The effect of felodipine on the uptake and degradation of acetylated LDL in mouse peritoneal cells and on the distribution of acetylated LDL in macrophage-rich organs of the rat.

The effect of felodipine on lipoprotein metabolism ex vivo and in vivo was investigated. In the ex vivo studies mice were given felodipine (40-125 mumol/kg body weight) or vehicle for one week. Peritoneal macrophages from these animals and controls were isolated and used in binding and degradation studies with human iodinated acetylated LDL (Ac-LDL). Macrophages from felodipine-treated mice showed a significant decrease of binding and degradation of Ac-LDL compared to macrophages from control animals (P < 0.05). The in vivo studies were performed in rats pretreated with felodipine or vehicle. To determine the distribution and plasma turnover of LDL and Ac-LDL, 125I-tyramine cellobiose labelled LDL or Ac-LDL were given i.v. No differences in the removal rate of Ac-LDL or LDL were observed between felodipine-treated or untreated rats. However, an increased uptake of Ac-LDL could be seen in the liver of the felodipine-treated rats. This increased uptake could be ascribed to the parenchymal cells because no differences in uptake could be seen in the liver endothelial cells. However, a significant decreased uptake was seen in the Kupffer cells and in the spleen, a macrophage-rich organ, of the felodipine-treated rats. The present study suggests a possible mechanism behind the antiatherogenic effects of calcium antagonists, a decreased uptake of atherogenic modified lipoproteins by peripheral macrophages and an increased uptake by the liver.

Functional consequences of structural adaptation of the heart in hypertension.

Extent of myocardial shortening is inversely related to afterload. Maintenance of normal stroke volume (SV) in hypertension will therefore require elevation of cardiac performance. The question of whether left ventricular hypertrophy, which develops during chronic hypertension, enhances or depresses cardiac function has been examined experimentally. Cardiac function curves have been constructed and maximal cardiac output has been determined during rapid volume load in intact animals or in isolated perfused hearts from spontaneously hypertensive rats (SHR) and from normotensive rats. When preload, afterload, heart rate, and contractility are controlled, maximal performance is enhanced in the SHR heart, and its ability to increase contractility on elevations in afterload (homeometric autoregulation) is reset in proportion to the increase in arterial blood pressure. Although a reduced volume compliance of the SHR left ventricle has not been documented, its diastolic properties will still be influenced by the increased wall thickness. The reason is that a higher pressure is required to induce a given diastolic wall stress when wall thickness/radius ratio is increased according to Laplace's law. Since wall stress in turn determines the extent of myocardial shortening, maintenance of normal stroke volume in SHR calls for increased diastolic pressures or increased inotropic stimulation. The structural adaptation of the heart to hypertension will thus enhance its systolic performance, but will influence its diastolic properties so that secondary adjustments are required to enhance ventricular filling or the inotropic state of the heart, or both.

Influence of long-term antihypertensive therapy on cardiac function, coronary flow and myocardial oxygen consumption in spontaneously hypertensive rats.

The relationships between cardiac performance, coronary flow, coronary vascular resistance at maximal vasodilatation and myocardial oxygen consumption were determined in isolated hearts from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY) and from SHR given metoprolol (beta 1-selective blocker) and felodipine (selective calcium antagonist) for 35 weeks. A working heart perfusion system was used. An oxygen electrode allowed continuous measurement of oxygen tension in the venous coronary effluent. Blood pressure was reduced close to normal levels in treated SHR. Treatment also caused a substantial reduction of left ventricular weight. In both treated and untreated SHR, maximal cardiac performance, expressed as peak stroke volume, was enhanced above that of WKY at high perfusion pressures, while performance at low perfusion pressures was clearly reduced in the former groups. At a given workload, myocardial oxygen consumption (mmol O2/min per g) was reduced in both groups of SHR. This suggests a physiological structural adaptation to an elevated cardiac load in hypertension, where more myofibrils contribute to produce a given amount of work and therefore less oxygen is consumed per unit muscle mass. Coronary flow was reduced at any given perfusion pressure and oxygen extraction was increased in untreated SHR versus WKY. By causing regression of hypertensive structural vascular changes, treatment markedly increased coronary flow and correspondingly decreased oxygen extraction. Thus, by enhancing the myocardial nutritional supply with antihypertensive treatment, the reduced cardiac function at low perfusion pressure in untreated SHR was almost normalized.

Autonomic control of the diurnal variation in arterial blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats.

