A current review on animal models of anti-hypertensive drugs screening
Mehvish BhatMohammad Abu ZaidShivam SinghKartik GillJunaid TantrayR. K. SharmaMithilesh SinghAnurag MishraRavindra Pal SinghSanjay Kumar SahuArun GargAshish Kumar Sharma
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Abstract:
One of the main contributors to death or disability from heart attack, stroke, and renal failure is hypertension. Experimental animal models have been extremely useful in learning more about the aetiology, pathophysiology, consequences, and treatment of hypertension and antihypertensive drugs are evaluated. There are several strains of genetically hypertensive rats available today, and most laboratories use these models to conduct therapeutic studies on hypertension. Both traditional and genetic models of hypertension animal models, their characteristics, and their significance are summarized as: In-Vitro Animal Models: Antagonism of Endothelin Receptors in Porcine Isolated Hearts and Monocrotaline induced pulmonary Hypertension. In-Vivo Animal Models: Rat Hypertension Models One-Kidney-Two Clip (Goldblatt hypertension, 2K1C), Rats with Chronic Renal Hypertension (1-kidney-1-clip method), Pithed rats blood pressure, Tail Cuff in rats, Blood pressure measurements using an ingestible catheter in conscious rats, Dahl salt-sensitive rat model, Model of Fructose- induced Hypertension in rats, DOCO Salt rats, Spontaneously Hypertensive Rats, Transgenic Rats Overexpressing Mouse Ren2 Gene (TGR (mRen 2) 27), Models of hypertension in dogs (Renal Chronic Hypertension), Neurogenic hypertension, Hypertension model of a monkey (Inhibition of renin in monkeys), Hypertension transgenic models and Hypertension by chronic inhibition of nitric oxide. Conclusion: In this article, experimental models of hypertension, traditional and genetic gives quick summary of the most popular animal models, their characteristics, and their significance.Keywords:
Pathophysiology of hypertension
Renovascular Hypertension
Animal model
genetic model
Spontaneously hypertensive rat
Stroke
The effect of aging on the renin angiotensin system (RAS) was studied in 30 patients with renovascular hypertension and 33 patients with essential hypertension. Plasma renin decreased with age in patients with renovascular hypertension and essential hypertension. However, in patients with renovascular hypertension, the change was not statistically significant. Plasma aldosterone concentration showed a tendency to decrease with age in both groups. Stimulated plasma renin activity and the net increase in plasma renin activity after captopril administration in patients with essential hypertension showed a significant decrease with age. In patients with renovascular hypertension, exaggerated response of renin secretion was observed in younger patients, but middle-aged and elderly patients did not demonstrate this hyper-responsiveness. The degree of decrease in blood pressure by administration of an angiotensin (Ang) II analog ([Sar1,Ile8] Ang II) was the same in both younger and elderly patients with either disease. These results suggest that the effect of aging on the RAS occurs not only in patients with essential hypertension, but also in patients with renovascular hypertension. Furthermore, although the Ang II analog infusion test and captopril stimulation test are considered to be useful screening tests for renovascular hypertension, we consider that the combination of Ang II analog test and captopril test may be favorable to screen renovascular hypertension, since the captopril stimulation test had a lower sensitivity in younger (under 35 years old) patients.
Renovascular Hypertension
Captopril
Plasma renin activity
Essential hypertension
Pathophysiology of hypertension
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Renovascular Hypertension
Plasma renin activity
Essential hypertension
Pathophysiology of hypertension
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Angiotensin-converting enzyme (ACE) inhibitors are now widely used as first-line treatment of essential hypertension. Their effectiveness is potentiated by a low-salt diet and, above all, by the simultaneous prescription of diuretics. When secondary hypertension is suspected, ACE inhibitors are a good pharmacological tool to study the renin-angiotensin system. Since activation of this system is the main mechanism responsible for renovascular hypertension, ACE inhibitors are very useful for diagnosis. Conversely, blood pressure is not influenced by ACE inhibitors in primary hyperaldosteronism because of the low plasma renin and angiotensin II levels. Pheochromocytoma activates the renin-angiotensin system, and ACE inhibitors combined with beta-blockers enable the hypertension to be controlled prior to surgical treatment of the tumour. Finally, ACE inhibitors can be used to explore the renin-angiotensin system in the experimental model of renovascular hypertension and therefore contribute to our knowledge of the complex pathophysiology of this most frequent type of secondary hypertension.
