the mean arterial pressure was higher at night than during the day, and was accompanied by a significantly enhanced baroreflex sensitivity of -13.6 +/- 0.8 at night compared with -9.7 +/- 0.7 beats min(-1) mmHg(-1) during the day (P < 0.001). On the other hand, diurnal changes in arterial pressure disappeared in Cry-deficient mice with remarkably enhanced baroreflex sensitivity compared with wild-type mice (P < 0.001): -21.9 +/- 1.6 at night and -23.1 +/- 2.1 beats min(-1) mmHg(-1) during the day. Moreover, the mean arterial pressure response to 10 microg kg(-1) of phenylephrine, an alpha1-adrenoceptor agonist, was severely suppressed in Cry-deficient mice regardless of time, while that for the wild-type mice was 10.1 +/- 1.9 mmHg in the night, significantly lower than 22.0 +/- 3.5 mmHg in the day (P < 0.01). These results suggest that CRY genes are involved in generating the circadian rhythm of baroreflex sensitivity, partially by regulating alpha(1)-adrenoceptor-mediated vasoconstriction in peripheral vessels.

The role of Rho kinase and extracellular regulated kinase-mitogen-activated protein kinase in alpha2-adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein.

Alpha2-adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon activation of the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase signal transduction pathway. Recent studies have shown that alpha2-adrenoceptor-mediated vasoconstriction in the rat aorta is also dependent upon activation of Rho kinase. The aim of this study was to determine whether Rho kinase and ERK-MAP kinase are part of the same signaling pathway. The Rho kinase inhibitor Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride) (10 microM) almost completely inhibited the contractile response to the alpha2-adrenoceptor agonist UK14304 (5-bromo-6-[2-imidazolin-2-ylamine]-quinoxaline bitartrate) in segments of porcine palmar lateral vein [maximum response 2.9 +/- 2.3% of 60 mM KCl response (mean +/- S.E.M.) in the presence of Y27632, compared with 64.9 +/- 7.1% in control tissues, n = 4]. However, Y27632 had no effect on alpha2-adrenoceptor-mediated ERK activation, as measured by Western blotting. Alpha2-adrenoceptor-mediated vasoconstriction was associated with an increase in phosphorylation of the myosin phosphatase-targeting subunit (MYPT) at Thr696 (the Rho kinase phosphorylation site). This phosphorylation was inhibited by 10 microM Y27632. In contrast, inhibition of ERK activation with the MAP kinase kinase inhibitor PD98059 (2-amino-3-methoxyflavone) (50 microM) had no effect on MYPT phosphorylation. Both Y27632 and PD98059 inhibited myosin light chain phosphorylation. These data indicate that alpha2-adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon both Rho kinase and ERK activation, although these are separate pathways. Rho kinase causes vasoconstriction through inhibition of myosin phosphatase and an increase in myosin light chain phosphorylation, whereas ERK causes vasoconstriction through a myosin phosphatase-independent pathway.

Enhancement of alpha2-adrenoceptor-mediated vasoconstriction by the thromboxane-mimetic U46619 in the porcine isolated ear artery: role of the ERK-MAP kinase signal transduction cascade.

1. Alpha(2)-adrenoceptor-mediated contractions in porcine blood vessels can be enhanced in the presence of the thromboxane-mimetic U46619, and forskolin. The aim of this study was to determine the role of U46619 in the enhanced contractions, and to determine whether signalling through the ERK-MAP kinase pathway is involved. 2. Responses to the alpha(2)-adrenoceptor agonist UK14304 (1 micro M) were increased from 22+/-3% of the response to 60 mM KCl to 68+/-12% (n=8, mean+/-s.e.m.) in the presence of a low concentration of U46619 (< 20% of the 60 mM KCl response). 3. Both the direct and the U46619-enhanced UK14304 responses were inhibited by 50 microM PD98059, an inhibitor of the ERK-MAP kinase pathway. UK14304-induced contractions were associated with an increase in ERK2 phosphorylation, indicating an increased activity. In the presence of U46619, there was an enhanced phosphorylation of ERK2. U46619 on its own had no effect on ERK phosphorylation. 4. Both the direct and enhanced UK14304 contractions were inhibited in the absence of extracellular calcium. These conditions also prevented the increase in ERK2 phosphorylation. This indicates a role for calcium influx in the enhanced contractions. 5. In conclusion, this study demonstrates that precontraction with the thromboxane-mimetic U46619 enhances alpha(2)-adrenoceptor-mediated vasoconstriction through the enhancement of the ERK-MAP kinase pathway, and influx of extracellular calcium.

Alpha 2 adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein: role of phosphatidylinositol 3-kinase and EGF receptor transactivation.