The relative influences of sympathetic and parasympathetic neural modulation on mean arterial pressure (MAP) and heart rate (HR), and their respective variabilities, were studied in young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and HR in unrestrained rats. In addition, the autonomic nervous control of MAP and HR was studied in ageing SHR and WKY. Both WKY and SHR showed diurnal rhythms with regard to MAP and HR. The MAP variability was higher in SHR than in WKY during both daytime (inactive) and night-time (active), and did not change in response to either beta 1-adrenoceptor- or cholinergic blockade. Structural vascular changes, with a resultant increase in reactivity, may explain the elevated MAP variability in SHR. HR variability was clearly reduced in SHR; this was not influenced by vagal blockade, whereas HR variability was significantly reduced in WKY. This pattern is suggested to be due to a reduced tonic vagal discharge in SHR, as part of a persistent, mild defence reaction. The initial reduction in vagal activity will in turn eliminate vagally mediated tachycardias. Furthermore, administration beta 1-blockade to SHR of different ages caused a greater fall in MAP and HR than in WKY, indicating an increased dependence upon the sympathetic nervous system in SHR with age.

Cardiac dimensions in spontaneously hypertensive rats following different modes of blood pressure reduction by antihypertensive treatment.

The present study examined changes in left ventricular design in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats in response to different types of antihypertensive therapy. Blood pressure was reduced for 12 weeks by either peripheral vasodilators [hydralazine or felodipine (calcium antagonist)] or by sympatholytic drugs (alpha-methyldopa or metoprolol). End diastolic volumes (EDV) were obtained in vitro by determining the diastolic pressure-volume relationships of isolated perfused hearts, arrested in diastole by excluding calcium from the perfusate. Wall thickness (w) and internal radius (ri) were calculated from a ventricle considered as a spherical model. Compared with WKY, untreated SHR had elevated EDV and w. Vasodilator therapy, particularly felodipine, increased EDV but reduced w, while sympatholytic therapy with alpha-methyldopa reduced EDV in SHR. It is suggested that cardiac design is affected not only by the prevailing arterial pressure level which will affect w, but also by the haemodynamic situation. Vasodilators turn such a situation into one characterized by increased cardiac output and hence increased cardiac filling, whereas sympatholytic drugs by venodilatation will turn the haemodynamic situation towards a state characterized by reduced cardiac filling. Left ventricular EDV (ri) therefore seems to adapt to long-term filling conditions, while w adapts to bring w:ri ratio in balance with the pressure load.

Regression of structural cardiovascular changes by antihypertensive therapy in spontaneously hypertensive rats.

Trophic adrenergic influences may in part potentiate the pressure dependent development of structural cardiovascular changes in hypertension. Regression of such changes by antihypertensive treatment should therefore be most successful if adrenergic blocking drugs are used. In the present study spontaneously hypertensive rats (SHR) received either alpha-methyldopa, metoprolol, felodipine, a new vasodilating Ca2+-antagonist, or metoprolol and felodipine in combination for 10 weeks. Their left ventricles were weighed and resistance vessel design was analysed using a haemodynamic technique. Arterial pressure (MAP) was equally reduced by metoprolol and felodipine. Despite their different modes of action cardiovascular design was also equally affected. The combined regimen reduced average MAP more than either drug alone. It also caused more pronounced regression of cardiovascular structural changes. Methyldopa lowered MAP less than either metoprolol or felodipine and had only modest effects on cardiovascular design. Thus, the extent of MAP reduction, regardless of which therapeutic regimen is used to induce it, determines the extent of regression of structural cardiovascular changes during antihypertensive treatment.

Haemodynamic effects of short and long term administration of felodipine in spontaneously hypertensive rats.

Short term administration of felodipine to spontaneously hypertensive rats reduced mean arterial pressure, due to peripheral vasodilatation. This vasodilatation is generalised, since blood flow, determined by the microsphere technique, is maintained or increased in most vascular beds despite substantial mean arterial blood pressure reduction. The resistance and mean arterial blood pressure reduction after felodipine was counterbalanced by an increase in cardiac output. In short term therapy, cardiac output increased because of an increase in both heart rate and stroke volume. Following long term administration of felodipine cardiac output remained elevated owing to an increase in stroke volume. The lack of tachycardia during long term felodipine administration was shown to be due to a rapid resetting of the baroreflex control of heart rate. The marked increase in stroke volume after long term administration is suggested to be due to regression of left ventricular hypertrophy and structural rebuilding of the heart towards that characteristic of the well-trained athlete. Thus, the haemodynamic pattern induced by short term felodipine administration, and probably also other antihypertensive drugs, will become modified by neurogenic and structural adaptations upon prolonged administration.

