Reduction In Maximum Response Research Articles

Halothane selectively attenuates alpha 2-adrenoceptor mediated vasoconstriction, in vivo and in vitro.

The mechanism by which halothane interferes with catecholamine-induced vasoconstriction was examined, utilizing specific agonists at postjunctional alpha 1- and alpha 2-adrenoceptors on vascular smooth muscle. Stimulation of either adrenoceptor subtype normally produces vasoconstriction. Two experimental models of drug-induced vasoconstriction were used: in vivo blood pressure response in pithed rats, and in vitro isometric tension development in canine saphenous vein rings. These models were then utilized to examine the anti-vasoconstriction properties of halothane. In vivo, halothane (1 MAC) produced a significant depression in the vascular response to azepexole (an alpha 2-adrenoceptor agonist), but halothane did not alter vasoconstriction by phenylephrine (an alpha 1-adrenoceptor agonist). Halothane caused a 24% reduction of maximal response (P less than 0.0001) to azepexole in pithed rats, and a 3.2-fold rightward shift of the log dose-response curve (P less than 0.0001). Similarly, in vitro, halothane significantly attenuated alpha 2- but not alpha 1-adrenoceptor responsiveness. Halothane (4%) depressed maximal vein contraction to azepexole by 26% (P less than 0.0001), and shifted the log concentration-response curve 2.4-fold to the right (P less than 0.0001). The observed selective interference with alpha 2-mediated vasoconstriction by halothane is unlikely to represent drug antagonism at the receptor level. Our observations may suggest, indirectly, that halothane interferes with Ca+2 entry into vascular smooth muscle. The phenomenon of selective anti-vasoconstriction at alpha 2-adrenoceptors by halothane may explain why alpha 1-adrenergic agonists often appear to retain their vasopressor activity during halothane anesthesia. The mechanism of halothane-induced vasodilation thus includes attenuation of alpha 2- but not alpha 1-adrenergic vasoconstriction; this further demonstrates the multifactorial nature of halothane-induced vasodilation.

A difference in pharmacological properties of histamine receptors in rabbit aorta and basilar artery.

An interaction of Ca entry blockers, D600 and diltiazem, with histamine receptors was tested in rabbit aorta and basilar artery. D600 caused a parallel rightward shift of the concentration response curve for histamine. The slope values from Schild plot analysis in aorta were not different from unity. Dibenamine pretreatment caused reduction of maximum response to histamine in aorta. Such reduction was diminished markedly by the presence of D600 or chlorpheniramine in aorta but not in basilar artery. However, diltiazem did not influence the concentration response curve for histamine. These findings suggest that pharmacological property of histamine receptors in rabbit aorta is distinct from that in basilar artery. Furthermore diltiazem seems not to interact with histamine receptors in both vascular tissues.

Receptor reserve at striatal dopamine autoreceptors: Implications for selectivity of dopamine agonists

The dose response curve for apomorphine reversal of γ-butyrolactone (GBL)-induced L-DOPA accumulation in rat striatum was shifted almost 6-fold to the right after partial irreversible blockade (83%) of dopamine (DA) autoreceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ); however, the maximal response was not reduced. In contrast, the major effect of a similar degree of irreversible blockade (86%) on the dose-response curve for the autoreceptor-selective agent EMD 23,448 was a reduction in maximal response (60% of control), indicating that EMD 23,448 is a partial agonist. A large receptor reserve therefore exists at the DA autoreceptor, which may explain in part why many DA agonists are more potent in models pre- than postsynaptic receptor activation.

Comparison of the effects of arylazido aminopropionyl ATP (ANAPP 3), an ATP antagonist, on responses of the smooth muscle of the guinea-pig vas deferens to ATP and related nucleotides

Contractile responses of the smooth muscle of the guinea-pig vas deferens to ATP and related analogs have been suggested previously to involve stimulation of cell-surface P 2-purinergic receptors and obligatory hydrolysis, depending on the concentration and structure of the nucleotide. This hypothesis was further tested by evaluating the antagonistic effect of arylazido aminopropionyl ATP (ANAPP 3), a specific P 2-purinergic receptor antagonist, on concentration-response relationships and on the profiles of individual responses to ATP and analogs containing phosphate-chain, ribose and adenine modifications. The concentration-response curves for ATP, β, γ-methylene ATP (APPCP), β, γ-imido ATP (APPNP) and adenosine 5′-O-(3-thiotriphosphate) (ATPγS) were bimodal and suggested the existence of two receptors, one with high and one with low affinity for adenine nucleotides. The type of antagonism observed was nucleotide-specific, and concentration-response curves were monosigmoidal after ANAPP 3 treatment. For ATP, antagonism was greatest at low concentrations (< 3 × 10 −5 M) and did not affect the maximum response; for APPCP and APPNP, it was greatest at high concentrations (> 3 × 10 −5 M) and resulted in a reduction in maximum response; for adenosine tetraphosphate (APPPP) the antagonism was pronounced at low and high concentrations; for ATPγS the antagonism was moderate at all concentrations. The concentration-response curves for a second group of less potent nucleotides was monosigmoidal. Included in this group was ADP, α, β-methylene ADP (APCP), 8-bromo ATP (8-BrATP) and 2-deoxy ATP (2d-ATP). Treatment with ANAPP 3 shifted the concentration-response curves for these analogs to the right but did not reduce maximum responses. The characteristics of individual response profiles were structurally related. For most analogs responses to low concentrations of nucleotides were phasic and spike-like. Discernible tonic phases appeared with higher concentrations of ATP, ADP, ATPγS, APPPP and 2d-ATP. ANAPP 3 antagonized the initial component of responses but did not affect the tonic phase. The initial phasic component of response has been related to receptor-mediated stimulation of the preparations, while the tonic component, characteristic of nucleotides without 5′-anhydride bridge substitutions, appears to be initiated by hydrolysis of the compounds, a process which is insensitive to ANAPP 3.

Effect of Diazoxide on Aortic Reactivity to Calcium in Spontaneously Hypertensive Rats

Diazoxide (10−4M) reduced the maximum response to noradrenaline of aortic strips from normotensive and spontaneously hypertensive rats (S.H.R.). The extent of this inhibition was the same for aortae from both types of rat and was greater than the depression of maximum response to KCl. The percent reduction of maximum response to noradrenaline after exposure of aortae to calcium-free solution for various times was the same for tissues from normotensive and hypertensive rats. When calcium was added to calcium-free solution containing either noradrenaline or KCl, a greater inhibition of contraction of aortae from S.H.R. than from normotensive rats was produced by diazoxide. Under the special conditions of the latter experiments, these results are consistent with the hypothesis that vascular smooth muscle of normotensive and S.H.R. differ in their reaction with diazoxide, and that this agent could exert its antihypertensive effect at a site that is not specifically related to adrenergic α-receptors.