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Morphologic evidence from patients with essential hypertension and Goldblatt-type hypertension reveals a subpopulation of narrowed afferent arterioles to ischemic nephrons. These ischemic nephrons, responding individually to their perception of underperfusion, secrete renin. In response, the normal nephrons are in adaptive natriuresis and have appropriately shut off their renin production. Nevertheless, they are affected adversely by the discordant renin-angiotensin II arising from the ischemic nephrons' presence, which exerts an unwanted sodium-retaining effect on the proximal tubules of the adapting nephrons. The end result is elevated blood pressure from too much sodium retention for the level of renin activity, that is, an abnormal renin-sodium product. Thus, "normal" renin levels in a hypertensive individual are abnormal because healthy kidneys shut off renin production entirely when blood pressure rises. This construction explains why angiotensin converting enzyme inhibition often corrects "normal" renin hypertension. Although such hypertension may be partly sodium-mediated as a consequence of inappropriate sodium retention by the normal and ischemic nephrons, the source of the problem lies in the renin production from ischemic nephrons. The correct treatment, then, is an antirenin therapy designed to block renin synthesis or secretion or angiotensin II formation or action. In view of modern studies suggesting that renin excesses also correlate with an increased risk of heart attack and stroke, the role of antirenin and antiangiotensin agents in treatment assumes additional relevance.
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PMID:Discordant nephron function. A pathogenic factor in hypertension and its vascular complications of stroke and heart attack. 200 43

High blood pressure (BP) is associated with increased risk of vascular disease, including myocardial infarction and stroke. Since drugs that lower BP will reduce the risk of those complications of hypertension that are due to high pressure (strokes due to small-vessel disease, including lacunar infarction and intracerebral hemorrhage due to rupture of microaneurysms, heart failure, and renal failure), it has been assumed that such drugs would also reduce the risk of myocardial infarction due to atherosclerosis. However, in addition to hypertension, many other factors are involved in the atherosclerotic process including blood lipids such as cholesterol, blood platelets, and arterial flow disturbances such as turbulence and vortex formation. Some drugs that lower BP have unwanted effects on blood lipids and arterial flow patterns, which are thought to offset the benefit of BP reduction, whereas other drugs have beneficial effects on such factors. Ames has calculated that the adverse effects of antihypertensive drugs on lipids are enough to completely offset the benefit of treating mild hypertension. We have shown that antihypertensive drugs have different effects on blood velocity, and that these effects are associated with differences in the effects of drugs on arterial flow disturbances at the site of carotid stenosis in man, such that propranolol reduced, and hydralazine increased, the occurrence of abnormal high-velocity flow patterns associated with turbulence and vortex formation. In cholesterol-fed hypertensive rabbits (one-kidney Goldblatt), propranolol was more effective than hydralazine in preventing the occurrence of aortic atherosclerosis, even though hydralazine lowered blood pressure more effectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypertension and atherosclerosis: effects of antihypertensive drugs on arterial flow patterns. 248 Nov 60

The present study evaluates cardiac function, plasma renin activity (PRA) and left ventricular (LV) myosin isoenzymes in untreated two-kidney, one-clip Goldblatt hypertensive rats (2KIC) and in 2KIC treated with felodipine and metoprolol. Normotensive rats (NCR) and another group of 2KIC, in which the renal artery constriction was removed (UC-2KIC), were also investigated. Cardiac performance was assessed by means of a working heart perfusion device, allowing also for measurements of myocardial oxygen consumption. Following antihypertensive therapy and unclipping, blood pressure became close to normotensive levels. PRA remained equally elevated in treated and untreated 2KIC, but became practically normalized after unclipping. Relative LV weight in 2KIC increased 74% above that in NCR but in treated 2KIC increased by only 20%. In UC-2KIC LV hypertrophy became reversed, LV weight/body being about the same as in treated 2KIC. In treated 2KIC, coronary resistance at maximal dilatation was significantly reduced, implying prevention of hypertensive, structural coronary vascular changes, and optimal LV function was improved markedly in the lower range of perfusion pressures compared with untreated 2KIC. When, however, the hearts were challenged at a high pumping resistance (perfusion pressure), LV function was similar in untreated and treated 2KIC. Myocardial oxygen consumption for given levels of stroke work was significantly lower in treated than in untreated 2KIC. The myosin isoenzyme pattern in the LV of 2KIC was shifted, with significantly higher amounts of VM-3 than in NCR. This shift was normalized by antihypertensive therapy or by unclipping. In conclusion, antihypertensive therapy with felodipine and metoprolol prevents the development of coronary vascular and left ventricular hypertrophy in 2KIC. This may contribute to enhance cardiac performance at low aortic pressure. The lack of improvement in optimal cardiac performance (at high aortic pressure) implies that the hypertensive state per se, rather than extent of pressure elevation, cardiac hypertrophy, or changes of LV isoenzymes, determines the reduced cardiac function in renal hypertensive rats (Friberg & Nordborg 1986).
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PMID:Functional and biochemical analyses of isolated rat hearts in renal and reversed renal hypertension. 252 66

