2K1C Goldblatt Hypertensive Rats Research Articles

Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats

This study examined the effects of a novel orally active 14,15-epoxyeicosatrienoic acid analog (EET-A) on blood pressure (BP) and myocardial infarct size (IS) in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats during sustained phase of hypertension. Between days 31 and 35 after clip placement the rats were treated with EET-A and BP was monitored by radiotelemetry; sham-operated normotensive rats were used as controls. Tissue concentrations of epoxyeicosatrienoic acids served as a marker of production of epoxygenase metabolites. The rats were subjected to acute myocardial ischemia/reperfusion (I/R) injury and IS was determined. We found that EET-A treatment did not lower BP in 2K1C rats and did not alter availability of biologically active epoxygenase metabolites in 2K1C or in sham-operated rats. The myocardial IS was significantly smaller in untreated 2K1C rats as compared with normotensive controls and EET-A reduced it in controls but not in 2K1C rats. Our findings suggest that during the phase of sustained hypertension 2K1C Goldblatt hypertensive rats exhibit increased cardiac tolerance to I/R injury as compared with normotensive controls, and that in this animal model of human renovascular hypertension short-term treatment with EET-A does not induce any antihypertensive and cardioprotective actions.

Kidney Injury Response to Elevated Blood Pressure vs Increased Intrarenal Ang II in 2K1C Goldblatt Hypertensive Rats

This study determined the relative role of elevated blood pressure (BP) versus increased Angiotensin II (Ang II) content on the tissue injury response in both kidneys (clipped ‐CK‐ and nonclipped ‐NCK) of two kidney‐one clip (2K1C) Goldblatt hypertensive rats. Kidney injury markers of arterial wall proliferation (α‐sma), fibrosis (Collagen III), inflammation (CD68), cell proliferation‐regeneration (PCNA, Vimentin), and hypoxia (HIF‐α1) were examined using immunohistochemistry on paraffin embedded kidney sections from 2K1C male Sprague‐Dawley (n=6) rats and sham (n=4) rats. After 25 days of unilateral renal clipping (0.25mm), systolic BP increased in 2K1C rats compared to sham rats (184±9 vs.121±6 mmHg). Semi‐quantitation of injury markers showed increased afferent arteriole wall proliferation, macrophages number, and interstitial expansion in both kidneys of 2K1C rats. However, tubular cell proliferation and regeneration were only augmented in the NCK of 2K1C rats compared to CK and sham kidneys. Increased intrarenal Ang II content in both kidneys of 2K1C rats contributes to renal fibrosis and inflammation in Goldblatt hypertension, but preferentially increases of epithelial‐to‐mesenchymal transition and tubule‐cell proliferation in the NCK seems to be associated to the concurrent effect of elevated BP and high intrarenal Ang II content.Support from the NIH and LAMP‐Tulane University.

Functional subtypes of renal α1-adrenoceptor in diabetic and non-diabetic 2K1C Goldblatt renovascular hypertension

This study investigates the subtypes of the alpha1-adrenoceptor mediating the adrenergically-induced renal vasoconstrictor responses in streptozotocin-induced diabetic and non-diabetic 2-kidney one clip (2K1C) Goldblatt hypertensive rats. The renal blood flow responses to renal nerve stimulation, noradrenaline, phenylephrine, and methoxamine were measured in the absence and presence of nitrendipine, 5-methylurapidil, chloroethylclonidine and BMY 7378. The renal vasoconstrictor responses were markedly attenuated by nitrendipine and 5- methylurapidil in the diabetic rats (all P< 0.05). In the non-diabetic rats, these responses were markedly attenuated by nitrendipine, 5-methylurapidil, and BMY 7378 (all P< 0.05). In both experimental groups, chloroethylclonidine markedly accentuated the renal vasoconstrictions caused by all the adrenergic stimuli (all P< 0.05). These observations indicate that alpha 1A-adrenoceptor subtypes play a major role in mediating adrenergically-induced renal vasoconstriction in the diabetic 2K1C Goldblatt hypertensive rats. In the non-diabetic 2K1C Goldblatt hypertensive rats, contributions of alpha 1A and alpha 1D-adrenoceptor subtypes were proposed. Apart from post-synaptic alpha 1-adrenoceptors, both in the diabetic and non-diabetic 2K1C Goldblatt hypertensive rats, the potential involvement of presynaptic alpha 1- adrenoceptors is also suggested.

The cardiovascular and renal functional responses to the 5‐HT1A receptor agonist flesinoxan in two rat models of hypertension