Renovascular Hypertension
Hyperaldosteronism
Pathophysiology of hypertension
Secondary hypertension
Plasma renin activity
Essential hypertension
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The experimental design which most closely reproduces clinical renovascular hypertension is constriction of one renal artery, with the other renal artery and kidney left intact. To test the role of renin and angiotensin in the pathogenesis of renovascular hypertension, attempts were made to induce such hypertension in rats previously immunized with angiotensin. In 29 highly immunized and 33 control rats, one renal artery was partially constricted and the other kidney and renal artery left intact. Preoperative blood pressures were equal in all rats (means: immunized, 118 ± SE 0.95; controls, 117 ± 0.70 mm Hg). Both groups developed hypertension during the 13 days following operation (means: immunized, 173 ± 3.42; controls, 169 ± 4.65 mm Hg). The high blood pressures persisted throughout the observation period (56 days). Immune sera completely inactivated large amounts of angiotensin (mean, 1130 ± SD 887 ng/ml antiserum; range 200-4000), and high intravenous doses of renin and angiotensin had no effect on the blood pressure of immunized rats. These data provide strong evidence that the direct pressor effect of circulating angiotensin is not essential for the development of hypertension evoked by constricting one renal artery in the rat.
Renovascular Hypertension
Pathophysiology of hypertension
Plasma renin activity
Essential hypertension
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Renal artery constriction in the unilaterally nephrectomized, trained dog, with maintained renal arterial hypotension, produces a prompt increase in systemic renin activity and blood pressure. The hypertension normally induced by renal artery stenosis is prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro (SQ 20, 881), which blocks conversion of angiotensin I to angiotensin II. Constant intravenous infusion of the inhibitor over several days of renal artery constriction prevents the development of chronic renovascular hypertension. Furthermore, a single injection of the nonapeptide restores blood pressure to normal in the early phase of renovascular hypertension, but becomes progressively less effective as salt and water retention occurs in the chronic stage when plasma renin activity returns to control levels. These data provide strong evidence that the renin-angiotensin system is responsible for the initiation of renovascular hypertension in the one-kidney Goldblatt dog, but that other factors become increasingly important in chronic renovascular hypertension.
Renovascular Hypertension
Constriction
Pathophysiology of hypertension
Renal Artery Obstruction
Plasma renin activity
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To clarify the pathophysiology of renovascular hypertension, we monitored intraarterial pressure continuously and measured hourly hormone levels for 24 hours under carefully controlled conditions in two hypertensive patients with unilateral renal artery occlusion. Comparison of the results with those obtained when the patients were normotensive 3 months after uninephrectomy indicated that, while the renin-angiotensin system played a central role in maintaining the hypertension, the sympathetic nervous system also contributed and, in addition, modulated short-term arterial pressure fluctuations. In the untreated state, the sympathetic regulation of renin secretion was heightened, and angiotensin II/aldosterone dose-responsiveness was augmented. It is suggested that these adaptive changes might serve to offset the tendency to severe sodium depletion and thence exacerbation of the hypertension.
