The relationship between alterations in alpha 1-adrenoceptor reserve by phenoxybenzamine and benextramine and the sensitivity of cirazoline-induced pressor responses to inhibition by nifedipine

Nifedipine does not inhibit the alpha 1-adrenoceptor-mediated pressor response of cirazoline at a dose that significantly antagonizes the alpha 2-adrenoceptor-mediated pressor response of B-HT 933. After elimination of the alpha 1-adrenoceptor reserve with either phenoxybenzamine or benextramine, the response to cirazoline was rendered highly sensitive to antagonism by nifedipine. These results support the hypothesis that the resistance of alpha 1-adrenoceptor-mediated pressor responses to inhibition by calcium channel antagonists may be caused by a large alpha 1-adrenoceptor reserve.     

Differential effects of alpha 1- and alpha 2-adrenoceptor agonists on peripheral vasoconstriction in pithed diabetic rats.

The pressor responses to selective alpha 1-adrenoceptor agonists (cirazoline and methoxamine) and to alpha 2-adrenoceptor agonists (UK-14,304 and B-HT 933) were investigated in pithed, streptozotocin-induced diabetic rats and age-matched control animals. Three months after induction of diabetes, the basal values of diastolic blood pressure (DBP) were the same in pithed diabetic and control rats (34.3 +/- 4.4 vs. 32.8 +/- 4.4 mm Hg, p greater than 0.05, n = 30). In pithed diabetic rats, dose-response curves for the vasoconstrictor effects of cirazoline and methoxamine were shifted to the right with a slight decrease in the maximum response as compared with those in control animals. In contrast, no shift in dose-response curves for the alpha 2-adrenoceptor-mediated vasoconstrictor effects was observed, as reflected by similar pD2 values. A pronounced decrease in the maximum pressor response to the alpha 2-adrenoceptor agonists could be demonstrated. This reduction was significantly greater than that of the alpha 1-adrenoceptor agonists. In conclusion, the functional role of alpha 1- and alpha 2-adrenoceptors in the peripheral resistance vessels appears to be differentially influenced by the diabetic state.     

Phenoxybenzamine-induced inhibition of cirazoline pressor responses in pithed rats pretreated with organic or inorganic calcium entry blocking drugs

In groups of propranolol-treated pithed rats pretreatment with either verapamil (1 mg/kg i.a., 20 min) or the inorganic calcium entry blocker (CEB), cobalt (23.8 mg/kg i.a., 20 min) reduced maximum obtainable pressor responses to the relatively selective alpha 2-adrenoceptor agonist B-HT 920 (0.1-1000 micrograms/kg i.v.) equally, by approximately 50%. Verapamil and cobalt at these doses had little or no effect upon pressor responses induced by the relatively selective alpha 1-adrenoceptor agonist cirazoline (0.1-1000 micrograms/kg i.v.). Phenoxybenzamine (0.1 mg/kg i.v., 15 min) displaced to the right and reduced by 44% the maximum obtainable pressor responses to cirazoline. Treatment of animals with the combination of either verapamil or cobalt followed by phenoxybenzamine, at the dose levels and pretreatment times given above, produced significantly greater inhibitions of cirazoline pressor responses (83% and 88% reduction in the maximum obtainable pressor responses to cirazoline respectively) than were observed following administration of phenoxybenzamine alone. Since yohimbine (1 mg/kg i.v.) did not significantly affect the residual responses to cirazoline following treatment with phenoxybenzamine the mechanism responsible for this interaction between CEBs and phenoxybenzamine is not mediated via postjunctional alpha 2-adrenoceptors. Additional studies are required to assess the involvement of a possible subtype of alpha 1-adrenoceptors which appear to mediate vascular responses sensitive to CEBs.     

