Vasoconstrictor activity

Sympathetic nerves are distributed to most vascular beds. They are most abundant in the renal, gastrointestinal, splenic, and cutaneous circulations. Recall that these tissues receive an abundant blood flow, more than is necessary simply to maintain metabolism. Therefore, when blood is needed by other parts of the body, such as working skeletal muscles, sympathetic vasoconstrictor activity reduces flow to the tissues receiving excess blood so that it may be redirected to the muscles. Interestingly, there is no sympathetic innervation to cerebral blood vessels. In fact, these vessels do not have a.j-adrenergic receptors, so they cannot be affected by circulating catecholamines. No physiological circumstance exists in which blood should be directed away from the brain. 

Baroreceptors. Partial depolarization of baroreceptors enables activation of the reflex to occur at a relatively smaller rise in blood pressure, leading to decreased sympathetic vasoconstrictor activity. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

D. Epinephrine is by far the most commonly employed vasoconstrictor. Phenylephrine is occasionally used with procaine for dental procedures. Levonordefrin is also used rarely in dental procedures. Dopamine has no vasoconstrictor activity. Cocaine is itself a local anesthetic with some vasoconstrictor properties. However, cocaine, because of its abuse potential and toxicity, is seldom used. Its only use is topical. 

This reaction is catalysed by enzyme methyl-transferases (catechol-o-methyl-transferase) and generally uses S-adenosylmethionine as a methyl donor. Examples are conversion of norepi-nephrine into normetanephrine, which has less than one percent of the vasoconstrictor activity of the parent compound. 

The endothelium is the source of a variety of substances with vasodilator (PGI2 and nitric oxide) and vasoconstrictor activities. The latter include the endothelin family, potent vasoconstrictor peptides that were first isolated from aortic endothelial cells. 

One of the earliest comparisons of thiophene to benzene in a biological system compared the vasoconstrictor activity of phenylethylamine (362 Ar = Ph) with that of 2-thienyIethyl-amine (362 Ar = 2-thienyl). It was shown to have vasopressor activity in the cat, but was only about one-tenth as potent. Phenylalanine is an essential amino acid for the growth of yeast, bacteria and mammals. It was found that /3-2-thienylalanine (363 Ar = 2-thienyl) was an antimetabolite of this essential amino acid, and numerous studies on the active L-form and simple peptides derived from it have been made. 

It has also been suggested that terlipressin has vasoconstrictor activity within the splanchnic vascular territory (21). Hypotension developed under general anesthesia in 32 patients undergoing carotid endarterectomy treated with renin-angiotensin inhibitors (22). They were randomized to received terlipressin 1 mg (n = 16) or noradrenaline infusion. Compared with baseline those who received terlipressin had reduced gastric mucosal perfusion for at least 4 hours. There was also reduced oxygen delivery and oxygen consumption index at 30 minutes and 4 hours in those who received terlipressin. 

The ergotoxine alkaloid mixture also has oxytocic and vasoconstrictor activity but is only employed medicinally as the 9,10-dihydro derivatives dihydroergotoxine (co-dergocrine), a mixture in equal proportions of dihydroergocornine, dihydroergocristine, and the dihydroergocryptines (a- and p- in the ratio 2 1). In the case of these alkaloids, reduction of the double bond appears to reverse the vasoconstrictor effect, and dihydroergotoxine has a cerebral vasodilator activity. The increased blood flow is of benefit in some cases of senility and mild dementia, and helps to improve both mental function and physical performance. 

Eieberthal W, Vogel WM,ApsteinCS, Valeri CR Studiesofthe mechanism ofthe vasoconstrictor activity of stroma-free hemoglobin in the isolated perfused rat kidney and rabbit heart. Prog Clin Biol Res 319 407-20,1989... 

Felypressin. Felypressin. 2-L-phenylalunine-il-t.-lysine vasopressin, has relatively low antidiuretic activity and little oxytocic activity. It has considerable pressor (i.c., vasoconstrictor) activity, which differs from that of epinephrine (i.e., following capillary con.striclion in the intestine it lowers the pressure in the vena portae, whereas epinephrine rai.ses the portal pre.ssiire). Felypressin al.so cau.ses increased renal blood flow in the cal. whereas epinephrine brings about a fall In renal bltxal How. Felypressin is 5 time.s more effective as a va.sopre.ssor than is lysine vasopressin and is recommended in surgery to minimi/.e blood How, especially in obstetrics and gynecology. 

Bova S, Cima L, Golovina V, Luciani S, and Cargnelli G (2001) Norbormide A calcium entry blocker with selective vasoconstrictor activity in rat peripheral arteries. Cardiovascular Drug Reviews 19(3) 226-233. 

The ACE catalyses two reactions which are supposed to play an important role in the regulation of the arterial pressure (1) conversion of angiotensin 1, which is an inactive decapeptide, into angiotensin II, an octapeptide with a very potent vasoconstrictor activity and (2) inactivation of the nonapeptide, bradykinin, which is a potent vasodilator (Figure 6.20). 