Renovascular Hypertension
Pathophysiology of hypertension
Pathophysiology
Sympathetic nervous system
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Recently, some angiotensin II analogues have been reported as competitive inhibitors for angiotensin II in renin dependent hypertension. 1-Sar, 8-Ile, angiotensin II, which is reported to have the strongest action among the angiotensin II analogues, was administrated, pre-and post-operatively, to 3 cases of renovascular hypertension, one case of hypertension due to remarkable unilateral hydronephrosis, malignant hypertension and hypertension with chronic glomerulonephritis.In this article, we designed to study the relationship between the kinds of hypertension related to plasma renin activity and response of blood pressure to 1-Sar, 8-Ile, angiotensin II, and to study whether this drug is used as a diagnostic aid or for decision of operative indication for renovascular hypertension.Under non-limited diet, or low-salt (NaCl: under 3.0g per day) diet and furosemide 120mg per day for 3 days, 1-Sar, 8-Ile, angiotensin II was administrated, dissolved in normal saline. When the blood pressure was decreased more over than 20mmHg systolic or 10mmHg diastolic by this drug, the response was judged to be positive.Two cases of renovascular hypertension, which had high peripheral plasma renin activity and lateralizing renal vein renin ratio, showed positive response to 1-Sar, 8-Ile, angiotensin II. The rest 2 cases of renovascular hypertension, of which one had high peripheral plasma renin activity increasing into abnormal high range by stimmulation, showed a positive blood pressure response after decreasing of total plasma volume by low-salt diet and furosemide administration, though they presented a negative blood pressure response under normal diet or normal condition.Isolateral nephrectomy, resection of stricture portion and end-to-end anastomosis of renal artery, and bypass formation between the aorta and normal renal artery, using auto-saphenous vein, were performed on each of 4 cases, and normalization of blood pressure were observed in all cases. Post operative 1-Sar, 8-Ile, angiotensin II infusion tests revealed a negative response in all 4 cases of renovascular hypertension.We concluded that 1-Sar, 8-Ile, angiotensin II infusion tests revealed the contributory degree of renin-angiotensin system in renovascular hypertension and this test was available for decision of operative indication or judgement of operative effect.Although the blood pressure response was positive in the case of malignant hypertension, transiently incresed blood pressure with slight headache was observed due to the agonistic action of this drug in the case of hypertension with chronic glomerulonephritis whose plasma renin activity was normal in spite of renin secretion stimmulation.To the remarkable hypertension following pyeloplastic operation in the case of hypertension due to hydronephrosis presenting high plasma renin activity, 1-Sar, 8-Ile, angiotensin II was administrated continuously for 28hours. The blood pressure decreased to almost normal and the patient was releaved from the dangerous state. Thus, 1-sar, 8-Ile, angiotensin II also could be used as a therapeutic aid in such a particular condition as hypotonics.
Renovascular Hypertension
Plasma renin activity
Pathophysiology of hypertension
Primary Aldosteronism
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Renovascular Hypertension
Pathophysiology of hypertension
Endothelial Dysfunction
Pathophysiology
Secondary hypertension
Fibromuscular Dysplasia
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Spontaneously hypertensive stroke-prone rats (SHR-SP) suffer spontaneous stroke in part as a result of abnormal cerebrovascular development. Reduction of regional cerebral blood flow in this model has already been demonstrated. This model has three distinct stages of hypertension: pre-hypertensive, typical hypertensive and malignant hypertensive. We investigated the level of endothelin-1 and its receptor expression in the frontal cortex of SHR-SP at the malignant hypertensive stage (35-40 weeks of age), during which time the rats suffer strokes. The cerebral endothelin-1 level, as determined by enzyme-linked immunosorbent assay, was highly increased at this severely hypertensive stage compared to their genetic control, normotensive Wistar-Kyoto rats. This upregulation was associated with an increased expression of endothelin-A receptor, however, another endothelin-1 receptor, endothelin-B, was downregulated. The regional cerebral blood flow in the frontal cortex was reduced by 60% in 40-week-old malignantly SHR-SP as compared to age-matched Wistar-Kyoto rats. Thus, cerebral endothelin-1 expression increased in malignant hypertension in SHR-SP. The enhanced endothelin-1 may activate the endothelin-A receptor, which would, in turn, result in reduced cerebral blood flow. Downregulation of the endothelin-B receptor may cause suppression of endothelium-derived relaxing factors in the brain of SHR-SP and be an underlying factor in their stroke susceptibility.
Spontaneously hypertensive rat
Stroke
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Pressor responsiveness to angiotensin II and noradrenaline have been examined using a blood perfused hind limb preparation in early and chronic renovascular hypertension before and after correction of the hypertension by removing the renal artery clip. Hypersensitivity was only partially developed in the early phase but markedly so in the chronic phase. After renal artery unclipping blood pressure returned to normal within 24 h despite the continued presence of enhanced vascular reactivity. When studied 60 days after unclipping, pressor responsiveness had returned to normal in both previously early and chronic hypertensive rats. These results suggest that hypersensitivity to pressor agents develops after hypertension has become established and as a consequence of structural vascular change in response to the raised blood pressure. Although these changes may play a role in the maintenance of blood pressure in chronic hypertension they are of little importance in the development of hypertension.
Renovascular Hypertension
Pathophysiology of hypertension
Chronic hypertension
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