Interaction of calmodulin antagonists with alpha-adrenergic responses in pithed rats and in the perfused hindquarters of the rat

The effect of calmodulin antagonists was studied on the alpha 1- and alpha 2-adrenoceptor-mediated increase in diastolic blood pressure in pithed rats and on the alpha 1-adrenoceptor-mediated reduction of flow in the perfused hindquarters of the rat. B-HT 920 was used as a selective alpha 2-adrenoceptor agonist in the pithed rat experiments, whereas cirazoline was used as a selective agonist for alpha 1-adrenoceptors. The latter was used after pretreatment with nifedipine (1 mg/kg) or phenoxybenzamine (30 micrograms/kg), revealing calcium influx-insensitive and -sensitive mechanisms of vasoconstriction, respectively. Papaverine, calmidazolium and W-7 did not influence the dose-response curves for the agonists in the pithed rat experiments. The modest effects of high doses of flunarizine and bepridil on the dose-response curve for B-HT 920 and of trifluoperazine on the dose-response curve for cirazoline can be explained by the well-known calcium entry (flunarizine) and alpha 1-adrenoceptor-blocking (bepridil) effects of these drugs. Bepridil and calmidazolium caused an elevation of the cirazoline dose-response curves in the perfused rat hindquarters; flunarizine and trifluoperazine showed a parallel and dose-dependent displacement of the cirazoline dose-response curve to the right, whereas W-7 was inactive. Our results do not implicate calmodulin-associated effects in the alpha-adrenoceptor-mediated vasoconstriction in pithed rats and in the perfused rat hindquarters.     

Differential effect of pertussis toxin on pre- and postjunctional alpha 2-adrenoceptors in the cardiovascular system of the pithed rat

The role of the pertussis toxin-sensitive guanine nucleotide binding regulatory protein in pre- and postjunctional alpha 2-adrenoceptor-mediated responses has been investigated in the pithed rat. Pertussis toxin (50 micrograms/kg i.v., administered 3 days prior to experimentation) markedly inhibited the alpha 2-adrenoceptor-mediated vasopressor response to B-HT 933, but had no effect on the alpha 2-adrenoceptor-mediated cardiac neuroinhibitory effect of B-HT 933. Thus, postjunctional alpha 2-adrenoceptor activation in vascular smooth muscle, but not prejunctional alpha 2-adrenoceptor activation on sympathetic neurons, utilizes a pertussis toxin-sensitive guanine nucleotide binding regulatory protein.     

Postsynaptic alpha 1- and alpha 2-adrenoceptors in the circulatory system of the pithed rat: selective stimulation of the alpha 2-type by B-HT 933

The antagonism by yohimbine (1 mg/kg, i.v.) of vasopressor responses in pithed rats was most pronounced towards B-HT 933 (dose ratio 18.3) and moderate towards clonidine (dose ratio 3.7) and especially L-phenylephrine (dose ratio 2.5). Prazosin (0.1 mg/kg, i.v.) had no effect on the pressor responses to B-HT 933, moderately affected those to clonidine (dose ratio 3.9), but strongly diminished those to L-phenylephrine (dose ratio 53). Phentolamine (1 mg/kg, i.v.) was devoid of a differential antagonism. The results obtained suggest a subclassification of postsynaptic alpha-adrenoceptors into alpha 1- and alpha 2-subtypes mediating pressor effects. B-HT 933 is a selective agonist and yohimbine an antagonist of postsynaptic alpha 2-adrenoceptors. L-Phenylephrine preferably stimulates and prazosin preferentially occupies the alpha 1-adrenoceptors. Clonidine is a potent agonist of both types and phentolamine behaves as a non-selective antagonist.     