Pharmacodynamic properties of felodipine.

This overview presents the pharmacodynamic properties of felodipine as studied in animal experiments with emphasis on results from our laboratory. Felodipine is 100-fold more potent in causing inhibition of spontaneously active vascular smooth muscle than myocardium in vitro. This vascular selectivity is significantly greater than that of nifedipine (potency ratio 15). Verapamil, D-600, La3+ and reduction of [Ca2+]o lack selectivity. The cellular mechanisms underlying this variable selectivity are not clear at present. In conscious spontaneously hypertensive rats (SHR), the plasma concentration required for 20% reduction of mean arterial pressure is approximately 10 nmol. Mean arterial pressure is lowered dose-dependently as a result of reduced peripheral vascular resistance accompanied by increased cardiac output due to transient tachycardia and increased stroke volume. There was rapid resetting of the baroreflex set point but unaltered sensitivity after felodipine and hydralazine in SHR. Therefore, the reflexogenic increase in heart rate and plasma renin activity subsided within 3 to 5 hours of continuous felodipine administration in SHR. In addition, there was a uniform dilatation of the peripheral vascular beds after felodipine administration. During long term treatment of SHR with felodipine, progression of left ventricular and vascular wall hypertrophy was prevented. Within the 'therapeutic dose range', the only primary effect observed in addition to arterial vasodilation is diuresis/natriuresis caused by a renal tubular action.

Baroreflex control of renin release in spontaneously hypertensive rats after administration of felodipine.

The baroreflex control of heart rate will be rapidly reset to operate at a lower pressure level after blood pressure reduction by felodipine. The present study investigates whether the baroreflex control of renin release in spontaneously hypertensive rats (SHR) will also be reset after prolonged felodipine administration. Conscious SHR, fitted with catheters in the tail artery and vein, were given felodipine intravenously for 5 hours. The initial reflexogenic elevation in plasma renin activity and heart rate caused by felodipine-induced blood pressure reduction were successively normalised with time. Heart rate returned to pre-drug values after 3 hours and plasma renin activity after 5 hours of stable blood pressure reduction. This indicates rapid resetting of baroreflex control of both cardiac and renal function after blood pressure reduction by felodipine.

Effects of chronic felodipine treatment on renal function and morphology in SHR.

To investigate if blood pressure reduction per se may prevent progressive renal disease in aging spontaneously hypertensive rats (SHR), 15-month-old SHR were treated with the calcium antagonist felodipine, with the beta-blocker metoprolol or with the combination for six months. The combined regimen caused the greatest blood pressure reduction over time, metoprolol caused the least, while felodipine had an intermediate effect. At the end of treatment, urinary protein excretion and endogenous creatinine clearance were determined in rats kept in individual metabolic cages. At autopsy, the kidneys were histologically examined and indices of chronic progressive nephrosis and glomerular sclerosis were determined. A positive correlation was found between urinary protein excretion and glomerular sclerosis. Glomerular sclerosis was low in the groups of rats with high endogenous creatinine clearance. In both groups treated with felodipine, glomerular sclerosis and urinary protein excretion were significantly reduced compared to untreated controls. These results illustrate that the calcium antagonist felodipine attenuates proteinuria and glomerular sclerosis in aging SHR. The blood pressure reduction may be of major importance in this respect, although a direct action on the sclerotic process within the glomeruli may also contribute.

Renal effects of felodipine--a review.

Felodipine is a dihydropyridine calcium antagonist which lowers total peripheral resistance and blood pressure in doses which have no effect on cardiac conduction and contractility. It increases the urinary excretion of sodium and water due to decreased renal tubular reabsorption from the glomerular ultrafiltrate. This is observed at low doses which do not affect blood pressure, renal blood flow (RBF) or glomerular filtration rate (GFR). Felodipine decreases total renal vascular resistance and causes a transient increase in RBF in patients with normal RBF. In patients with low pretreatment values, RBF is increased during chronic treatment. Felodipine does not affect normal GFR. Thus filtration fraction may decrease. In patients with severe hypertension and reduced GFR, felodipine treatment results in good blood pressure control and increased GFR. In animal models of progressive renal disease due to hyperfiltration, felodipine has no negative effect on GFR, glomerulosclerosis or survival although proteinuria may increase. In salt-sensitive rats given high salt diet, resulting in hypertension, hypoperfused kidneys and progressive renal damage, felodipine treatment results in reduced blood pressure, increased RBF and GFR, and reduced proteinuria and glomerulosclerosis. In patients with previously refractory hypertension and progressive impairment of renal function, felodipine treatment results in good blood pressure control and a reduced rate of progression. In animals, felodipine limits the extent of renal damage after ischemia and reperfusion.

Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR.

Renal function and salt and water turnover were studied in SHR during acute and chronic administration of felodipine, which is an efficient antihypertensive vasodilating Ca2+ antagonist. In conscious SHR acute administration of felodipine in hypotensive doses increased renal sympathetic nerve activity but caused renal vasodilation, increases in GFR and a 2-3 fold increase in urinary flow rate and sodium excretion. The fraction of filtered sodium excreted (FENa) was approximately doubled. The diuretic and natriuretic effects of felodipine are therefore suggested to be due to a direct inhibitory action on the renal tubular cells, resulting in reduced sodium reabsorption. Nifedipine also induced diuresis and natriuresis in this system, while minoxidil reduced water and sodium excretion. Throughout 6 months of felodipine treatment, the mean arterial pressure (MAP), remained 25-20 per cent reduced. Felodipine in combination with metoprolol reduced MAP 25-30 per cent and also caused regression of left ventricular hypertrophy, while felodipine alone prevented its further progression. Also during chronic administration, felodipine induced diuresis but had no effect on plasma volume and on sodium or potassium excretion in SHR. It is concluded that in SHR felodipine induces diuresis; on acute treatment this is secondary to reduced tubular sodium reabsorption, although during chronic treatment the sodium loss is compensated for while the diuresis remains. Thus, the cardiovascular and renal effects of Ca2+ antagonists like felodipine differ substantially from those of other potent antihypertensive vasodilators e.g. minoxidil.

Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y(1) receptor antagonist, in vivo.

The object of the present paper was to investigate the in vivo pharmacological profile of the dihydropyridine neuropeptide Y Y(1) receptor antagonist 1,4-Dihydro-4-[3-[[[[3-[spiro(indene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine dicarboxylic acid, dimethylester (H 394/84). The renal vasoconstrictor response to neuropeptide Y in anaesthetized rats was dose-dependently antagonized by H 394/84 (ID(50) value=41+/-4 nmol/kg/min), whereas the renal vascular responses to noradrenaline and angiotensin II were only slightly affected by H 394/84 (500 nmol/kg/min). In pigs pretreated with reserpine and transection of sympathetic nerves (depleted of noradrenaline), H 394/84 dose-dependently antagonized renal and femoral vasoconstrictor responses evoked by sympathetic nerve activation (neuronally released neuropeptide Y) and exogenous neuropeptide Y. Significant inhibition was seen already at 1.0 nmol/kg/min, when plasma levels of the antagonist reached 29+/-4 nM. Around 70% of the antagonism remained 90 min after H 394/84 was given. The disposition of H 394/84 fits a biexponential model with initial and terminal half-lives of 2.6 and 48 min, respectively. H 394/84 (100 nmol/kg/min) did not inhibit vascular responses to neuropeptide Y Y(2) receptor-, alpha-adrenoceptor- or purinoceptor-activation in the pig in vivo. It is concluded that H 394/84 is a potent neuropeptide Y Y(1) receptor antagonist with rather long duration of action in vivo. The selectivity and specificity in vivo is more than 100-fold, and H 394/84 antagonizes vascular responses to exogenous and endogenous, neuronally released, neuropeptide Y with similar potency.

Cardiac inotropic vs. chronotropic selectivity of isradipine, nifedipine and clevidipine, a new ultrashort-acting dihydropyridine.