1 Alpha(2) adrenoceptors cause vasoconstriction in the porcine palmar lateral vein through a mechanism involving the ERK signal transduction cascade, calcium influx, and a Src tyrosine kinase. The aim of the present study was to determine if phosphatidylinositol 3-kinase (PI 3-kinase) and/or epidermal growth factor (EGF) receptor transactivation are also involved. 2 alpha(2) Adrenoceptor-mediated vasoconstriction and ERK2 activation in the porcine palmar lateral vein was inhibited in the presence of either the PI 3-kinase inhibitor LY294002, or the EGF receptor tyrosine kinase inhibitor AG1478 suggesting the involvement of both PI 3-kinase and EGF receptor transactivation. 3 Akt phosphorylation was increased in segments of porcine palmar lateral vein contracted with UK14304 indicating an increase in Akt activation. This is a further indication that PI 3-kinase is involved in alpha(2) adrenoceptor-mediated vasoconstriction. Akt activation was inhibited by the Src tyrosine kinase inhibitor PP2, and removal of extracellular calcium. 4 UK14304 (10 microM) stimulated an increase in intracellular calcium in segments of palmar lateral vein. This was inhibited by removal of extracellular calcium, but not by nifedipine suggesting the rise in calcium is due to influx of calcium through non-L type calcium channels. The increase in calcium was also inhibited by LY294002 indicating that PI 3-kinase is upstream of calcium influx. 5 These data indicate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon stimulation of PI 3-kinase, leading to an influx of calcium. This results in activation of the EGF receptor tyrosine kinase, and finally activation of ERK-MAP kinase.

Role of the extracellular signal-regulated kinase (Erk) signal transduction cascade in alpha(2) adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein.

The mechanism of alpha(2) adrenoceptor-mediated vasoconstriction is unknown, but may involve activation of voltage-sensitive calcium channels, and/or a protein tyrosine kinase. Recently the extracellular signal-regulated kinase (Erk) cascade, often an event downstream of tyrosine kinase activation, has been shown to mediate vasoconstriction to a variety of agents. The aim of this present study was to determine the involvement of the Erk signal transduction cascade in alpha(2) adrenoceptor-mediated vasoconstriction, and to confirm the involvement of activation of voltage-sensitive calcium channels, and protein tyrosine kinase. Contractions to the alpha(2) adrenoceptor agonist UK14304 in the porcine palmar lateral vein in vitro were reduced 70 - 80% by the MEK inhibitors PD98059 (10 - 50 microM) and U0126 (10 - 50 microM), indicating the involvement of the Erk signal transduction cascade. Immunoblots also demonstrated an increase in the phosphorylated (activated) form of Erk in palmar lateral vein segments after contraction with UK14304, which was inhibited by PD98059 and U0126. The calcium channel blockers nifedipine and verapamil, or removal of extracellular calcium inhibited UK14304-induced contractions and phosphorylation of Erk, demonstrating the importance of an influx of extracellular calcium. UK14304-induced contractions were inhibited by PP2 (1 - 10 microM), a selective inhibitor of Src tyrosine kinases, but not by PP3, an inactive analogue. PP2 also prevented the phosphorylation of Erk by UK14304. These data demonstrate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon activation of the Erk signal transduction cascade, which is downstream of an influx of extracellular calcium, and activation of Src tyrosine kinases.

Noradrenaline provokes axon reflex hyperaemia in the skin of the human forearm

High doses of noradrenaline increase the sensitivity of skin to heat, presumably by sensitizing nociceptive afferent fibres. Since activation of these fibres increases local blood flow by an axon reflex mechanism, noradrenaline might simultaneously evoke adrenoceptor-mediated vasoconstriction and axon reflex vasodilatation. To investigate this possibility, noradrenaline was introduced into the skin of the human forearm by iontophoresis, and changes in blood flow were monitored in nearby skin. Increases in blood flow were greater near the site of noradrenaline iontophoresis than near the site of saline iontophoresis. Since the response was limited in its distribution to a few centimeters from the site of iontophoresis, hyperaemia was most likely due to a local mechanism rather than a spinal or supraspinal reflex. In addition, pretreatment of the skin with a local anaesthetic cream inhibited the increase in flow, indicating that the response was mediated neurally. These findings suggest that activation of nociceptive afferents by noradrenaline provokes axon reflex hyperaemia.

Lack of effect of a selective vasopressin V1A receptor antagonist SR 49,059, on potentiation by vasopressin of adrenoceptor-mediated pressor responses in the rat mesenteric arterial bed.