Invariable susceptibility to blockade by nifedipine of vasoconstriction to various alpha 2-adrenoceptor agonists in pithed rats

The sensitivity of the increase in diastolic pressure brought about by the selective agonists of alpha 2-adrenoceptors, B-HT 920, B-HT 933, xylazine, UK-14,304, M-7, TL-99 and DP-6, 7-ADTN in pithed normotensive rats to blockade by the calcium entry inhibitor nifedipine has been investigated. To exclude any participation of vascular alpha 1- and beta 2-adrenoceptors, as well as cardiac beta 1-adrenoceptors, in the pressor responses, the study was made after treatment of the pithed rats with prazosin (0.1 mg kg-1) and (-)-propranol (1 mg kg-1). Without exception, the preferential agonists of alpha 2-adrenoceptors elicited vasoconstrictor responses which were susceptible to inhibition by nifedipine (0.03-1 mg kg-1) in a dose-dependent manner regardless of the differences in intrinsic activity of the compounds. The pressor activity was almost completely abolished after 1 mg kg-1 of nifedipine. The results show that vasoconstriction induced in pithed rats by various selective stimulating agents of postjunctional vascular alpha 2-adrenoceptors is invariably and equally sensitive to attenuation by nifedipine. This susceptibility of alpha 2-adrenoceptor-mediated vasoconstriction to impairment by blockade of calcium entry is not dependent on the nature, the potency or the efficacy of the agonist.     

Effect of adrenalectomy and demedullation of the adrenals on vasopressor responses to stimulation of postjunctional alpha 2-adrenoceptors

After adrenalectomy performed 18-12 h previously, the vasopressor responses induced by stimulation of postjunctional alpha 2-adrenoceptors (agonist: B-HT 920) were attenuated in pithed normotensive rats in contrast to pressor responses mediated by postjunctional alpha 1-adrenoceptors (agonist: cirazoline). Aldosterone and desoxycorticosterone both enhanced the vasopressor responses to the alpha 2-adrenoceptor agonist B-HT 920 in adrenalectomized rats, but did not fully restore the effects. Demedullation of the adrenals also attenuated the vasoconstrictor processes evoked by stimulation of postjunctional alpha 2-adrenoceptors 18-22 h later. This effect was reversed after an infusion with adrenaline. The combination of aldosterone and adrenaline produced full recovery of the increase in diastolic pressure elicited via alpha 2-adrenoceptors in adrenalectomized (18-22 h) animals. The results suggest that circulating adrenaline and aldosterone (or corticosterone) are required for optimal functioning of vascular postjunctional alpha 2-adrenoceptors.     

Heterogeneity of the interaction between alpha 1- and alpha 2-adrenoceptor agonists with their respective receptors in the vascular system of the pithed rat

The subdivision of alpha 1- and alpha 2-adrenoceptor-mediated pressor responses to different agonists based upon the influence of beta 2-adrenoceptor-mediated vasodilatation was further investigated in the pithed normotensive rat. The effect of salbutamol (4.18 X 10(-6) mol/kg) on the alpha 1-adrenoceptor-mediated increase in diastolic pressure due to dopamine and amidephrine as well as on the alpha 2-adrenoceptor-mediated pressor response to azepexole, DP-6,7-ADTN, M-7, TL-99 and dopamine was assessed. The alpha 1-pressor responses to amidephrine and dopamine were only slightly attenuated by salbutamol. The alpha 2-adrenoceptor-mediated increase in diastolic pressure due to B-HT 933 was strongly antagonized by salbutamol in contrast to the effect of dopamine, DP-6,7-ADTN and M-7. TL-99 occupied in intermediate position. The data do not support the existence of distinctly different subtypes of alpha 1- and alpha 2-adrenoceptors but favor the hypothesis that both alpha 1- and alpha 2-adrenoceptors are activated in a unique way by each of their respective agonists.     

Interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 2-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat

With pithed normotensive rats we studied the interaction between beta 2-adrenoceptor-mediated vasodilation and pressor responses elicited by vasopressin, the selective alpha 2-adrenoceptor agonists B-HT 920 and UK 14,304, and the alpha 2-adrenoceptor-mediated pressor responses of (--)-norepinephrine, tyramine [via neuronally released (--)-norepinephrine], alpha-methylnorepinephrine, and (--)-epinephrine. Salbutamol was used as a selective agonist of beta 2-adrenoceptors. The selective beta 2-adrenoceptor antagonist ICI 118,551 was employed to reveal the intrinsic beta 2-adrenoceptor activation induced by alpha-methylnorepinephrine and (--)-epinephrine, measured as a potentiation of the increase in diastolic pressure. Two types of interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 2-adrenoceptor-mediated vasoconstriction were found. The effect of the alpha 2-adrenoceptor agonists was attenuated in most cases. However, intravenously administered (--)-norepinephrine elicited an alpha 2-adrenoceptor-mediated vasoconstriction not attenuated by beta 2-adrenoceptor-mediated vasodilation. These results are interpreted as indications for two different populations of vascular alpha 2-adrenoceptors. Neuronally released (--)-norepinephrine activated alpha 2-adrenoceptors, and its effect was attenuated by beta 2-adrenoceptor-mediated vasodilation in contrast to that of intravenously administered (--)-norepinephrine. Therefore, an intrasynaptic and extrasynaptic population of vascular alpha 2-adrenoceptors as postulated. In contrast to (--)-norepinephrine, intravenously administered (--)-epinephrine seems to activate predominantly intrasynaptic alpha 2-adrenoceptors.     

Effect of diltiazem upon contractile responses to phenylephrine, cirazoline, Sgd 101/75, St 587 and B-HT 920 in rabbit aorta and dog saphenous vein preparations

Diltiazem (10 microM) did not significantly affect concentration-response curves to the full, relatively selective alpha 1-adrenoceptor agonists phenylephrine and cirazoline in rabbit aorta and dog saphenous vein preparations. The effects of these 2 agonists remained resistant to diltiazem even in tissues pretreated with phenoxybenzamine (0.03 or 0.1 microM, 20 min) to reduce the alpha-adrenoceptor reserve. Sgd 101/75 and St 587 were partial agonists in both vascular preparations. The concentration-response curves to these relatively selective alpha 1-adrenoceptor agonists were also unaffected, or only slightly attenuated, by diltiazem. B-HT 920 at low concentrations preferentially stimulated the dog saphenous vein preparation and only at high concentrations elicited small contractions of the rabbit aorta. The responses to B-HT 920 were mediated by alpha 2-adrenoceptors in the vein and by alpha 1-adrenoceptors in the aorta yet concentration-response curves to this agonist were significantly attenuated by diltiazem in both tissues. The results indicate that the resistance of certain alpha-adrenoceptor-mediated responses in vascular preparations to calcium entry blockers need not be associated with the presence of a significant receptor reserve and that calcium dependency of a response may be determined by the agonist.     

An investigation into the selectivity of a novel series of benzoquinolizines for alpha 2-adrenoceptors in vivo.

The potencies and selectivities of a novel series of benzoquinolizines for the alpha 2-adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin. Peripheral postjunctional alpha 2- and alpha 1-adrenoceptor blockade was measured as the reversal of B-HT 933 and methoxamine-induced pressor responses, respectively, in the pithed rat. Peripheral prejunctional alpha 2-adrenoceptor blockade was measured as the reversal of B-HT 933-induced inhibition of an electrically evoked tachycardia in the pithed rat. Central alpha 2-adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine. Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3-3 mg kg-1 i.v.) evoked dose-dependent shifts to the right of the dose-response curves to B-HT 933 whilst having minimal effects on the methoxamine dose-response curve. The selectivity for alpha 2-adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 greater than Wy 26392 greater than Wy 26703 greater than yohimbine. Indoramin (1 mg kg-1 i.v.) shifted the methoxamine pressor dose-response curve to the right without affecting the B-HT 933 dose-response curves, confirming its selective alpha 1-antagonist activity. Peripheral administration of all three benzoquinolizines (1-100 micrograms kg-1 i.v.) led to a dose-dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. (ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of Bay k 8644 on pressor effects of B-HT 920 and cirazoline in pithed cats

