J. O. Streefkerk

Vasopressin-induced presynaptic facilitation of sympathetic neurotransmission in the pithed rat.

Objective Several studies have shown that arginine vasopressin (AVP) potentiates the sympathetic nervous transmission in isolated vessels. The present study investigates such a potentiation in the pithed rat model. Methods Male Wistar rats weighing 270–310 g were used. Spinal-cord stimulation was applied, with frequencies of 0.25–4 Hz, in the presence or absence of a subpressor dose of intravenous (i.v.) AVP (1 pmol/kg per min). In addition, the effect of AVP on postsynaptic α-adrenoceptor-mediated responses was studied using exogenously administered noradrenaline (NA). For this purpose dose–response curves (DRCs) for NA (i.v.) were constructed. Results In the pithed rat model endogenously generated angiotensin II facilitates neurally mediated increments in vascular resistance. Without the administration of the angiotensin II type 1 (AT1) antagonist, irbesartan, the facilitating effect of AVP was not visible. However, after the administration of the AT1 antagonist, irbesartan, the facilitating effect of AVP became apparent. The stimulation-induced rise in diastolic blood pressure (DBP) was enhanced in the presence of AVP from 63.7 ± 4.5 to 78.6 ± 4.2 mmHg, at a stimulation frequency of 4 Hz. The vasopressin receptor V1 antagonist, SR-49059, completely inhibited this AVP-induced facilitation, whereas the V2 antagonist, SR-121463B, or the V2 agonist, desmopressin, did not. The DRC of exogenously administered NA was not influenced by AVP. Conclusion The stimulating effect of AVP on sympathetic neurotransmission is completely dependent on the stimulation of presynaptically located V1 receptors. The facilitating effect of angiotensin II on the sympathetic nervous system (SNS) in the pithed rat model masks the facilitating effect of AVP in this preparation.

Influence of the nature of pre-contraction on the responses to commonly employed vasodilator agents in rat-isolated aortic rings.

The relaxing properties of vasodilator drugs in vitro may depend on the characteristics of the contractile state of the vessel investigated.

Endothelium-dependent, vasopressin-induced contractions in rabbit renal arteries.

Objectives To identify and quantify the stimulatory and inhibitory activity of endothelial factors on Arginine vasopressin (AVP)-induced contractions. Methods In a standard organ bath set-up for isometric force recording, rabbit isolated renal artery rings were exposed to cumulative concentrations of AVP. Experiments were performed in the presence or absence of functional endothelium, or in the presence of N-Nitro-L-Arginine 10 &mgr;M (L-NNA) (NO-synthase inhibitor). Results Arginine vasopressin induced a maximal contractile response of 6.5 ± 0.1 mN in vessels with and 6.3 ± 0.3 mN in vessels without endothelium. The preincubation with l-NNA resulted in an enhanced response to AVP of 12.6 ± 0.8 mN (P < 0.05). The augmentation of the AVP induced contractile response by NOS inhibition, which was not seen in preparations after the removal of the endothelium, suggests an endothelium dependent factor that is co-released with NO. The unknown nature of this endothelium dependent contractile factor was not influenced by indomethacin 100 &mgr;M (cyclooxygenase inhibitor), meclofenamic acid 20 &mgr;M (cyclooxygenase and lipoxygenase inhibitor), or bosentan 100 &mgr;M (endothelin antagonist). Charybdotoxin 0.1 &mgr;M (inhibitor of Ca2+ -activated K+ channels) specifically increased the contractile force in preparations with and without endothelium, or in the presence of l-NNA to 11.2 ± 0.4 mN, 14.0 ± 0.8 mN, and 19.0 ± 0.8 mN, respectively (P < 0.05 compared with the experiments without charybdotoxin). SR 49059 (vasopressin 1 receptor (V1) antagonist) antagonized the effects of AVP, whereas SR 121463 B (V2 antagonist) was ineffective. In contrast to the results obtained with AVP, desmopressin (V2 agonist) showed no effect. Conclusion The completely V1 dependent AVP-induced contraction is partly inhibited by the stimulated release of NO. This was only demonstrable in endothelium intact vessels in the presence of l-NNA and not after removal of the endothelium. This strongly suggests the involvement of an unknown endothelium V1 receptor dependent contractile factor that is not influenced by inhibition of the prostaglandin, lipoxygenase, or endothelin pathway, or by blockade of the V2 receptor.

Vasopressin-induced vasoconstriction is dependent on MAPKerk1/2 phosphorylation.

To investigate the involvement of the mitogen‐activated protein kinase (MAPK) family of extracellular signal‐regulated kinase (ERK) 1 and 2 (MAPKerk1/2) in the vasopressin‐mediated vasoconstriction in the rat aorta. Vasopressin‐induced vasoconstriction was measured in isolated rat thoracic aortae in the presence or absence of MAPKerk1/2 kinase (MKKmek1/2) inhibitors. Thereafter the MAPKerk1/2 phosphorylation in the rat aorta was quantified using Western blot analysis. Vasopressin (1–300 nm) induced a concentration‐dependent vasoconstriction, which could be inhibited concentration dependently by the selective MKKmek1/2 inhibitors, PD 98059 (10 and 100 μm) and U 0126 (10 and 100 μm). Western blot analysis revealed a 2.7 ± 0.6‐fold increase in the MAPKerk1/2 phosphorylation induced by vasopressin (300 nm). This phosphorylation could be dose dependently prevented by both PD 98059 (100 μm) and U 0126 (10 and 100 μm). These results indicate that vasoconstriction induced by vasopressin is partly regulated by the MAPKerk1/2 pathway.

Vasopressin facilitates presynaptic sympathetic nerve activity in humans.

Objective It was the objective of this study to investigate whether a facilitatory role of vasopressin (AVP) on sympathetic nerve activity can be demonstrated in humans at the peripheral level. Methods Eight subjects (32 ± 2.3 years) participated in this study. Forearm blood flow (FABF) was measured using the venous occlusion plethysmography model. Each session was performed in the presence of a continuous infusion (into the brachial artery) of AVP in sub-pressor dosage of 0.008 ng/kg per min, or NaCl 0.9%. Using lower-body negative pressure (LBNP) (−10, −20 and −30 mmHg) the combined pre- and postsynaptic action of AVP on the sympathetic nervous system was investigated. This was followed by a second protocol in which the possible postsynaptic effects of AVP were evaluated with intra-arterial infused norepinephrine (NE). Results The baseline FABF was 5.2 ± 0.6 ml/100 ml per min. After infusion of AVP (0.008 ng/kg per min), the FABF remained unchanged at a flow of 5.5 ± 0.6 ml/100 ml per min (P = 0.26). LBNP caused a pressure-dependent decrease in FABF (25.6 ± 4.4, 29.0 ± 6.1 and 38.6 ± 6.9%, for −10, −20 and −30 mmHg, respectively). AVP significantly enhanced the FABF responses to lower-body negative pressures (38.0 ± 8.6, 49.3 ± 5.1 and 58.9 ± 6.3%, respectively (P = 0.014). NE caused a dose-dependent vasoconstriction by 3.1 ± 4.6, 17.0 ± 4.3 and 23.2 ± 4.9%, at dosages of 10, 20 and 40 pg/min, respectively, unaffected by AVP (P = 0.91). Conclusions We conclude that AVP can facilitate vasoconstriction mediated by the peripheral sympathetic nervous system at the presynaptic level in humans.