The vasopressin receptor subtype involved in the enhancement by vasopressin of adrenoceptor-mediated vasoconstriction was investigated in rat isolated perfused mesenteric arteries. [Arg8]vasopressin (1-10 nM) dose-dependently increased the perfusion pressure and enhanced the pressor response to the adrenoceptor agonist methoxamine (40 nmol) or electrical stimulation of periarterial nerves (16 Hz), at the concentration of 10 nM of [Arg8]vasopressin up to 4 and 3 fold, respectively. During prolonged exposure (45 min) the direct vasoconstrictor effect of [Arg8]vasopressin (10 nM) rapidly declined whereas the potentiation of methoxamine-induced vasoconstriction was maintained. The selective vasopressin V1A receptor antagonist SR 49,059 (1-3 nM) and the non-selective V1A/B and oxytocin receptor antagonist [deamino-Pen1,Tyr(Me)2,Arg8]vasopressin (15-45 nM) inhibited the direct vasoconstrictor action of [Arg8]vasopressin but had no effect on the enhancement of the pressor response to methoxamine or electrical stimulation. The V1B receptor agonist [deamino-Cys1,beta-(3-pyridyl)-D-Ala2,Arg8]vasopressin (100-1000 nM) and the V2 receptor agonist [deamino-Cys1,D-Arg8]vasopressin (1-10 nM) were devoid of any pressor activity and did not potentiate methoxamine-evoked vasoconstriction. In contrast, [1-triglycyl,Lys8]vasopressin (100 - 1000 nM) potentiated the methoxamine responses without per se inducing vasoconstriction. In arteries precontracted with methoxamine (7.5 microM) pressor responses to [Arg8]vasopressin (3-10 nM) were not inhibited by a dose of SR 49,059 (3 nM) which abolished the peptide's vasoconstrictor effect under control conditions. These data show that the direct vasoconstrictor effect of [Arg8]vasopressin is mediated by V1A receptors while the enhancement of adrenoceptor-mediated pressor responses is insensitive to V1A, V1B, and oxytocin receptor antagonists and is not mimicked by selective agonists of V1B and V2 receptors. In conclusion, an unusual interaction of vasopressin with V1A receptors, or even the existence of a novel receptor subtype, has to be considered.

Interaction of dopamine, (+/-)-dobutamine and the (-)-enantiomer of dobutamine with alpha- and beta-adrenoceptors in the pulmonary circulation of the dog.

The effects of dopamine, (+/-)-dobutamine (racemic mixture) and (-)-dobutamine on alpha-adrenoceptor-mediated vasoconstriction were evaluated in the pulmonary circulation of the anesthetized dog. The drugs were studied in the absence and presence of propranolol (1 mg/kg, i.v.) in order to assess beta-adrenoceptor-mediated effects in the pulmonary circulation. Intra-arterial administration of dopamine, (+/-)-dobutamine and (-)-dobutamine elicited dose-dependent increases in pulmonary perfusion pressure, reflecting increases in pulmonary vascular resistance. In control animals, dopamine elicited the largest increases in pulmonary perfusion pressure (45% above resting pulmonary pressure) followed by (-)-dobutamine (30% increase) and (+/-)-dobutamine (15% increase). The pressor effects of dopamine in the pulmonary circulation were mediated by both postjunctional vascular alpha 1- and alpha 2-adrenoceptors, since prazosin, (100 micrograms/kg, i.v.), a selective alpha 1-adrenoceptor antagonist, and rauwolscine (100 micrograms/kg, i.v.), a selective alpha 2-adrenoceptor antagonist, both inhibited the vasopressor response elicited by dopamine to roughly equivalent degrees. Pulmonary vasoconstriction produced by (+/-)-dobutamine and (-)-dobutamine was mediated primarily by postsynaptic vascular alpha 1-adrenoceptors, although alpha 2-adrenoceptor-mediated vasoconstriction was observed. In propranolol-pretreated animals, the increase in pulmonary perfusion pressure elicited by dopamine and (-)-dobutamine was qualitatively and quantitatively similar to that observed in control animals, suggesting that these agents have little activity on vascular beta 2-adrenoceptors in the pulmonary circulation. In marked contrast, the maximum pulmonary vasopressor response obtained with (+/-)-dobutamine were greater in propranolol-pretreated animals, indicating that (+/-)-dobutamine also has the capacity to stimulate pulmonary vascular beta 2-adrenoceptors which mediate pulmonary vasodilation that, in part, mask alpha-adrenoceptor-mediated pulmonary vasoconstriction. Since the (-)-enantiomer of dobutamine has little or no beta 2-adrenoceptor agonist activity, the beta 2-adrenoceptor-mediated effect of (+/-)-dobutamine must result from the (+)-enantiomer as has been previously proposed. The results of the present study indicate that dopamine has a greater propensity for increasing pulmonary vascular resistance, and therefore pulmonary arterial blood pressure, relative to (+/-)-dobutamine. This results, at least in part, from the relatively weaker activity of dopamine in stimulating pulmonary vascular beta 2-adrenoceptors which mediate vasodilation.(ABSTRACT TRUNCATED AT 400 WORDS)

Alpha-Adrenoceptors, Adrenaline, and Exaggerated Vasoconstrictor Response to Stress in Essential Hypertension

Stressful sympathetic stimulation by cold pressor test in patients with essential hypertension results in an exaggerated response of the already elevated plasma adrenaline, heart rate, blood pressure, and α-adrenoceptor-mediated vasoconstriction when compared with normotensive subjects. The stress-induced increase in adrenaline was correlated with the attendant increase in blood pressure. The stress-induced reduction in forearm flow was reversed during infusion of the postjunctional α₁-adrenoceptor blocker prazosin. Therefore, enhanced responses to sympathetic stress, as reflected and perhaps caused by an exaggerated rise in plasma adrenaline, may contribute to an increased α₁-adrenoceptor-mediated vasoconstriction in essential hypertension.