sr-142801 and phosphoramidon

1. This study was designed to investigate the mechanisms for the contractions induced by tachykinins (substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)) in the rabbit corpus cavernosum strips, using fura-PE3 fluorimetry and alpha-toxin permeabilization. 2. Tachykinins induced contractions in the rabbit corpus cavernosum in a concentration-dependent manner. The potency order was SP>NKA>NKB. 3. The tachykinin-induced contractions were enhanced by phosphoramidon (PPAD), an endopeptidase inhibitor, but not by N(omega)-nitro-L-arginine methylester (L-NAME). 4. The NK(1) receptor selective antagonist, SR 140333 significantly inhibited the tachykinin-induced contractions. Although the NK(2) receptor selective antagonist, SR 48968 alone did not influence the effects of tachykinins, it potentiated the inhibitory effect of SR 140333. The NK(3) receptor selective antagonist, SR142801 had no effect. 5. In the rabbit corpus cavernosum, tachykinins induced sustained increases in [Ca(2+)](i) and tension in normal PSS, while only small transient increases in [Ca(2+)](i) and tension were observed in Ca(2+)-free solution. 6. In alpha-toxin permeabilized preparations, tachykinins induced an additional force development at a constant [Ca(2+)](i). 7. These results indicated that in the rabbit corpus cavernosum: (1) Tachykinins induced contractions by increasing both the [Ca(2+)](i) and myofilament Ca(2+) sensitivity; (2) The tachykinin-induced [Ca(2+)](i) elevations were mainly due to the Ca(2+) influx; (3) Tachykinin-induced contractions were mainly mediated through the activation of NK(1) receptor expressed in the rabbit corpus cavernosum smooth muscle, and affected by the endopeptidase activity and (4) Tachykinins may thus play a role in controlling the corpus cavernosum tone.

Topics: Animals; Benzamides; Calcium; Dose-Response Relationship, Drug; Glycopeptides; In Vitro Techniques; Male; Muscle Contraction; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; NG-Nitroarginine Methyl Ester; Penis; Permeability; Piperidines; Quinuclidines; Rabbits; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Substance P; Tachykinins; Type C Phospholipases

We identified the predominance of neurokinin-2 receptors and evaluated the inhibition of spontaneous contraction via the blockade of neurokinin-2 receptors in human ureteral segments.. Excess ureteral segments from human subjects undergoing donor nephrectomy or reconstructive procedures were suspended in tissue baths containing Krebs buffer. After spontaneous contractions were recorded, tissues were incubated with 1 microM. solutions of phosphoramidon and captopril (to inhibit peptide degradation) and either the neurokinin-1 receptor antagonist CP 99,994, the neurokinin-2 receptor antagonist SR 48,968, the neurokinin-3 receptor antagonist SR 142,801 or dimethyl sulfoxide (control) for 1 hour. Contraction magnitude and frequency were again recorded and compared with spontaneous levels. Concentration-response curves to the tachykinins substance P, and neurokinins A and B were determined in the presence and absence of antagonists.. Neurokinin A increased contractility at lower concentrations than substance P or neurokinin B (p <0.013). Neurokinin-2 receptor blockade produced a 100-fold rightward shift of the concentration-response curves (p <0.013), while neurokinins 1 and 3 receptor blockade had no effect. SR 48,968 significantly reduced contractility during the 1-hour incubation period, causing a 97% reduction in spontaneous rates compared with a 29% reduction in control tissues. CP 99,994 and SR 142,801 had no significant effect.. Neurokinin-2 is the predominant receptor subtype responsible for tachykinin induced contraction of human ureteral smooth muscle. In vitro treatment with the neurokinin-2 antagonist SR 48,968 reduces the spontaneous contraction rate by 97% in vitro. Neurokinin-2 receptor antagonists may have clinical applications for ureteral disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzamides; Captopril; Dose-Response Relationship, Drug; Glycopeptides; Humans; Metalloendopeptidases; Muscle Contraction; Piperidines; Receptors, Neurokinin-2; Tachykinins; Ureter