NSAIDs have an overall favorable safety profile resulting in OTC availability in the United States of ibuprofen, naproxen, and keto-profen for short-term therapy. WWle potential adverse renal effects from OTC NSAIDs have been a concern, activity of vasodilatory prostaglandins is not necessary to maintain renal function in healthy individuals. NSAIDs are unlikely to impair renal function in the absence of renal ischemia or excess renal vasoconstrictor activity. Nevertheless, given the fact that 50 million U.S. citizens report NSAID use, it has been estimated that 500,000 to 2.5 million people will develop NSAID nephrotoxicity in this country annually. ... 

Interestingly, 1,4-dihydropyridines, such as Bay K 8644 (2.13), CGP 28392 (2.14) and YC-170 (2.15), have been discovered which show calcium agonist effects. For instance, these compounds demonstrate positive cardiac inotropic and vasoconstrictor activities [81]. Bay K8644 increases twitch tension in guinea-pig atria in a frequency-dependent manner and prolongs action poten-... 

The vasoconstrictor action of shed blood tested by perfusion of the rabbit ear is markedly decreased by heparin and this was known long before the identification of the vasoconstrictor activity as serotonin (5-hydroxytryp-tamine). Heparin inhibits the release of both 5-hydroxytryptamine and a polypeptide from platelets into plasma, and in vitro there is mutual antagonism between heparin and 5-hydroxytryptamine . Heparin effectively antagonizes the effect of serotonin on pulmonary vascular bed and bronchial wall musculature and prevents the symptoms of 5-HT release in pulmonary embolism, in the cardiopulmonary by-pass, in experimental burn injuries and in carcinoid tumour. 

Because of its rapid vasoconstrictor activity, the drug produces a marked reflex bradycardia, due to stimulation of vagal reflexes. The increase in vagal tone increases the threshold for firing of the sinoatrial (SA) node and atrial tissue, resulting in a slower rate of firing and atrial conduction. 

Increasing Vj selectivity has been more difficult than increasing selectivity. Vasopressin receptors in the adenohypophysis that mediate vasopressin-induced ACTH release are neither classical Vj nor Vj receptors. Since the vasopressin receptors in the adenohypophysis appear to share a common signal-transduction mechanism with classical Vj receptors, and since many vasopressin analogs with vasoconstrictor activity release ACTH, Vj receptors have been subclassified into Vj (vascular/hepatic) and Vjj (pituitary) receptors. Vjj receptors also are called Vj receptors. Vasopressin analogs that are selective agonists for Vj and Vjj receptors have been synthesized but are not available clinically. 

Cocaine is the only local anesthetic with intrinsic vasoconstrictor activity. It also has significant surface activity and is favored for head, neck, and pharyngeal surgery. Cocaine is an ester. The answer is (C). 

An investigation of the vasoconstrictor activity of substituted imidazolines by Fritz Uhlmann at Ciba in Basle, Switzerland during the early 1940 s resulted in the introduction of the sympathomimetic drug, naphazoline its analogs, xylometazoline and oxymetazoline, used as decongestants and... 

Aiken, J.W. and Vane, J.R. (1973). Intrarenal prostaglandin release attenuates the renal vasoconstrictor activity of angiotensin. ]. Pharmacol Exp. Ther., 184, 67S-6S7... 

In isolated perfused kidney and in pressurized renal microvessels, treatment with an aqueous yohimbe extract demonstrated dose-dependent vasoconstrictor activity. Endothelin A (ETA) and B (ETB) receptor antagonists separately and significantly attenuated the renal vasoconstrictor actions of the extract (Ajayi et al. 2003). 

Fig. 2. Interplay among superoxide anion, nitric oxide, and eicosanoids in high oxidative stress. The biological function of nitric oxide in target cells is influenced by the cellular redox state. In increased oxidative stress, which results in an oxidizing environment, NO readily form free radicals, including the highly reactive peroxynitrite (OONO ). Peroxynitrite can influence eicosanoid synthesis by interfering with different enzyme systems of the arachidonic acid cascade. Increased free radicals may also catalyze nonenzymic peroxidation of membrane PUFA (e.g., arachidonic acid), resulting in increased production of isoprostanes that possess potent vasoconstrictor activity. PLA, phospholipase NO, nitric oxide NOS, nitric oxide synthase NADPH oxidase, vascular NAD(P)H oxidase 02 , superoxide anion PUFA, polyunsaturated fatty acids EPA, eicosapentaenoic acid DHA, docosahexaenoic acid COX, cyclooxygenase PGI2 synthase, prostacyclin synthase.

Rubanyl, G. M., Frye, R. L., Holmes, D. R., Jr., and Vanhoutte, P. M. (1987). Vasoconstrictor activity of coronary sinus plasma from patients with coronary artery disease. J. Am. Coll Cardiol 9, 1243-1249. 

Barry BW, Woodford R (1977) Vasoconstrictor activities and bioavailabilities of seven proprietary corticosteroid creams assessed using a non-occluded multiple dosage regimen clinical considerations. Br J Dermatol 97 555-560... 

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