1. This study investigated the importance of renal sympathetic nerves in regulating sodium and water excretion from the kidneys of stroke prone spontaneously hypertensive and 2K1C Goldblatt hypertensive rats anaesthetized with chloralose/urethane (17.5/300 mg initially and supplemented at regular intervals), and prepared for measurement of renal function. 2. In stroke prone spontaneously hypertensive rats, flesinoxan, 30-1000 micrograms kg-1, i.v., caused graded reductions in blood pressure and heart rate of 74 +/- 5 mmHg and 63 +/- 9 beats min-1, respectively at the highest dose (P < 0.001). Renal blood flow did not change at any dose of drug while glomerular filtration rate fell by some 20% (P < 0.001) at the highest dose of drug, absolute and fractional sodium excretions, approximately doubled at 100 micrograms kg-1, and thereafter fell to below the baseline level at 1000 micrograms kg-1. 3. This pattern of excretory response was abolished following acute renal denervation when flesinoxan caused dose-related reductions in urine flow and sodium excretion, similar to that obtained by a mechanical reduction of renal perfusion pressure. 4. Flesinoxan administration (30-1000 micrograms kg-1, i.v.) into 2K1C Goldblatt hypertensive rats caused a maximum decrease in blood pressure and heart rate (both P < 0.001) of 34 +/- 3 mmHg and 20 +/- 6 beats min-1 and while renal blood flow and glomerular filtration rate were autoregulated, from 160 to 125 mmHg, there were dose-related decreases in urine volume and sodium excretion from the clipped and non-clipped kidneys of approximately 50-60% at the highest dose. 5. These findings suggest that in the stroke prone spontaneously hypertensive rat the renal nerves importantly control sodium and water reabsorption at the level of the tubules, whereas in 2K1C Goldblatt hypertensive rats, they play a minor role.

Effect of nitrendipine on renal cortical and papillary autoregulation in hypertensive rats

Renal cortical and papillary perfusions were asscssed by laser-Doppler flowmetry and autoregulatory indices. There was cortical autoregulation (autoregulatory index of 0.31 ± 0.08) in Wistar from 160 to 100 mm Hg, but not in the papilla, which was abolished by nitrendipine, 0.125 and 0.25 μg kg −1 min −1. In SHRSP the cortex, but not the papilla, exhibited autoregulation from 180 to 120 mm Hg (autoregulatory index of 0.27 ± 0.10) but not during low and high doses of nitrendipine. The non-clipped kidney cortex of 2K1C Goldblatt rats autoregulated from 190 to 130 mm Hg (autoregulatory index of 0.20 ± 0.13), but was inhibited only by the higher dose of nitrendipine. In mature Wistar and SHRSP cortical autoregulation is blocked effectively by nitrendipine whereas the 2K1C Goldblatt hypertensive rats are relatively resistant.

Alpha 1-adrenoceptor subtypes mediating adrenergic vasoconstriction in kidney, one-clip Goldblatt and deoxycorticosterone acetate-salt hypertensive rats.

We characterised the functional alpha 1-adrenoceptors involved in mediating adrenergic vasoconstrictor responses in kidney of two-kidney one-clip (2K1C) Goldblatt and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In sodium pentobarbital-anaesthetised rats, frequency- and dose-dependent renal vasoconstrictor responses were obtained by direct electrical renal nerve stimulation, close renal arterial administration of phenylephrine (PE), and methoxamine. Administration of amlodipine, a dihydropyridine calcium channel antagonist (bolus dose of 200 and 400 micrograms/kg and an infusion of 50 and 100 micrograms/kg/h, respectively) and the alpha 1-adrenoceptor antagonist 5-methylurapidil (5 micrograms/kg plus 1.25 micrograms/kg/h and twice this dose) suppressed renal nerve-, PE-, and methoxamine-induced vasoconstrictions 14-70% (p < 0.05-0.001) in 2K1C Goldblatt and DOCA-salt hypertensive rats. The alpha 1B-adrenoceptor alkylating agent, chloroethylclonidine (5 micrograms/kg plus 1.25 micrograms/kg/h and twice this dose) caused significant attenuation (p < 0.001) of renal nerve-induced vasoconstriction by 19-23% in DOCA-salt hypertensive rats but did not affect PE- and methoxamine-induced vasoconstriction in either 2K1C Goldblatt or DOCA-salt hypertensive rats. In contrast, in 2K1C Goldblatt rats vasoconstrictor responses were potentiated by renal nerve stimulation and methoxamine. The data show that the functional renal postjunctional alpha 1-adrenoceptors on the vasculature of both hypertensive models are primarily of the alpha 1A-subtype, as reflected by their sensitivity to amlodipine and 5-methylurapidil. Moreover, an interaction appears to occur between the alpha 1-adrenoceptor subtypes at renal vessels in 2K1C Goldblatt hypertensive rats.

The characteristics of alpha-adrenoceptors mediating the renal nerve induced antinatriuresis and antidiuresis in hypertensive rats.

Selective alpha-adrenoceptor and calcium antagonists have been used to determine both the alpha 1-adrenoceptor subtype and the extracellular calcium requirement for renal nerve-mediated antinatriuresis and antidiuresis in deoxycorticosterone acetate (DOCA)-salt and two-kidney, one clip (2K1C) Goldblatt hypertensive rats. Stimulation of the renal nerves at low frequencies reduced urine flow and absolute and fractional sodium excretions by 40-60% in pentobarbitone anaesthetized control, sham-operated, DOCA-salt and 2K1C Goldblatt hypertensive rats. Administration of prazosin, but not idazoxan, inhibited the renal nerve-induced excretory responses in both models of hypertension, a result compatible with the involvement of alpha 1-adrenoceptors. By contrast, the calcium antagonist inhibited the renal nerve-dependent antinatriuresis and antidiuresis in DOCA-salt but not 2K1C Goldblatt hypertensive rats. These results showed that the renal nerves mediated their action via alpha 1-adrenoceptors, but that the postreceptor responses were dependent on extracellular calcium in DOCA-salt but not 2K1C Goldblatt rats.