An orally effective, nonpeptide, vasopressin V1 receptor antagonist, OPC-21268, has been identified. This compound selectively antagonized binding to the V1 subtype of the vasopressin receptor in a competitive manner. In vivo, the compound acted as a specific antagonist of arginine vasopressin (AVP)-induced vasoconstriction. After oral administration in conscious rats, the compound also antagonized pressor responses to AVP. OPC-21268 can be used to study the physiological role of AVP and may be therapeutically useful in the treatment of hypertension and congestive heart failure.

https://science.sciencemag.org/content/sci/252/5005/572.full.pdf

OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist

1. The pharmacological profile of valsartan, (S)-N-valeryl-N-([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl)-vali ne, a potent, highly selective, and orally active antagonist at the angiotensin II (AII) AT1-receptor, was studied in vitro and in vivo. 2. Valsartan competed with [125I]-AII at its specific binding sites in rat aortic smooth muscle cell membranes (AT1-receptor subtype) with a Ki of 2.38 nM, but was about 30,000 times less active in human myometrial membranes (AT2-receptor subtype). 3. In rabbit aortic rings incubated for 5 min with valsartan, at concentrations of 2, 20 and 200 nM, the concentration-response curve of AII was displaced to the right and the maximum response was reduced by 33%, 36% and 40%, respectively. Prolongation of the incubation time with valsartan to 1 h or 3 h, further reduced the maximum response by 48% or 59% (after 20 nM) and by 59% or 60% (after 200 nM) respectively. After 3 h incubation an apparent pKb value of 9.26 was calculated. Contractions induced by noradrenaline, 5-hydroxytryptamine, or potassium chloride were not affected by valsartan. No agonistic effects were observed in the rabbit aorta at concentrations of valsartan up to 2 microM. 4. In bovine adrenal glomerulosa, valsartan inhibited AII-stimulated aldosterone release without affecting the maximum response (pA2 8.4). 5. In the pithed rat, oral administration of valsartan (10 mg kg-1) shifted the AII-induced pressor response curves to the right, without affecting responses induced by the electrical stimulation of the sympathetic outflow or by noradrenaline. Animals treated with valsartan 24 h before pithing also showed significant inhibition of the response to AII. 6. In conscious, two-kidney, one-clip renal hypertensive rats (2K1C), valsartan decreased blood pressure in a dose-dependent manner after single i.v. or oral administration. The respective ED30 values were 0.06 mg kg-1 (i.v.) and 1.4 mg kg-1 (p.o.). The antihypertensive effect lasted for at least 24 h after either route of administration. After repeated oral administration for 4 days (3 and 10 mg kg-1 daily), in 2K1C renal hypertensive rats, systolic blood pressure was consistently decreased, but heart rate was not significantly affected. 7. In conscious, normotensive, sodium-depleted marmosets, valsartan decreased mean arterial pressure, measured by telemetry, after oral doses of 1-30 mg kg-1. The hypotensive effect persisted up to 12 h after 3 and 10 mg kg-1 and up to 24 h after 30 mg kg-1. 8. In sodium-depleted marmosets, the hypotensive effect of valsartan lasted longer than that of losartan(DuP 753). In renal hypertensive rats, both agents had a similar duration (24 h), but a different onset of action (valsartan at 1 h, losartan between 2 h and 24 h).9. These results demonstrate that valsartan is a potent, specific, highly selective antagonist of AII at theAT1-receptor subtype and does not possess agonistic activity. Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats and in conscious normotensive,sodium-depleted primates.

Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype.