We studied interactions between the putative calcium entry promotor Bay k 8644 and alpha 1-adrenoceptor-mediated increases in diastolic pressure elicited by cirazoline as well as alpha 2-adrenoceptor-mediated pressor responses induced by B-HT 920 in pithed cats. Bay k 8644 (0.01-1 mg/kg, i.a.) did not affect the log dose-pressor response curve of cirazoline, but slightly potentiated the increase in diastolic pressure elicited by B-HT 920. After attenuation of the B-HT 920-induced pressor effects by the calcium entry blocker nifedipine (0.1 mg/kg, i.a.), Bay k 8644 (0.1 mg/kg, i.a.) strongly enhanced the pressor response. The increase in diastolic pressure elicited by cirazoline was not affected by nifedipine (0.1 mg/kg, i.a.), and the addition of Bay k 8644 (0.1 mg/kg, i.a.) had no effect. We conclude that in contrast to the increase in diastolic pressure elicited by B-HT 920, calcium channels are not involved in the cirazoline-induced pressor responses in the pithed cat. The activation of the calcium channels by B-HT 920 is already so efficient that it cannot be further enhanced by Bay k 8644.     

Relationship between alpha 2-adrenoceptor occupancy and response for B-HT 933 in canine saphenous vein

The relationship between alpha 2-adrenoceptor occupancy and contractile response for B-HT 933 was investigated in canine saphenous vein. B-HT 933 produced a concentration-dependent, alpha 2-adrenoceptor mediated contractile response in canine saphenous vein with an ED50 of 0.65 microM. The dissociation constant (KA) of B-HT 933 was calculated to be 5 microM. The relationship between alpha 2-adrenoceptor occupancy and contractile response for B-HT 933 in canine saphenous vein was hyperbolic, typical of full agonists or agonists with high intrinsic efficacies. B-HT 933 produced a half-maximal response in canine saphenous vein at only 11% alpha 2-adrenoceptor occupancy, with a maximal response being obtained with 40-60% alpha 2-adrenoceptor occupancy. We conclude that the selective alpha 2-adrenoceptor agonist, B-HT 933, has high efficacy at alpha 2-adrenoceptors, such that a significant alpha 2-adrenoceptor reserve, or spare alpha 2-adrenoceptors, exists for this compound in canine saphenous vein.     

Interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat

With pithed normotensive rats we studied the interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 1-adrenoceptor-mediated vasoconstriction. The selective beta 2-adrenoceptor agonist salbutamol was used to elicit vasodilatation. To induce alpha 1-adrenoceptor-mediated vasoconstriction, the selective alpha 1-adrenoceptor agonists cirazoline, St 587, and methoxamine were used. Furthermore, the alpha 1-adrenoceptor-mediated vasopressor effects of intravenously administered (--)-norepinephrine, and (--)-norepinephrine released from neurons by the nicotinic agonist 1,1-dimethyl-4-phenylpiperazine iodide (DMPP), the muscarinic ganglionic stimulant McN-A-343, electrical stimulation of the spinal cord, and the indirect sympathomimetic agent tyramine, were studied. By using the selective beta 2-adrenoceptor antagonist ICI 118,551, the interaction between the alpha 1-adrenoceptor-mediated vasoconstriction of (--)-epinephrine and alpha-methylnorepinephrine with their intrinsic beta 2-adrenoceptor agonistic effects was investigated. Two types of interaction between alpha 1-and beta 2-adrenoceptor-mediated vascular effects were found. Cirazoline and McN-A-343 activated alpha 1-adrenoceptors, inducing a vasoconstriction not affected by beta 2-adrenoceptor-mediated vasodilation. However, methoxamine at low doses, St 487, DMPP, electrical stimulation, intravenously administered (--)-norepinephrine, (--)-epinephrine, and alpha-methylnorepinephrine activated alpha 1-adrenoceptors, and their effect was attenuated by vasodilation. At low doses, tyramine stimulated alpha 1-adrenoceptors that were not sensitive to beta 2-adrenoceptor-mediated vasodilation, in contrast to the population of alpha 1-adrenoceptors activated at high doses of tyramine. It is hypothesized that there exist two different populations of alpha 1-adrenoceptors.     

