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Mechanisms of action for estrogen in cardioprotection
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
Another mode of regulation of estrogen. related changes in heart rate is modulation of cardiac autonomic mechanisms. A number of studies described that estrogens modulate the effects of adrenergic and cholinergic agents on coronary vascular reactivityw106,107 However, only a few studies looked into effects in cardiac cells. Klangkalya and Chan110 studied regulation by sex hormones of expression and binding affinities of β-adrenergic and cholinergic receptors in hearts of female rats in vivo. Estrogen or progesterone alone had no significant effect on the binding affinities of [3H]dihydroalprenolol (β-adrenergic agonist) and [3H)quinuclidinyl (muscarinic agonist). Treatment with estrogen increased the density of β-adrenergic receptors in the heart while progesterone had no effect. Combined estrogen plus progesterone treatment increased β- adrenergic receptors by two-fold. Treatment with estrogen or with progesterone alone decreased the density of muscarinic receptors mildly, while combined estrogen plus progesterone treatment increased the density of muscarinic receptors significantly. These results suggest a complex mode of regulation of autonomic receptors in cardiac cells by the sex hormones in the rat.
Effects of Calcium Channel Antagonists on The Myometrium
Published in Gabor Huszar, The Physiology and Biochemistry of the Uterus in Pregnancy and Labor, 2020
Ronald A. Janis, David J. Triggle
The binding characteristics of [3H]nitrendipine and [3H]nimodipine in uterine membranes, reported to date, appear to be the same as those of other smooth muscles and similar to those of brain and cardiac membranes. A high affinity binding site is present in rat and rabbit myometrium for which nitrendipine, nicardipine, nisoldipine, and nimodipine exhibit an affinity of 0.1 to 0.8 nM.57,115,118 Neither estrogen treatment of rats nor pregnancy produced a marked change in this affinity.57,116 Similarly, the maximum number of binding sites was not significantly changed with pregnancy between day 1 and term.116 This is in contrast to a large change in the number of OT receptors at term.119,120 Of related interest is the report that [3H]dihydroergocryptine (a-receptor) sites in the rabbit myometrium are reduced during the second week of gestation, but progressively return to a normal level thereafter, and the number of [3H]dihydroalprenolol (β) receptors declines by 55% at the end of gestation; no change in receptor affinity was seen in either case.121 The maximal number of these adrenergic binding sites in rabbit myometrium was 0.7 to 0.9 pmol/mg protein, which is much larger than that for nitrendipine binding sites.116 Thus, the synthesis of Ca2+ channel binding sites does not appear to be linked to those of OT or adrenergic receptors.
Quantitative Changes in Receptor Concentrations as a Function of Disease
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2017
Of the metabolic disorders, hyper- and hypothyroidism are of particular interest because of the cardiovascular abnormalities associated with these disorders. The properties of the three receptors listed above have been determined in the hearts of normal, thyroidectomized (hypothyroid), and T3 (hyperthyroid) treated rats. In the case of the m-AChR, hypothyroidism leads to a 60% increase in receptor concentration as measured by 3H-quinuclidinyl benzilate (3H-QNB, Figure 7) binding while hyperthyroidism (effected by chronic T3 injections) decreased receptor concentrations by a modest 20%.73 These results are paralleled by the alpha-adrenergic receptor in which thyroidectomy increases specific binding of the alpha-adrenergic antagonist 3H-dihydroergocryptine (Figure 7) by 71%.74 The beta-adrenergic receptor contrastingly is decreased in concentration by 50% upon thyroidectomy which chronic T3 injections increases the receptor concentration by 2-fold (100%).75 The concentration of beta-adrenergic receptors was determined by the interaction of the specific antagonist, 3H-dihydroalprenolol (Figure 7). The affinities of each antagonist did not change as a result of hypo- and hyperthyroidism. Influences on the affinities of agonists have not been determined.
Insights into the operational model of agonism of receptor dimers
Published in Expert Opinion on Drug Discovery, 2022
Nowadays, oligomerization of GPCRs is a well-established phenomenon supported especially by fluorescent techniques, like resonance energy transfer, that are effective in visualizing homo- and heterodimers [29]. However, early indications that GPCRs form dimers came from pharmacological experiments. Notably, negative cooperativity in the binding of nonselective antagonists dihydroalprenolol to β2-adrenergic receptors indicated allosterically connected orthosteric binding sites, meaning receptor oligomers as GPCRs possess a single orthosteric site only [30]. Dimerization of β2-adrenergic receptors as well as α1- and α2-adrenergic receptors was then confirmed by immunoaffinity chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis [31–33]. Another pharmacological hint for the existence of dimeric GPCRs was a difference in affinity of both agonists, e.g. synthetic bivalent U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide), pentapeptide [D-Pen2,D-Pen5]enkephalin, and antagonists, e.g. synthetic norbinaltorphimine, pseudo peptide TIPPΨ) between κ-δ heteromers of opioid receptors on the one hand and δ- and κ-homomers on the other hand [34]. The myriad ways in which GPCRs assemble together to form oligomeric complexes may be one of the key features responsible for tissue-specific, cell-specific, GPCR-mediated signaling [35]. Thus, heterodimerization brings not only higher plasticity of functional responses but brings novel therapeutic possibilities. For example, agonists functionally selective for µ-δ heteromers of opioid receptors, like CYM51010 (ethyl 1-[(4-acetamidophenyl)methyl]-4-(2-phenylethyl)piperidine-4-carboxylate), represent a drug class for the treatment of pain with reduced propensity to addiction and abuse [12,36]. Besides naturally occurring dimers of GPCRs, dimerization can be elicited by bivalent ligands possessing 20 to 30 Å long linkers as demonstrated for adrenergic, opioid and dopaminergic receptors [37–39]. These artificial dimers exert altered signaling properties, confirming allosteric modulation between protomers.