1. A simple method of stimulating different segments of the autonomic outflow from the spinal column in the pithed cat and rat is described.2. Using a movable Teflon-shielded electrode inserted into the vertebral canal and an indifferent electrode under the skin, reproducible responses were obtained from the adrenals, the bladder, the blood vessels, the colon, the heart and the vas deferens. The level and number of segments stimulated was altered by varying the depth of insertion of the Teflon tube and the length of central steel electrode protruding from it.3. The degree of localization of the stimulus seemed satisfactory since it was possible by stimulating the sacral parasympathetic outflow to the bladder and colon or the lumbar sympathetic outflow to the vas deferens, to elicit responses from these organs with little effect on the cardiovascular system. Stimulation at higher levels of the thoracic sympathetic outflow permitted discrimination between the pressor and cardio-accelerator responses.4. Hexamethonium (1 mg/kg) inhibited all the responses, but the colonic response, which occurred only after a latent period, was especially sensitive to ganglion blockade. Atropine (1 mg/kg) inhibited the bladder response by 50% but only prolonged the latency of the colonic response without affecting its magnitude. Physostigmine (1 mg/kg) enhanced the bladder and colonic responses and reversed the effects of hexamethonium on these organs. Phentolamine (1 mg/kg) abolished the pressor responses to stimulation of the thoracolumbar sympathetic outflow but did not affect the cardio-accelerator response.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1970.tb09919.x

A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat

Cardiocytes in the atria contain a prohormone that gives rise to atrial natriuretic peptides (ANP's), which have intrinsic hemodynamic regulatory activity. The distribution of ANP's in the brain suggests the involvement of these peptides in central cardiovascular regulation. In conscious rats with chronic indwelling catheters, volume loading with isotonic saline or glucose increased the amount of circulating immunoreactive ANP's by a factor of 4 to 5, as determined by radioimmunoassay. Hyperosmotic challenge with a hypertonic NaCl solution or anesthesia with halothane caused similar increases in plasma ANP's. Results obtained with the denervated-heart preparation indicate that neuronal influences are important in the release of ANP's induced by volume loading. As judged from reversed-phase high-performance liquid chromatography of extracted plasma and radioimmunoassay of collected fractions, the circulating physiologically important ANP's in the conscious rodent appear to be alpha-rANP(5-28) (atriopeptin III) and either alpha-rANP(3-28) [ANF(8-33)] or alpha-rANP(1-28) (ANF).

Circulating atrial natriuretic peptides in conscious rats: regulation of release by multiple factors.

The sections in this article are:


1
Morphology of Adrenergic Innervation

2
Adrenergic Transmission: Presynaptic and Synaptic Events
2.1
Transmitter Synthesis, Storage, and Release

2.2
Mode of Transmitter Release

2.3
Feedback Control of Transmitter Release

2.4
Transmitter Distribution and Movement

2.5
Transmitter Concentrations During Neural Activity

2.6
Transmitter Disposition and Termination of Its Effect




3
Adrenergic Transmission: Postsynaptic Events
3.1
Receptor Analysis and Variation

3.2
Bimodal Transmitter Action

3.3
Contractile Properties of Endothelium




4
Functional Consequences of Variation in Vascular Neuroeffector Apparatus
4.1
Synaptic Cleft Width

4.2
Innervation Density

4.3
Innervation Distribution




5
Functional Description of Specific Vessels

6
Adrenergic Neuron in Hypertension
6.1
Changes in Presynaptic Mechanisms

6.2
Neurogenic Transmission and Postsynaptic Function

6.3
Distribution of Adrenergic Transmitter in Hypertensive Arteries

6.4
Plasma Norepinephrine and Dopamine β-Hydroxylase Levels

6.5
Interpretation of Changes in Adrenergic Mechanisms




7
Development of Adrenergic Control: Trophic Regulation
7.1
Ontogenetic Development of Innervation of Blood Vessels

7.2
Specificity of Adrenergic Innervation of Blood Vessels

7.3
Smooth Muscle Specificity for Nerve

7.4
Interactions of Nerve and Smooth Muscle

7.5
Influence of Adrenergic Nerves on Smooth Muscle

7.6
Influence of Smooth Muscle on Adrenergic Nerves

7.7
Factors Influencing Development and Maturation of Peripheral Sympathetic Nerve Terminals

7.8
Regulation of Sympathetic Function in Adults

7.9
Morphological and Functional Plasticity of Adrenergic Neurons

Adrenergic Regulation of Vascular Smooth Muscle

/pdf/a-method-of-stimulating-the-complete-sympathetic-outflow-40s4xylroo.pdf

T. C. Muir

Papers

A method of stimulating the complete sympathetic outflow from the spinal cord to blood vessels in the pithed rat