Acute effects of phenoxybenzamine on alpha-adrenoceptor responses in vivo and in vitro: relation of in vivo pressor responses to the number of specific adrenoceptor binding sites

Pressor responses to intravenous phenylephrine, an adrenoceptor agonist, and to the alpha 2-adrenoceptor-selective agonist guanabenz were examined in conscious rabbits 30 min after treatment with a range of doses of phenoxybenzamine (10(-5) to 5 mg/kg). The maximum number of specific prazosin- and clonidine-binding sites in the spleen of rabbits sacrificed 30 min after receiving phenoxybenzamine were measured using radioligand binding techniques. Treatment with phenoxybenzamine resulted in a dose-dependent reduction in the maximum pressor response to both phenylephrine and guanabenz, although phenoxybenzamine was a more potent antagonist at postsynaptic alpha 1- than at postsynaptic alpha 2-adrenoceptors. Phenoxybenzamine treatment also caused a dose-dependent reduction in specific [3H]prazosin and [3H]clonidine binding. The maximum in vivo pressor response to guanabenz was observed only when all specific clonidine-binding sites were present. There was a close correlation between in vitro receptor number and in vivo pressor responses for alpha 2-adrenoceptor stimulation but not for alpha 1-adrenoceptor-mediated responses. The maximum pressor response to phenylephrine could be obtained in rabbits in which the number of specific prazosin-binding sites was reduced by 60%. These experiments provide an approach to relating in vitro receptor number to in vivo responses.     

8-Bromo cyclic guanosine monophosphate mimics the actions of nitroglycerin on alpha-adrenergic mechanisms in canine saphenous vein

The purpose of the present study was to determine if 8-bromo cyclic guanosine monophosphate (cGMP) mimics the actions of nitroglycerin in inhibiting alpha 1- versus alpha 2-mediated constrictor responses in vitro using rings prepared from isolated canine saphenous vein. Contractions were produced by phenylephrine, a selective alpha 1-adrenoceptor agonist and B-HT 920, a selective alpha 2-adrenoceptor agonist. The inhibitory effects of nitroglycerin and 8-bromo cGMP on contractions produced by submaximal concentrations (EC75) of phenylephrine and B-HT 920 were determined. 8-Bromo cGMP like nitroglycerin produced a selective antagonism of alpha 2-adrenoceptor-mediated responses and had minimal effects on alpha 1-adrenoceptor-induced constriction. However, after removal of spare postsynaptic vascular alpha 1-adrenoceptors by treatment with the irreversible alpha-adrenoceptor antagonist phenoxybenzamine (5 X 10(-8) M, 1 X 10(-7) M), the alpha 1-adrenoceptor-mediated vasoconstrictor responses of phenylephrine became highly sensitive to antagonism by 8-bromo cGMP and nitroglycerin. These data suggest that the action of 8-bromo cGMP like nitroglycerin is 'buffered' by the presence of a large alpha 1-adrenoceptor reserve in canine saphenous vein. The similarity in the efficacy and potency of these two agents suggests that the effects of nitroglycerin in canine saphenous vein may be the result of an increase in intracellular cGMP.     

Effects of alpha-adrenoceptor agonists on cardiac output and its regional distribution in the pithed rat.

Cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in pithed rats during pressor responses elicited by either alpha 1-adrenoceptor agonists (cirazoline, phenylephrine) or alpha 2-adrenoceptor agonists (xylaxine, B-HT 933). Two doses were used for each of cirazoline and B-HT 933 and phenylephrine was investigated in the presence of propranolol (3 mg kg-1). The rats were pithed under halothane anaesthesia. Cardiac output was increased by xylazine, the higher dose of B-HT 933 and phenylephrine. Heart rate was increased by phenylephrine and the higher doses of both cirazoline and B-HT 933. Stroke volume was greater in those groups given xylazine, phenylephrine and the higher dose of B-HT 933 but was decreased in those animals given the higher dose of cirazoline. Both alpha 2-adrenoceptor agonists increased the number of microspheres trapped in the lungs and the proportion of the cardiac output passing through the hepatic artery but decreased that flowing through the spleen and gastrointestinal tract. The higher dose of B-HT 933 also decreased the fraction of cardiac output flowing to the kidneys but kidney blood flow was maintained as a result of the increased cardiac output. Also, this treatment reduced blood flow in the epididimal fat pads. Both alpha 1-adrenoceptor agonists increased the fraction of cardiac output received by the coronary vasculature but the only other effect on distribution common to these agents was an increase in the percentage of the cardiac output passing to the hepatic artery. Cirazoline decreased the proportion of cardiac output distributed to the gastrointestinal tract and spleen but the total fraction of cardiac output passing to the hepatosplanchnic region was maintained as a result of the increase to the hepatic artery. Cirazoline markedly reduced the proportion of the cardiac output received by the kidneys and absolute flow in these organs was only 1.4% of control after the higher dose of this agonist but flow at the lower dose was maintained by the higher cardiac output. It is concluded that there is a significant contribution to the pressor responses elicited by alpha-agonists resulting from an alpha-adrenoceptor-mediated increase in cardiac output that may result from greater heart rates or stroke volumes. Also, there is a differential distribution of alpha-receptor subtypes throughout the vasculature which is especially noticeable in the kidneys.     

Vascular smooth muscle contraction initiated by postsynaptic alpha 2-adrenoceptor activation is induced by an influx of extracellular calcium

Vasoconstriction in pithed, normotensive rats elicited via stimulation of postsynaptic alpha 2-adrenoceptors by B-HT 920 was antagonized by EDTA and the calcium antagonists nifedipine, D 600 and verapamil, whereas pressor responses to the alpha 1-agonist methoxamine were unaffected. This indicates that vasoconstriction in vivo initiated via postsynaptic alpha 2-adrenoceptors requires an influx of extracellular calcium. Thus, the antihypertensive effect of calcium antagonists may be based upon a diminution of vascular tone maintained by postsynaptic alpha 2-adrenoceptors.     

The influence of blood gases on alpha 1- and alpha 2- adrenoceptor-mediated pressor responses in the pithed rat.

The influence of blood gases on alpha 1- and alpha 2-adrenoceptor-mediated pressor responses was studied in the pithed rat by varying the inspired gas mixture or the ventilation stroke volume. Acidosis favoured the peak responses to the alpha 2-adrenoceptor agonist, xylazine, while alkalosis favoured the peak responses to the alpha 1-adrenoceptor agonist, phenylephrine. A combination of hypoxia and hypercapnia greatly depressed the alpha 1 response to phenylephrine whereas the alpha 2 response to xylazine remained relatively unaffected. When Pao2 was varied in either acidotic or alkalotic conditions the response to the phenylephrine increased as Pao2 increased. To prevent hypoxia in air ventilated rats, large stroke volumes were required. This caused alkalosis and hence decreased responsiveness to xylazine. Consequently, air ventilated pithed rats gave poorer responses to xylazine than did those ventilated on 100% O2. The results show that alpha 1- and alpha 2-adrenoceptor-mediated pressor responses can be differentially affected by blood gases. The relative contribution of alpha 1- and alpha 2-adrenoceptors to vascular tone may be either under- or over-estimated depending on the arterial blood gases.