Experimental Hypertension

A number of methods have been described for the production of persistent hypertension in animals. Neurogenic hypertension follows the impairment of cerebral blood supply. This can be achieved either through 

In the Goldblatt method hypertension is induced by moderate constriction of both main renal arteries (by adjustable silver clamps) or by the constriction of one main renal artery and extirpation of the contralateral kidney. The Goldblatt procedure is applicable not only to dogs, but also to the monkey, rat, rabbit, goat, and sheep. Historically, it is interesting that Katzenstein (100) in 1905 had already observed a slight temporary elevation of blood pressure after partial occlusion of the renal arteries in dogs. 

There are many similarities between human essential hypertension and experimental renal hypertension. To mention a few In both cases cardiac rate and output, blood volume, and blood viscosity, as well as peripheral blood flow, are normal. Renal blood flow seems to be reduced, while renal excretory function remains normal in the benign phase of both the human and the experimental disease and becomes reduced in the malignant phase. In both types of hypertension cardiac hypertrophy occurs and is chiefly left ventricular. 

Most workers in this field agree that human essential hypertension and experimental renal hypertension are closely related, if not identical. Ultimate proof of such a relationship will probably have to await the development of a therapy for experimental hypertension and demonstration of the 

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From what has already been published, and from what is contained in this symposium, it is abundantly clear that at least the early period of the hypertension which develops after constriction of the main renal arteries of animals is of humoral origin. The difficulty has been, and still is, the direct application of what has been learned about experimental renal hypertension to the problem of the pathogenesis of human essential hypertension. Of the greatest importance would be the determination of the exact cause of the relatively long period of experimental hypertension and of human hypertension in which, up to the present time, the existence of a humoral mechanism has not been proved. 

By the use of specific enzymes, studies have been made in an attempt to classify the pressor substances in experimental hypertension. If a specific enzyme lowered blood pressure in hypertensive animals and not in normal ones, it was assumed that the substrate of that enzyme was attacked, and therefore contributed to the hypertension. Such assumptions, while not wholly valid, nevertheless pointed to certain substances as possibly concerned in hypertension. 

Kunes J, Hojna S, Kadlecova M, et al. Altered balance of vasoactive systems in experimental hypertension the role of relative NO deficiency. Physiol Res. 2004 5 3 (suppl 1) S23—S34. 

Alterations in G-protein levels and functions such as altered adenylyl cyclase responsiveness to various agonists have also been demonstrated in cardiovascular and noncardiovascular tissues from genetic as well as experimental hypertensive rats (Anand-Srivastava et al. 1991, 1993 Anand-Srivastava 1992, 1993 Thibault and Anand-Srivastava 1992 Bohm et al. 1993 Li et al. 1994). 

Fig. 1.7 Possible mechanisms involving angiotensin II, oxidative stress and nitric oxide in enhanced Gi oc protein expression in hypertension. Gi protein expression is enhanced in genetic (SHR) and experimental hypertension including 1 kidney 1 clip (1K1C) and L-NAME-induced hypertension. Inhibition of nitric oxide synthase (NOS) by L-NAME activates renin angiotensin system, and also decreases the level of NO. 1K1C hypertensive rats also exhibit enhanced levels of Ang II. Ang II increases oxidative stress that through increased MAP kinase activity results in enhanced expression of Gi oc proteins and thereby hypertension. On the other hand, increased levels of NO and cGMP decrease the expression of Gia proteins in VSMC which may be an additional mechanism through which NO decreases blood pressure in L-NAME-induced hypertensive rats.

Wu, X., Tolvanen, J.P., Hutri-Kahonen, N., Kahonen, M., Makynen, H., Korpela, R., Ruskoaho, H., Karjala, K., and Porsti, I. 1998. Comparison of the effects of supplementation with whey mineral and potassium on arterial tone in experimental hypertension. Cardiovasc. Res. 40, 364-374. 

