Hypertensive Vessels Research Articles

Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats.

We previously reported that apoptosis is increased in smooth muscle cells cultured from the aorta of spontaneously hypertensive rats versus normotensive controls. As an initial in vivo exploration, we now examined smooth muscle cell apoptosis regulation during the regression of vascular hypertrophy in the thoracic aorta media of spontaneously hypertensive rats receiving the antihypertensive drug enalapril (30 mg.kg-1.d-1), losartan (30 mg.kg-1.d-1), nifedipine (35 mg.kg-1.d-1), hydralazine (40 mg.kg-1.d-1), propranolol (50 mg.kg-1.d-1), or hydrochlorothiazide (75 mg.kg-1.d-1) for 1 to 4 weeks starting at 10 to 11 weeks of age. Three criteria were used to evaluate smooth muscle cell apoptosis: (1) oligonucleosomal fragmentation of the extracted aortic DNA, (2) reduction in aortic DNA content, and (3) depletion of smooth muscle cells in the arterial media. Arterial DNA synthesis was evaluated by [3H]thymidine incorporation in vivo. After 4 weeks of treatment, systolic blood pressure was reduced significantly by > 42% with losartan, enalapril, and hydralazine, and by 23% with nifedipine, versus control values of 220 +/- 5 mm Hg. However these agents affected vascular growth and apoptosis differently. Losartan, enalapril, and nifedipine stimulated smooth muscle cell apoptosis threefold to fivefold before there was a significant reduction in DNA synthesis (> 25%), vascular mass (> 19%), or vascular DNA content (> 38%), and these treatments markedly reduced (by 38% to 50%) medial cell number as measured at 4 weeks by the three-dimensional disector method. Losartan and nifedipine stimulated smooth muscle cell apoptosis before reducing blood pressure. In contrast, hydralazine did not affect vascular mass, apoptosis, or DNA synthesis, although blood pressure was lowered. Propranolol or hydrochlorothiazide failed to affect hypertension or vascular growth. Thus, smooth muscle cell apoptosis represents a novel therapeutic target for the control of hypertensive vessel remodeling in response to therapeutic agents.

Role of adventitia in vascular remodeling in hypertension: a trophobiological view

The vascular wall has the capacity to undergo remodeling in response to long-term changes or injuries. This is a process of structural rearrangement that involves cell growth, cell death, cell migration, cell modulation and secretion/degradation of extracellular matrix molecules. Vascular remodeling is an adaptive phenomenon, e.g. Glagov's compensatory enlargement in atherosclerosis, but it may grow into vascular diseases, such as hypertension, atherosclerosis, and coronary restenosis after angioplasty. Nowadays paradigms defining the cell biology of vascular diseases are the following: (i) the hypertensive vessel is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell (SMC) hypertrophy/hyperplasia and increased extracellular matrix content, (ii) the atherosclerotic plaque is characterized by SMC/immune cells/increased extracellular matrix-containing intimal thickening, and (iii) the restenotic coronary artery is characterized by SMC/immune cells-containing neointimal thickening. The spontaneously hypertensive rats (SHR), the stroke-prone SHR (SHRSP), the genetically hypertensive (GH) rats, and other genetically hypertensive strains are widely used as a model of human essential hypertension. In this volume of Biomedical Reviews, Bell updates the knowledge about vascular wall neurotrophobiology in relation to the pathogenesis of hypertension in SHR and GH rats. Also, Kondo et al systematize the perivascular nerve-related SMC structural changes in the development of hypertension in SHR and SHRSP. The data presented in these reviews are evaluated mainly in terms of Levi-Montalcini's neurotrophic theory. Biomedical Reviews 1996; 6: 5-10.