Cardiac effects of clevidipine, a new ultrashort-acting dihydropyridine Ca2+ channel antagonist were investigated in Langendorff-perfused rat hearts and compared to those of nifedipine and isradipine. The aim was to determine and compare the negative inotropic vs. chronotropic potency of these drugs. The hearts were perfused with oxygenated Krebs-Henseleit buffer at a perfusion pressure of 90 cm H2O. After stabilization, one concentration of each drug was administered for 45 min followed by a higher concentration for an additional 45 min. The concentrations of each drug in this study were 10(-9), 3 x 10(-9), 10(-8), 10(-7), 10(-6.5) and 10(-6) M for clevidipine and nifedipine, and 10(-10), 3 x 10(-10), 10(-9), 10(-8), 10(-7.5) and 10(-7) M for isradipine. Each concentration of each drug was tested in six hearts. Coronary flow, left ventricular dP/dt max, left ventricular systolic pressure and heart rate were recorded when the hearts were beating spontaneously and during pacing at a constant rate for 1 min. Spontaneous heart rate and atrio-ventricular conduction were not affected by clevidipine at any of the concentrations studied, while nifedipine and isradipine caused a concentration-dependent decrease. These two drugs caused atrio-ventricular block at high concentrations. All three compounds reduced cardiac contractility in a concentration-dependent manner. When isradipine was administered, at a given concentration, heart rate and contractility decreased proportionately. When clevidipine or nifedipine was given, at a given concentration, the proportionate reduction in left ventricular dP/dt max was greater than that in heart rate, resulting in a high inotropic vs. chronotropic selectivity. It is concluded that in contrast to nifedipine and isradipine, clevidipine does not impair atrio-ventricular conduction. Like nifedipine, clevidipine is selective for inotropic vs. chronotropic cardiac effects.

Attenuation of renal ischaemic injury by felodipine.

Felodipine is a vasodilating calcium channel blocker of the dihydropyridine type. The effects of felodipine on post-ischaemic renal function were evaluated in rats subjected to bilateral renal artery occlusion for 30 or 60 min. In a first set of experiments the recovery of renal function after 30 or 60 min of renal artery occlusion was followed intermittently for 16 days by endogenous creatinine clearance. Renal function was better preserved in rats given felodipine (45 nmol/kg i.v.) during the occlusion period than in vehicle-treated control rats. The survival rate after 60-min occlusion was 11% in controls but 70% in the felodipine-treated rats. After occlusion for 30 min the survival rate was similar in the two groups, but renal function recovered faster in the felodipine group than in the controls. In a second series, acute renal damage was evaluated by the extent of erythrocytes trapped in the kidney after 30-min reperfusion following 60-min renal artery occlusion. Felodipine administration (45 nmol/kg) during the occlusion reduced renal damage compared with vehicle controls. Kidney weight and systemic haematocrit were also better maintained in the felodipine-treated rats. Furthermore, renal damage was reduced by the t-butyl analogue or felodipine. H 186/86, which is devoid of vasodilatory effects. The results demonstrate that treatment with the vasodilator calcium channel blocker felodipine protects the kidney from ischaemic/reperfusion injuries. The tissue protection is not related to the haemodynamic effects alone, since the haemodynamically inactive dihydropyridine H 186/86 also reduced the extent of renal damage. An additional antiperoxidant or scavcnger-like effect inherent in the dihydropyridine molecule is suggested.

Inhibition of vascular myogenic tone and reactivity by calcium antagonists.

In most organs basal vascular tone is maintained by the myogenic tone in the smooth muscles of the resistance vessels. Commonly used antihypertensive calcium antagonists reduce peripheral resistance and hence vascular tone, suggesting inhibition of myogenic tone. The findings supporting this hypothesis are reviewed here. Evidence for direct inhibition of myogenic tone by calcium antagonists includes findings in the hindleg of the anaesthetized cat, in which basal myogenic tone (prevailing resistance minus the resistance at maximal dilation) was dose-dependently reduced by felodipine. Furthermore, induced responses to vasomotor nerve stimulation were depressed by felodipine to the same relative extent as was the basal myogenic tone. The phasic spontaneous force development, which is of myogenic origin in the rat portal vein, was reduced after the administration of verapamil, diltiazem or felodipine. The adrenergic potentiation of this myogenic activity was also depressed to the same relative extent as felodipine depressed the spontaneous contractile force. The effect of calcium antagonists on myogenic reactivity seems to be even more pronounced than their effect on myogenic tone. Thus, transient vasoconstriction in response to a rapid increase in transmural pressure in the hindleg of the anaesthetized cat was reduced to a relatively greater extent by calcium antagonists than the basal myogenic tone. The attenuation of renal and cerebral blood flow autoregulation that has been observed after the administration of calcium antagonists also suggests a direct effect on myogenic reactivity. These results suggest that calcium antagonists interfere with activation in myogenically active vascular smooth muscle, resulting in reductions in myogenic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms behind myocardial depression in rat renal hypertension.

