Anti-hypertensive and natriuretic effect of glucagon-like
`peptide 1 in Dahl S rats: a novel function for a pleotrophic
`hormone?
`Peter Vollenweider
`
`Editorial comment 1079
`
`Journal of Hypertension 2003, 21:1079–1080
`
`Department of Internal Medicine and the Botnar Centre for Clinical Research,
`Centre Hospitalier Universitaire Vaudois, Lausanne Switzerland.
`
`Correspondence and requests for reprints to Peter Vollenweider, Department of
`Internal Medicine, BH 10.647, Centre Hospitalier Universitaire Vaudois,
`CH- 1001 Lausanne, Switzerland.
`Tel: +41 21 314 09 30; fax: +41 21 314 09 28;
`e-mail: peter.vollenweider@chuv.hospvd.ch
`
`See original paper on page 1125
`
`is
`The hormone glucagon-like peptide 1 (GLP-1)
`produced as a proteolytic processing product of the
`preproglucagon molecule in the L cells of the small
`and large intestine, as well as in some areas of the
`brain. GLP-1 released from the gut is best known for
`its insulinotropic action. Following nutrient ingestion,
`in particular glucose and fatty acids it is released into
`the blood and stimulates â-cell insulin secretion in a
`glucose dependent manner. This effect is mediated
`after binding to a specific plasma membrane receptor of
`the G protein coupled receptor family [1]. The GLP-1
`receptor (GLP-1R) is expressed not only in the pan-
`creatic â-cell, but also in the brain, the lungs, the
`kidneys, the pituitary gland, the heart, the stomach and
`the small intestine. This widespread distribution of the
`GLP-1R suggested that GLP-1 may exert a large
`variety of biological actions. Indeed, we now know that
`GLP-1 administration inhibits gastric acid secretion and
`gastric emptying, induces satiety, decreases food intake,
`regulates surfactant secretion from type II pneumo-
`cytes, and increases thyroid-stimulating hormone and
`luteinizing hormone-releasing hormone release in a
`variety of animal and cellular models [2].
`
`GLP-1 receptors are abundant in the kidney, but their
`role remains obscure. Recent studies by Roman et al.
`[3] shed some light on this issue, by demonstrating that
`GLP-1 increases natriuresis and diuresis in Sprague–
`Dawley rats due to inhibition of tubular sodium reab-
`sorption.
`
`tension. This increase in blood pressure is associated
`with sodium retention and volume expansion. Treat-
`ment of Dahl S rats with GLP-1 for 14 days almost
`completely abolished the salt-induced increase in blood
`pressure. Additional experiments indicated that GLP-1
`had a diuretic and strong natriuretic action, resulting in
`a negative cumulative sodium balance [4].
`
`Whether these effects of GLP-1 are mediated through
`renal GLP-1 receptors remains unanswered.
`
`Could the extra-renal effects of GLP-1 have contribu-
`ted to its anti-hypertensive action? In previous experi-
`ments, diuretic and natriuretic responses to GLP-1
`were attenuated in denervated kidneys, suggesting that
`some effects of GLP-1 on the kidney may be centrally
`mediated [3]. Further experiments are required to
`address this issue.
`
`In addition to its insulinotropic effect, GLP-1 has been
`suggested to improve insulin sensitivity [5,6]. Similar to
`other models of hypertension, Dahl S rats are insulin
`resistant, and improving insulin sensitivity may have
`beneficial effects on blood pressure. In the present
`study, glucose and insulin levels were not different in
`GLP-1 treated and control rats, but they represent
`unfortunately a poor index of insulin sensitivity. Eu-
`glycemic hyperinsulinemic clamp studies to assess the
`effects of GLP-1 on insulin sensitivity in Dahl-S rats
`would have provided interesting mechanistic data.
`
`In this issue of the journal, Yu et al. [4] extend their
`observations and describe a blood pressure-lowering
`effect of GLP-1 in a hypertensive rat model. Dahl salt-
`sensitive rats, when fed a high salt diet, develop hyper-
`
`Finally, the authors show that GLP-1-treated Dahl S
`rats had reduced end-organ damage, in particular renal
`injury (with decreased microalbuminuria and proteinur-
`ia) and left ventricular hypertrophy, as well as improved
`
`0263-6352 & 2003 Lippincott Williams & Wilkins
`
`DOI: 10.1097/01.hjh.0000059031.65882.df
`
`MPI EXHIBIT 1147 PAGE 1
`
`

`

`2 Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999;
`20:876–913.
`3 Moreno C, Mistry M, Roman RJ. Renal effects of glucagon-like peptide in
`rats. Eur J Pharmacol 2002; 434:163–167.
`4 Yu M, Moreno-Quinn C, Hoagland KM, Dahly A, Ditter K, Mistry M,
`Roman RJ. Antihypertensive effect of glucagon-like peptide 1 in Dahl S
`rats. J Hypertens 2003; 21:1125–1135.
