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Prostanoids and blood pressure: which way is up?
Helene Francois and Thomas M. Coffman
Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
Address correspondence to: Thomas M. Coffman, Building 6/Nephrology (111I), Durham Veteran Affairs Medical Center, 508 Fulton Street, Durham, North Carolina 27705, USA. Phone: (919) 286-6947; Fax: (919) 286-6879; E-mail: tcoffman@acpub.duke.edu.
Find articles by Francois, H. in: JCI | PubMed | Google Scholar
Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
Address correspondence to: Thomas M. Coffman, Building 6/Nephrology (111I), Durham Veteran Affairs Medical Center, 508 Fulton Street, Durham, North Carolina 27705, USA. Phone: (919) 286-6947; Fax: (919) 286-6879; E-mail: tcoffman@acpub.duke.edu.
Find articles by Coffman, T. in: JCI | PubMed | Google Scholar
Published September 15, 2004 - More info
J Clin Invest. 2004;114(6):757–759. https://doi.org/10.1172/JCI22929.
© 2004 The American Society for Clinical Investigation
Prostanoids are generated by COX-mediated metabolism of arachidonic acid. These lipid mediators have a myriad of biological actions (1, 2). A role for prostanoids in the regulation of blood pressure was originally suggested by early observations that prostaglandins and thromboxanes affect vascular tone and renal excretory functions (3). Later, the impact of prostanoids upon blood pressure in humans was clearly demonstrated through clinical experiences with NSAIDs. NSAIDs, among the most widely prescribed drugs worldwide, act by inhibiting COX enzymes and hence blocking prostanoid production. Sodium retention leading to edema and hypertension is often observed in patients treated with NSAIDs (4, 5). However, increased blood pressure after treatment with NSAIDs is observed primarily in patients with pre-existing hypertension (6–8), suggesting a compensatory role for the prostanoid system in attenuating or preventing the development of high blood pressure.
Data from clinical trials suggest that nonselective NSAIDs, which inhibit both COX isoforms (COX-1 and -2), and selective COX-2 inhibitors (9–12) have similar propensities to cause hypertension. The theory that COX-2–dependent prostanoids resist the development of hypertension is further supported by experiments showing that COX-2 inhibitors or the genetic absence of COX-2 markedly augment the vasoconstrictor actions of Ang II (13). Among the prostanoids, prostaglandin E2 (PGE2) and PGI2 are potent vasodilators that promote renal sodium excretion and thus are logical candidates to mediate these counter-regulatory functions. In this regard, studies in humans suggest that COX-2 may be specifically linked to the generation of PGI2 in the systemic circulation (14). The predominant inhibition of PGI2 by COX-2 inhibitors has been posited as an explanation for putative associations between COX-2 inhibitors and the development of cardiovascular complications (15), including hypertension (16, 17).
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Prostanoids and renovascular hypertension
In this issue of the JCI, Fujino and associates show that the absence of the receptor for PGI2 (the I-prostanoid [IP] receptor) confers substantial resistance to the development of renovascular hypertension (18). Based on the discussion above, these findings may seem surprising. However, along with the well-characterized effects of prostanoids on vascular tone, the role of prostanoids in the regulation of renin release has long been recognized For example, studies dating back to the 1970s have documented potent actions of both PGE2 and PGI2 in stimulating renin secretion (19). These actions depend on the intracellular generation of cAMP. In this regard, the IP receptor, along with the E-prostanoid 2 (EP2) and EP4 receptors for PGE2, signal via Gs protein activation of adenyl cyclase (20). To test the role of individual prostanoid receptors in renovascular hypertension, Fujino et al. evaluated blood pressure and renin responses in mice lacking the IP receptor or one of the 4 individual EP receptors using a Goldblatt kidney model wherein a stenosis is created in one renal artery. The consequent reduction in renal blood flow stimulates synthesis and release of renin by granular cells of the juxtaglomerular apparatus (JGA) (Figure 1). The resulting generation of Ang II promotes vasoconstriction and impaired sodium excretion by the kidney. In the mice lacking IP receptors, stimulation of renin by renal artery stenosis and the subsequent development of hypertension were markedly attenuated.
Figure 1The juxtaglomerular apparatus. Integration of the regulated secretion of renin is carried out at the JGA. There are three major pathways regulating the secretion of renin by granular cells at the JGA: the baroreceptor, the macula densa mechanism, and direct stimulation by the sympathetic nervous system. The renal baroreceptor monitors renal perfusion pressure and signals an increase in renin when renal perfusion pressure falls. In the macula densa mechanism, macula densa cells sense the decrease in chloride ions in the filtrate in the distal tubule, thereby stimulating release of renin. Increased activity of renal sympathetic nerves directly stimulates renin release via activation of β adrenergic receptors. Sympathetic innervation also modulates both the baroreceptor and macula densa mechanisms.
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