Effects of Angiotensin-Converting Enzyme Inhibitors on the Heart and Vessels in Clinical and Experimental Hypertension

The primary aim of antihypertensive therapy is to reduce blood pressure. Whatever their mechanisms of action, almost all the antihypertensive drugs currently available can be considered to achieve this goal. However, the most common complications of hypertension (myocardial infarction, thrombolytic stroke and sudden cardiac death) are related to structural cardiovascular changes rather than being directly related to blood pressure elevation. Thus, it would appear logical that an optimum antihypertensive drug should also prevent and reverse the cardiovascular abnormalities associated with hypertension before irreversible damage occurs. The different classes of antihypertensive drug are in fact largely successful in preventing or reversing these target abnormalities, in particular cardiac and vascular abnormalities. In hypertensive patients, angiotensin-converting enzyme (ACE) inhibitors appear to be particularly effective in achieving this goal, probably because they alter vascular wall and cardiac structure, irrespective to some extent of the haemodynamic changes they produce. ACE inhibitors may have particularly beneficial effects on left ventricular mass because of their favourable interference with growth factors; an increased production of bradykinin, and hence of nitric oxide, may add further benefit. ACE inhibitors also prevent and/or reduce reactive perivascular and interstitial growth, as well as fetalisation of cardiac myocytes. Furthermore, in common with calcium channel antagonists and nitrates, ACE inhibitors improve arterial compliance, and thus decrease cardiac load. Indirect evidence suggests that a reduction in left ventricular hypertrophy during antihypertensive therapy reverses the pathological consequences of an increased left ventricular mass, although further studies are needed to assess the true clinical impact of these treatment-induced changes in the morbidity and mortality of hypertensive patients.

Elevated pressure stimulates protooncogene expression in isolated mesenteric arteries.

The aim of this study was to determine whether an increase in pressure alone is a sufficient stimulus in isolated small arteries to induce the immediate early genes that are associated with vascular wall growth. Mesenteric arteries (303-506 microm diam) were isolated from Wistar rats and subjected to static pressure of 90 mmHg (control) or 140 mmHg (hypertensive). The arteries possessed little active tone or myogenic response to pressure elevation; therefore, both sets of vessels were stretched by similar amounts, but wall stress in the hypertensive vessels was 60-80% above that of controls. After 30, 60, 180, and 360 min, the arteries were fixed in Formalin, embedded in paraffin, and sectioned for in situ hybridization. The levels of mRNA for c-fos increased in the hypertensive arteries 2.33-fold at 30 min and 6.64-fold at 60 min. mRNA for c-myc increased 5.13-fold at 60 min and 5.25-fold at 180 min. After this early response gene induction, 18S rRNA increased in hypertensive vessels: 3.35-fold at 180 min and 4.2-fold at 360 min. These changes were not the result of a nonspecific activation of total gene expression in hypertensive vessels, inasmuch as levels of mRNA for beta-actin did not differ from controls; however, hypertensive and control vessels showed increases at 60 min. These results indicate that increased pressure is a sufficient stimulus for protooncogene induction and rRNA production in vascular smooth muscle cells in the arterial wall and suggest that the mechanical signal is wall stress. Therefore, this model represents a unique tool to complement cultured cells for the study of the signaling pathways in the mechanotransduction of a pressure stimulus.

Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats

Background/Aim: Portal hypertension is characterized by splanchnic hyperemia due to a reduction in mesenteric vascular resistance. Mediators of this hyperemia include nitric oxide. This is based on several reports indicating a marked splanchnic hyporesponsiveness in portal hypertension to vasoconstrictor stimuli both in vitro and in vivo, and a subsequent reversal using specific inhibitors of nitric oxide synthase. The objective of this study was to determine firstly whether the functional activity and/or expression of nitric oxide synthase is altered in portal hypertensive vasculature and secondly which isoenzyme form was responsible for the preferential response to nitric oxide blockade in these animals. Methods: We compared nitric oxide synthase functional activity in the hyperemic vasculature of sham and portal hypertensive rats (following partial portal vein ligation). Nitric oxide synthase activities were determined by measuring the conversion of L-arginine to citrulline using ion-exchange chromotagraphy and the amount of immunodetectable nitric oxide synthase in sham and portal hypertensive vessels was determined by Western blot. Results: Ca 2+-dependent nitric oxide synthase activity was significantly elevated ( p<0.05) in portal hypertensive particulate fractions from the superior mesenteric artery, thoracic aorta and portal vein. Vascular tissue cGMP levels and plasma nitrite levels were both significantly elevated in portal hypertension. Immunodetection with specific antisera raised against the inducible nitric oxide synthase demonstrated a lack of induction within the hyperemic vasculature. Immunodetection with antisera against endothelial nitric oxide synthase showed a significant increase in portal hypertensive portal vein only. These results demonstrate enhanced calcium-dependent nitric oxide synthase activity in portal hypertension hyperemic vessels concurrent with elevated tissue cGMP levels. Conclusion: We conclude that enhanced endothelial nitric oxide synthesis may in part contribute to the hyperdynamic circulation of portal hypertension.

