General Pharmacology: The Vascular System
Combined effects of AT1 and ETA receptor antagonists, candesartan, and A-127722 in DOCA–salt hypertensive rats
Introduction
Angiotensin II (Ang II) is responsible for producing hypertension and associated renal dysfunction in many pathological states. In addition to hemodynamic actions, Ang II contributes to vascular hypertrophy and fibrosis, i.e., overproduction of extracellular matrix (ECM) proteins Laragh, 1995, Levy, 1998, Nicholls et al., 1998. Along these lines, blockade of AT1 receptors has been reported to decrease production of TGF-β and the subsequent deposition of ECM components such as fibronectin and collagen Border and Noble, 1998, Kim et al., 1994. TGF-β has been reported to be elevated in the renal medulla of the DOCA–salt hypertensive rat and so it has been hypothesized that Ang II may be responsible for elevating TGF-β in this model (Kim et al., 1994). Several recent studies have also indicated that many of the hemodynamic and mitogenic actions of Ang II are mediated by endothelin-1 (ET-1) d'Uscio et al., 1997, Herizi et al., 1998, Rajagopalan et al., 1997. In the deoxycorticosterone acetate (DOCA)-salt rat, blockade of ETA receptors reduces hypertension but not the associated decline in GFR (Allcock et al., 1998). Ang II blockade either by AT1 antagonists or ACE inhibition have no effect on arterial pressure or GFR but they do attenuate renal interstitial fibrosis (Kim et al., 1994). Similar to Ang II, ET-1 has actions similar to TGF-β in terms of promoting cell growth and synthesis of ECM proteins suggesting that these mediators may serve to exacerbate renal injury Benigni and Remuzzi, 1998, Gomez-Garre et al., 1996, Hutchinson, 1998, Pönicke et al., 1997. Taken together, these findings have led us to hypothesize that Ang II and ET-1 act synergistically to promote a decline in renal function and the development of renal fibrosis in the DOCA–salt model of malignant hypertension and renal dysfunction. To test this hypothesis, experiments were conducted to (1) determine if ET-1 and Ang II act synergistically in the DOCA–salt model to cause a chronic decline in renal function and (2) determine if ET-1 and Ang II synergistically promote fibrosis in the kidney.
Section snippets
Methods
Male Sprague–Dawley rats (200–250 g, Harlan Laboratories, Indianapolis, IN) were housed under controlled light, temperature, and humidity while in metabolism cages to facilitate 24-h urine collection and monitoring of food and water intake. Systolic arterial pressure was determined on a weekly basis using a tail cuff pressure (TCP) measurement system as previously described (Pollock et al., 2000). Following baseline measurements, rats were anesthetized with methohexital sodium (50 mg/kg ip,
Results
Separate groups were treated with either ETA antagonist, A-127722, AT1 antagonist, candesartan cilexetil, or both. ETA blockade attenuated the development of hypertension in DOCA–salt rats, which was significant after 2 weeks but not after 3 weeks (Fig. 1). AT1 antagonism reduced arterial pressure after 3 weeks when given alone. The combination of ETA and AT1 blockade produced additive effects with arterial pressure being significantly lower than untreated controls at both Weeks 2 and 3.
In
Discussion
Recent studies have established that blockade of ETA receptors can lower arterial pressure in salt-dependent models of hypertension (Pollock, 2000). In the DOCA–salt hypertensive rat, we recently reported that ETA blockade lowers arterial pressure, but has little effect on improving renal function (Allcock et al., 1998). In contrast to most animal models, the hypertension developed in the DOCA–salt model has been shown to have little dependence on the renin–angiontensin system as both
Acknowledgements
The authors wish to express their appreciation for the expert technical assistance provided by Ms. Deborah Garner and Ms. Jean Roscow. The authors also wish to thank Dr. Peter Morsing of AstraZeneca Pharmaceuticals for kindly providing the candesartan cilexetil and Dr. Jerry Wessale of Abbott Laboratories for kindly providing the A-127722.
These studies were supported by grants from the National Institute of Health (HL 60653 and HL 64776), the American Heart Association (Scientist Development
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