Hayakawa H, Hirata Y, Suzuki E, SugimotoT, Matsuoka H, Kikuchi K, Nagano T, Hirobe M Mechanisms for altered endothelium-dependent vasorelaxation in isolated kidneys from experimental hypertensive rats. Am J Physiol 264 1535-41,1993 Hirata Y, Hayakawa H, Kakoki M,Tojo A, Suzuki E, Nagata D, Kimura K,Goto A, Kikuchi K, NaganoT, Hirobe M, Omata M Receptor subtype for vasopressin-induced release of nitric oxide from rat kidney. Hypertension 29 58-64,1997 Hirata Y, Hayakawa H, Suzuki E, Omata M Does endothelin work as an intrarenal mechanism to alter pressure natriuresis in spontaneously hypertensive rats J Hypertens 12 251-7,1994... 

Goldblatt, H., Lynch, J., Hanzal, R. F, Summerville, W. W. Studies on experimental hypertension. 1. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J. Exp. Med. 1934,59, 347. 

Varma DR, Goldbaum D (1975) Effect of delta9-tetrahydrocannabinol on experimental hypertension in rats. J Pharm Pharmacol 27 790-791... 

Central and peripheral alterations in noradrenergic transmission in experimental hypertension modulation by prejunctional receptors. J. Cardiovasc. Pharmacol. 10 (Suppl. 4), S62-S67. 

Hayakawa H, Hirata Y, Suzuki E, Sugimoto T, Matsuoka H, Kikuchi K, Nagano T, Hirobe M Mechanisms for altered endothelium-dependent vasorelaxation in isolated kidneys from experimental hypertensive rats. Am J Physiol 264 1535-41, 1993... 

Losartan blocks the vascular constrictor effect of Ang II, the Ang Il-induced aldosterone synthesis and/or release, and the All-induced cardiovascular growth. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to angiotensin converting enzyme (ACE) inhibitors. Subsequently con-tolled clinical trials revealed that losartan is a new and valuable drug for treatment of hyper-... 

Pauletto P, Sarzani R, Rappelli A, Chiavegato A, Pessina AC, Sartore S (1994) Differentiation and growth of vascular smooth muscle cells in experimental hypertension. Am J Hypertens 7 661-674... 

PED was recently shown to inhibit an additional steroid biosynthetic enzyme, namely steroid 19-hydroxylase (aromatase) from bovine adrenals. The observation that steroid 19-hydroxylase is the rate-limiting enzyme in the metabolic formation of 19-nordeoxy-corticosterone, a natural mineralo-corticosteroid that has been implicated in some forms of human and experimental hypertension may bear some implications for the treatment... 

Scholze J, Bauer B, Massaro J (1999) Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER. Clinical and Experimental Hypertension 21 1447-1462. 

M.-C. Fournie-Zaluski, P. Coric, S. Turcaud, N. Rousselet, W. Gonzalez, B. Barbe, I. Pham, N. Jullian, J.-B. Michel, and B. P. Roques, J. Med. Chem., 37, 1070 (1994). New Dual Inhibitors of Neutral Endopeptidase and Angiotensin-Converting Enzyme Rational Design, Bioavailability, and Pharmacological Responses in Experimental Hypertension. See also references therein. 

Marche, P., Limon, L, Blanc, J., and Girard, A. (1990) Platelet Phosphatidylcholine liimover in Experimental Hypertension, Hypertension 16,190-193. 

Guynn JB, Poretz DM, Duma RJ (1973) Growth of various bacteria in a variety of intravenous fluids. Am J Hosp Pharm 30 321-325 Hahn E, Timpl R, Miller EJ (1975) Demonstration of a unique antigenic specificity for the collagen alpha l(II) chain from cartilaginous tissue. Immunology 28 561-568 Hall CE, Hall O (1961) Experimental hypertension elicited by injections of methylcellulose. Experientia 17 544-545... 

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