The fall in blood pressure observed in both early and chronic phase Goldblatt 2-kidney 1-clip hypertension produced by removing or unclipping the ischaemic kidney is due to a profound fall in peripheral resistance. The two procedures have an equal effect upon peripheral resistance and the lesser efficacy of nephrectomy in lowering blood pressure is due to a greater rise in stroke volume perhaps associated with a greater degree of sodium retention. Neither changes in sodium balance, in the renin-angiotensin system nor in vascular reactivity explain the fall in blood pressure. A reduction in renal sympathetic afferent activity and a medullary based vasoactive humoral system may play a role although the nature and extent of that role remain to be defined.
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PMID:Reversal of renovascular hypertension. 635 29

One-kidney Goldblatt hypertensive rabbits (New Zealand White) were studied after durations of renal artery clipping that varied from 6 to 17 days. Measurements included arterial pressure (ABP), iliac venous pressure (IVP), left atrial pressure (LAP), cardiac output (CO) (by thermodilution), blood volume (BV), cardiopulmonary volume (CPV), and hindleg thermodilution volume (HLV). These were determined at steady-state as well as during acute blood volume expansion. In sham-clipped animals, ABP was 74 +/- 1 mm Hg. This increased to 92 +/- 3 mm Hg by 6 to 9 days post-clipping, to 96 +/- 3 mm Hg by 10 to 13 days, to 89 +/- 4 mm Hg by 14 to 17 days. CO remained near 150 ml/min . kg until Day 13 and fell to 127 +/- 8 ml/min . kg at 14 to 17 days because of a fall in heart rate. Blood volume and stroke volume did not change significantly from 62 +/- 1 ml/kg and 0.60 +/- 0.04 ml/kg, respectively. The development of hypertension was due entirely to changes in peripheral resistance. CPV was 8.5 ml/kg initially and increased significantly as hypertension developed. HLV did not change significantly from about 10 ml/kg. During acute blood volume expansion, hypertensive animals showed smaller transient increases in CO than did sham-clipped normotensives, but the associated blood pressure rise was greater. This reduced vasodilator capacity was accompanied by reduced distensibility of the cardiopulmonary bed. In sham-clipped animals, the cardiopulmonary pressure/volume slope was between 0.05 and 0.07 mm Hg per ml/kg. This increased to 0.44 mm Hg per ml/kg by 14--17 days of clipping. The corresponding value for the hindleg region did not change significantly from 0.2 mm Hg per ml/kg. Cardiac output and stroke volume were directly correlated with cardiopulmonary volume. The slope of this correlation decreased significantly during hypertension. The data suggest that decreased cardiopulmonary compliance in hypertension minimizes transient changes in cardiac output. This is especially important for arterial blood pressure control in view of the impaired vasodilator capacity of the hypertensive circulation.
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PMID:Regional vascular capacitance in rabbit one-kidney, one clip hypertension. 661 33

1. Within 24 h of surgical reversal of chronic Goldblatt two-kidney, one-clip hypertension in the rat, of greater than 4 months duration, blood pressure had fallen to normal levels. At this time there was no difference between the effects of removal of the clip or the ischaemic kidney but, at 60 days after reversal, the blood pressure of rats which had been nephrectomized was significantly higher than that of normal controls. 2. The fall in blood pressure was associated with a fall in total peripheral resistance to normal by 24 h despite the previous established fact that structural vascular changes take much longer to reverse. There was a corresponding rise in cardiac output, mainly due to an increase in stroke volume. Nephrectomized rats had a significantly higher stroke volume compared with those unclipped 24 h after operation. 3. As blood pressure can become normal in the presence of structural cardiovascular change by a fall in total peripheral resistance it would seem unlikely that resistance vessel hypertrophy is responsible for the maintenance of blood pressure in this model. Another peripherally acting mechanism therefore has to be postulated.
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PMID:Haemodynamic changes after surgical reversal of chronic two-kidney, one-clip hypertension in the rat. 731 10