Cardiac function in rat renal hypertension has been shown repeatedly to be depressed. The reason for this impairment has not been fully understood, although cardiac hypertrophy and increased collagen content have been claimed as possible causes. To further unravel the mechanisms underlying the deterioration of left ventricular function in rat renal hypertension, we investigated cardiac function, myocardial morphology, myosin iso-enzymes, plasma renin activity and levels of myocardial high-energy compounds in hearts from rats exposed to renal and reversed renal hypertension. Maximal cardiac function was unaltered in hearts exposed to antihypertensive therapy from the time of renal artery clipping compared with untreated hypertensive rats. The observed alterations of iso-enzyme pattern, plasma renin activity levels and myocardial morphology among the groups showed to be of less importance with respect to cardiac performance. Together with previous results from our laboratory, the present findings suggest that some negative inotropic agent of renal or non-renal origin is released during two-kidney, one clip renal hypertension, which counteracts the enhanced left ventricular performance induced by cardiac hypertrophy.

Sympathetic and parasympathetic influence on blood pressure and heart rate variability in Wistar-Kyoto and spontaneously hypertensive rats.

The relative influence of sympathetic and parasympathetic nervous control of heart rate and heart rate variability, of mean arterial pressure (MAP) and MAP variability was investigated in young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and heart rate every 2.5 min in freely moving rats with indwelling arterial catheters. Variability was expressed as the standard deviation in each rat. Heart rate and MAP showed clear diurnal rhythms, both in WKY and SHR. Blood pressure variability was clearly higher in SHR than in WKY, both during dark active hours and during light hours of relative sleep, and it did not change in response to either beta-adrenoceptor or vagal blockade. Structural vascular changes with the consequent increase in vascular reactivity may be one explanation for the elevated blood pressure variability in SHR. Heart rate variability was clearly reduced in SHR compared with WKY. This may be due to a reduced tonic vagal discharge in SHR, whereby a vagally mediated tachycardia is eliminated. The vagal withdrawal is part of the defence reaction, which is more easily elicited in SHR than in WKY.

Peripheral haemodynamics after surgical reversal of two-kidney, one clip renal hypertension in rats.

The changes in peripheral haemodynamics and regional resistances were studied during the rapid fall in mean arterial pressure (MAP) after surgical reversal of two-kidney, one clip renal hypertension in rats (RHR). The controls used were sham-declipped RHR and normotensive control rats (NCR). During the 2 h following renal artery declipping or sham-operation, MAP and heart rate (HR) were followed continuously. Finally, the regional blood flows in the kidneys, small intestine and skeletal muscle were determined by the microsphere technique. Declipping caused MAP to fall from 167 +/- 5 to 108 +/- 5 mmHg (n = 10) with a concomitant fall in HR from 424 +/- 11 to 363 +/- 14 beats/min (P less than 0.01). The calculated vascular resistances fell in the intestinal and declipped renal vascular beds by 50-60% compared with sham-operated rats (P less than 0.01). However, vascular resistances remained unchanged in skeletal muscle and in the untouched kidney. This indicates that the reduction in flow resistance varies in the different vascular beds, presumably reflecting a mixture of suppressed sympathetic activity and direct vasodilatory actions induced by mechanisms activated upon reversal of two-kidney, one clip renal hypertension by renal artery declipping.

Structural and functional adaptations within the myocardium and coronary vessels after antihypertensive therapy in spontaneously hypertensive rats.

The relationships between cardiac performance, coronary flow, minimal coronary vascular resistance and myocardial oxygen consumption (MVO2) were explored in isolated hearts from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and in hearts from SHR given a combination of metoprolol and felodipine (selective calcium antagonist) for 35 weeks. Antihypertensive therapy markedly reduced arterial pressure and caused a substantial regression of left ventricular hypertrophy. An antegrade working-heart perfusion system was used, allowing measurements of stroke volume, coronary flow and MVO2 at varying pre- and afterloads. In untreated SHR cardiac function was reduced at low and enhanced at high perfusion pressure compared with WKY. Minimal coronary vascular resistance, which was greatly increased in SHR, was significantly reduced by treatment, allowing higher coronary flow for any given perfusion pressure and consequently a lower degree of oxygen extraction. In addition, at a given workload, MVO2 was reduced in both untreated and treated SHR. These results stress the importance of having adequate coronary perfusion within a hypertensive structurally redesigned coronary vascular bed in order to maintain cardiac performance. With antihypertensive therapy in SHR, an improved coronary flow capacity was created due to regression of the hypertensive vascular changes.