The aim of our study was to characterize the tachykinin receptor population in the oestrogen‐primed rat uterus. For this purpose, we investigated the receptor type(s) responsible for tachykinin‐induced contraction of longitudinally‐arranged smooth muscle layer. The effects of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and several of their analogues with well‐defined selectivities for tachykinin NK1, NK2 and NK3 receptors were studied and their inhibition by the selective nonpeptide tachykinin receptor antagonists (S)1‐(2‐[3‐(3,4‐dichlorophenyl)‐1‐(3‐isopropoxyphenylacetyl)piperidin‐3‐yl]ethyl)‐4‐phenyl‐1‐azoniabicyclo[2.2.2]octane chloride (SR 140333, NK1‐selective), (S)‐N‐methyl‐N[4‐(4‐acetylamino‐4‐phenylpiperidino)‐2‐(3,4‐dichlorophenyl)butyl]benzamide (SR 48968, NK2‐selective) and (R)‐(N)‐(1‐(3‐(1‐benzoyl‐3‐(3,4‐dichlorophenyl)piperidin‐3‐yl)propyl)‐ 4‐phenylpiperidin‐ 4‐yl)‐N‐ methylacetamide (SR 142801, NK3‐selective) was evaluated. Additionally, expression of tachykinin receptor mRNA was examined by using the reverse transcription‐polymerase chain reaction (RT‐PCR). SP, NKA, [Nle10]‐NKA(4‐10), the analogue with selectivity at the tachykinin NK2 receptor type, and NKB elicited concentration‐dependent contractions of the rat uterus. The pD2 values were 5.95±0.19; 6.73±0.21; 7.53±0.12 and 5.76±0.21, respectively. The selective agonist for the tachykinin NK1 receptor [Sar9Met(O2)11]‐SP produced a small phasic response in the nanomolar concentration range. The selective tachykinin NK3 receptor agonist [MePhe7]‐NKB failed to induce any significant contraction. In the presence of the neutral endopeptidase inhibitor phosphoramidon (1 μM), the log concentration‐response curves to exogenous tachykinins and their analogues were shifted significantly leftwards. The pD2 values were 6.12±0.10, 8.04±0.07, 7.89±0.03 and 6.59±0.07 for SP, NKA, [Nle10]‐NKA(4‐10) and NKB, respectively. In the presence of phosphoramidon (1 μM), [Sar9Met(O2)11]‐SP (1 nM–0.3 μM) induced concentration‐dependent contractions of increasing amplitude when only one concentration of drug was applied to each uterine strip and the pD2 value was 7.61±0.89. [MePhe7]‐NKB induced small, inconsistent contractions and, therefore, a pD2 value could not be calculated. In experiments performed in the presence of phosphoramidon (1 μM), SR 48968 (3 nM–0.1 μM) caused parallel and rightward shifts in the log concentration‐response curves of NKA. The calculated pKB value was 9.16±0.08 and the slope of the Schild regression was 1.28±0.24. SR 48968 (0.1 μM) also antagonized responses to SP with an apparent pKB value of 7.63±0.13. SR 48968 (0.1 μM) inhibited contractions elicited by NKB (1 nM–3 μM) and [Nle10]‐NKA(4–10) (0.1 nM–3 μM) but had no effect on the response evoked by [Sar9Met(O2)11]‐SP (0.1 μM). SR 140333 (0.1 μM) inhibited responses to SP with an apparent pKB value of 7.19±0.22. This compound did not significantly affect responses to NKA, [Nle10]‐NKA(4‐10) and NKB, but suppressed [Sar9Met(O2)11]‐SP (0.1 μM)‐induced contraction. SR 142801 (0.1...

In the mammalian female reproductive tract, tachykinin neuropeptides, such as substance P (SP), are localized to a population of sensory fibers and their precise physiological role is still unknown. The aim of the present study was to characterize the population of tachykinin receptors in the pregnant rat uterus and to assess their regulation during the course of pregnancy and after delivery. The expression of the tachykinin NK(1) receptor (NK(1)R), the tachykinin NK(2) receptor (NK(2)R), and the tachykinin NK(3) receptor (NK(3)R) in uteri from rats at different stages of pregnancy and on Day 1 postpartum was investigated by using a semiquantitative reverse transcription-polymerase chain reaction. The contractile effect of tachykinin receptor agonists acting selectively on the NK(1)R, the NK(2)R, or the NK(3)R was investigated by conventional organ bath techniques. Serum levels of estrogen and progesterone were measured by RIA. Our data show that the expression and function of NK(1)R and NK(3)R varied along the course of pregnancy and at postpartum. Uterine NK(2)R mRNA levels remain stable during the course of pregnancy and at Day 1 postpartum; and the contractions elicited by activating selectively the NK(2) receptor in the presence of the neutral endopeptidase inhibitor phosphoramidon (1 microM) were similar in early, mid, or late pregnancy. These results show that the expression and function of tachykinin receptors within the uterus vary with reproductive state and length of gestation, supporting a role for tachykinins in pregnancy and/or parturition in the rat.

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Background: Apparent resistant hypertension (aRH) carries excess cardiovascular risk beyond nonresistant forms of hypertension; however, our understanding of this at-risk population, as defined by current US practice guidelines, is limited. Accordingly, we sought to evaluate the prevalence, clinical characteristics, and pharmacotherapeutic patterns of patients with aRH using contemporary blood pressure guidance. Methods: We classified patients at 3 large healthcare systems by hypertensive status using contemporary hypertension guidelines. We subsequently described the demographic and clinical characteristics of patients with aRH and compared these factors among hypertensive patients without aRH and between those with controlled and uncontrolled aRH. Results: A total of 2 420 468 patients were analyzed, of whom 1 343 489 (55.6%) were hypertensive according to contemporary guidelines. Among hypertensive patients, 11 992 (8.5%) met criteria for aRH, with nearly all assessed comorbid conditions, particularly diabetes and heart failure, being more common in those with aRH. When compared with patients with uncontrolled aRH, those with controlled aRH were more frequently prescribed a beta-blocker, diuretic, and nitrate, with the largest standardized difference observed for a mineralocorticoid receptor antagonist (35.4% versus 10.4%, Cohen D 0.62). Consistent findings were noted in sensitivity analyses using the blood pressure threshold of 140/90 mm Hg. Conclusions: In an analysis of over 2.4 million individuals, a lower prevalence of aRH was observed than previously reported (12%–15%), but with a high burden of comorbidities. Identification of differences in pharmacotherapy between patients with controlled and uncontrolled aRH, particularly lower rates of mineralocorticoid receptor antagonist use, help define potential opportunities to improve care and lower cardiovascular risk.