`5 Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1
`augments insulin-mediated glucose uptake in the obese state. J Clin
`Endocrinol Metab 2002; 87:3768–3773.
`6 Meneilly GS, McIntosh CH, Pederson RA, Habener JF, Gingerich R, Egan
`JM, et al. Glucagon-like peptide-1 (7-37) augments insulin-mediated
`glucose uptake in elderly patients with diabetes. J Gerontol A Biol Sci
`Med Sci 2001; 56:M681–M685.
`7 Barragan JM, Rodriguez RE, Blazquez E. Changes in arterial blood
`pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide
`in rats. Am J Physiol 1994; 266:E459–E466.
`8 Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME,
`et al. Glucagon-like peptide-1 receptor stimulation increases blood
`pressure and heart rate and activates autonomic regulatory neurons.
`J Clin Invest 2002; 110:43–52.
`9 Barragan JM, Eng J, Rodriguez R, Blazquez E. Neural contribution to the
`effect of glucagon-like peptide-1-(7-36) amide on arterial blood pressure
`in rats. Am J Physiol 1999; 277:E784–E791.
`10 Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of
`glucagon-like peptide-1. Diabetes Metab Res Rev 2002; 18:430–441.
`11 Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of
`glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-
`cell function in type 2 diabetes: a parallel-group study. Lancet 2002;
`359:824–830.
`12 Edwards CM, Todd JF, Ghatei MA, Bloom SR. Subcutaneous glucagon-
`like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycae-
`mia in fasted healthy subjects. Clin Sci (Lond) 1998; 95:719–724.
`13 Egan JM, Meneilly GS, Elahi D. Effects of one month bolus subcutaneous
`administration of exendin-4 in type 2 diabetes. Am J Physiol Endocrinol
`Metab 2002; in press.
`14 Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmaco-
`kinetics, pharmacodynamics, safety and tolerability of NN2211, a new
`long-acting GLP-1 derivative, in healthy men. Diabetologia 2002;
`45:195–202.
`15 Ahren B, Simonsson E, Larsson H, Landin-Olsson M, Torgeirsson H,
`Jansson PA, et al. Inhibition of dipeptidyl peptidase IV improves metabolic
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`1080 Journal of Hypertension 2003, Vol 21 No 6
`
`endothelial function compared to control animals [4].
`These effects are most likely related to the antihyper-
`tensive action of GLP-1 in this model, even though a
`direct effect of GLP-1 cannot be excluded.
`
`The results contrast with previously published data
`showing that GLP-1 or GLP-1 receptor agonist admin-
`istration acutely increased blood pressure and heart rate
`in rats [7,8] through a central neural action because it
`could be blocked by intracerebro-ventricular adminis-
`tration of GLP-1 receptor antagonists [9]. The origin of
`these discrepancies is not clear, but may be related to
`differences
`in the dose or duration (acute versus
`chronic) of GLP-1 administration, or differences in the
`animal models used (normal versus hypertensive ani-
`mals). Additional experiments directly addressing these
`issues, particularly in humans, will help to resolve some
`of these questions. This is important because GLP-1 is
`under intensive investigation for its therapeutic use in
`type 2 diabetes mellitus. Indeed, GLP-1 is a very
`interesting candidate drug for this indication, because
`its insulinotropic actions are maintained in diabetic
`patients, and it has additional beneficial effects, such as
`decreasing food intake and promoting weight
`loss,
`inhibiting gastric emptying and glucagon secretion, and
`potentially increasing insulin sensitivity and â-cell pro-
`liferation [10]. Preliminary data on the metabolic
`effects of short-term administration of GLP-1 in dia-
`betic patients are encouraging [11]. With the new data
`provided by Yu et al.
`[4],
`it
`is now important
`to
`carefully monitor arterial blood pressure in trials using
`GLP-1 for
`the treatment of patients with type 2
`diabetes mellitus. To date, only limited data in a small
`number of subjects are available. Acute administration
`of GLP-1 increases blood pressure in healthy subjects
`[12], whereas blood pressure remained unchanged in
`diabetic patients treated over 6 weeks [11]. Clearly,
`long-term studies are needed to settle this issue and,
`ideally, such studies should include subjects with salt-
`sensitive forms of high blood pressure. Unfortunately,
`the therapeutic use of GLP-1 is
`limited by two
`important factors: its peptidic nature necessitates intra-
`venous or subcutaneous administration and its half-life
`is extremely short due to rapid inactivation by dipepti-
`dyl peptidase IV (DPP IV). New analogs with signifi-
`cantly longer half-lives [13,14] and inhibitors of DPP
`IV have been developed [15]
`that should help to
`overcome some of these limitations. With such new
`tools,
`it will be possible to test whether the anti-
`hypertensive actions of GLP-1 seen in Dahl salt-
`sensitive rats are also encountered in human disease
`states.
`
`References
`1 Thorens B. Expression cloning of the pancreatic beta cell receptor for the
`gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA
`1992; 89:8641–8645.
`
`MPI EXHIBIT 1147 PAGE 2
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