Hypotensive and antihypertensive effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) in Wistar Kyoto rat (WKY), spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and DOCA-salt hypertensive rat (DOCA-HR) were compared with those of other representative calcium antagonists. The minimal effective hypotensive dose of S-312-d in WKY was 3 mg/kg p.o. and those in SHR, SHRSP, and DOCA-HR were 1 mg/kg p.o. in gum arabic suspension. The minimal antihypertensive dose of S-312-d in polyethylene glycol solution was 0.3 mg/kg p.o. in SHRSP. The antihypertensive effects of S-312-d was the most potent and long-lasting compared with the calcium antagonists, nifedipine, nicardipine, nimodipine, nilvadipine, and flunarizine. In conscious two-kidney Goldblatt-type hypertensive dogs, a significant antihypertensive effect and concomitant increases of heart rate with S-312-d at 1 mg/kg lasted for 4 to 6 h after oral administration. Determination of the plasma concentration of S-312-d by HPLC showed that more than 4.3 ng/ml of S-312-d is required for a significant antihypertensive effect. Subcutaneous administration of atenolol at 20 mg/kg 30 min before S-312-d significantly inhibited the tachycardia with S-312-d at 1 mg/kg p.o. but not its antihypertensive effect. S-312-d is considered useful for the treatment of essential hypertension and related organ disorders.
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PMID:Pharmacological studies on a new dihydrothienopyridine calcium antagonist. 3rd communication: antihypertensive effects of S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3-b] pyridine-5-carboxylate in hypertensive rats and dogs. 814 15

Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (> 35 mg/dL, n = 6), intermediate Lp(a) concentrations (20-25 mg/dL, n = 6), and low Lp(a) concentrations (< 12 mg/dL, n = 6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flow reductions (indicative of transient thrombosis) or permanent cessation of flow velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p < 0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flow but did not progress to permanent cessation of flow. There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a). 846 90

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.
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PMID:The cardiovascular and renal functional responses to the 5-HT1A receptor agonist flesinoxan in two rat models of hypertension. 886 20

Endothelins (ET) are 21-aminoacid peptides produced ubiquitously, which were discovered originally as endothelial products. These peptides may play important roles in cardiovascular physiology and pathophysiology. As the pathophysiologic roles of endothelins in cardiovascular disease become increasingly apparent, the potential therapeutic use of endothelin antagonists or endothelin converting enzyme inhibitors is recognized. The main endothelin produced by the endothelium is ET-1. Endothelin-1 is overexpressed in the vascular wall of salt-dependent models of hypertension, such as DOCA-salt hypertensive rats, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, and in stroke-prone SHR, angiotensin II-infused rats and 1-kidney 1 clip Goldblatt hypertensive rats, but not in SHR, 2-K 1C hypertensive rats or L-NAME-treated rats. The vasoconstrictor effect of ET-1 may contribute to blood pressure elevation and its growth-promoting action to vascular hypertrophy in the hypertensive models which overexpress ET-1 in blood vessels. In rats without generalized activation of the endothelin system, expression of ET-1 is often enhanced in coronary arteries, which suggests a role for ET-1 in myocardial ischemia in hypertension. In rats overexpressing ET-1, ETA/B and ETA-selective antagonists lowered blood pressure slightly, and significantly reduced vascular growth, particularly of small arteries, suggesting that ET-1 has a direct effect on growth. Protection from renal injury and from stroke has also been demonstrated in hypertensive rats treated with endothelin antagonists. In normotensive human subjects endothelin-dependent tone can be shown in the forearm. In a study of mild hypertensive patients, the ETA/B antagonist bosentan reduced blood pressure similarly to an ACE inhibitor. Moderate to severe hypertensive patients presented enhanced expression of ET-1 mRNA in the endothelium of subcutaneous resistance arteries. In blacks with familial hypertension increased plasma levels of endothelin have been found. Thus, ET-1 may play a role in some experimental hypertensive models and in human hypertension. In summary, endothelial ET-1 may be overexpressed in the more severe forms of hypertension, and in certain special populations which may respond particularly well to endothelin antagonism. Endothelin antagonists may prove to be effective disease-modifying agents if in future clinical trials they are shown clinically to blunt vascular growth and endothelial dysfunction, reduce stroke and exert the cardioprotective and renal protective effects already reported in experimental hypertension. These agents could contribute to reduce the long-term complications of hypertension, which remains to be demonstrated in humans.
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PMID:Endothelin: role in hypertension. 983 May 7


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