Renal and vascular effects of chronic endothelin receptor antagonism in malignant hypertensive rats

The effect of the combined ETA/ETB endothelin receptor antagonist bosentan on blood pressure, vascular hypertrophy, and pathologic renal changes was investigated in a model of malignant hypertension, severe vascular hypertrophy, and enhanced vascular expression of endothelin-1, the deoxycorticosterone acetate (DOCA), and salt-treated spontaneously hypertensive rat (SHR). DOCA-salt treated SHR received 100 mg bosentan per kilogram weight per day mixed with their food. Systolic blood pressure of untreated DOCA-salt SHR rose to 241 +/- 1.5 mm Hg, whereas that of bosentan-treated rats rose to 221 +/- 5.1 mm Hg (P < .01). Cardiac and conduit artery mass were not affected by treatment. Small arteries from the coronary, renal, and mesenteric circulations showed a smaller media width and cross-sectional area of the media in rats treated with bosentan than in untreated rats. The kidneys showed the presence of fibrinoid necrosis in a high percentage of afferent arterioles and glomeruli of untreated DOCA-SHR. Some kidneys of treated rats exhibited less severe vascular hypertrophy and lesser extent of vascular or glomerular fibrinoid necrosis, but the renal injury score of bosentan-treated DOCA-SHR was only at the limit of significance from that of untreated rats (P = .06). These results suggest a role for endothelin-1 in blood pressure elevation and the severe vascular hypertrophy of small arteries of the coronary, renal, and mesenteric vasculature, but not of the heart or larger conduit vessels in the malignant hypertension that SHR develop after treatment with DOCA and salt. Although some bosentan-treated rats showed fewer renal lesions, a significant effect on renal pathology could not be unambiguously demonstrated. Further studies will be necessary to determine whether endothelin antagonists may indeed offer some degree of renal protection and have therapeutic potential in severe or malignant hypertension.

Effect of endothelin antagonism on blood pressure and vascular structure in renovascular hypertensive rats.

To investigate the potential pathogenic role of endothelin in blood pressure elevation and vascular hypertrophy in renovascular hypertensive rats, which present twofold elevations in endothelin-1 mRNA abundance in blood vessels, the response of blood pressure and vascular structure to chronic treatment with the endothelin receptor antagonist bosentan was evaluated. One-kidney, one clip (1K,1C) and two kidney, one clip (2K,1C) Goldblatt hypertensive rats were treated for 2 wk with bosentan (100 mg.kg-1.day-1) in their chow, and systolic blood pressure was measured by the tail-cuff method. Vascular structure was studied in small arteries mounted on a wire myograph. Treatment with bosentan did not result in a significant change in systolic blood pressure or in the structure of small coronary, renal cortical, mesenteric, or femoral arteries in 1K, 1C or in 2K, 1C hypertensive rats. In conclusion, modest (twofold) elevations of endothelin-1 gene expression in blood vessels in renovascular hypertension are not associated with hypotensive responses or regression of vascular hypertrophy during treatment with endothelin antagonists in contrast to what is found in deoxycorticosterone acetate salt hypertensive rats, which exhibit very dramatic increases in endothelin-1 expression (five-to eightfold) and do respond to endothelin antagonism with blood pressure lowering and regression of vascular hypertrophy. These small elevations of vascular endothelin-1 gene expression thus do not appear to indicate the presence of an endothelin component in blood pressure elevation in renovascular hypertension in rats.

DIPYRIDAMOLE ENHANCES RELAXATIONS AND cGMP GENERATION TO NITRIC OXIDE IN LAMBS WITH PERSISTENT PULMONARY HYPERTENSION (PPHN). • 2090

We have previously shown that the cGMP specific phosphodiesterase inhibitor zaprinast enhances the effect of NO in lambs with PPHN (AJRCCM 1995; 152: 1605). We now studied the effect of an equimolar concentration of the commercially available phosphodiesterase inhibitor dipyridamole (DIP) on relaxations to sodium nitroprusside (SNP). Fourth generation pulmonary arteries were isolated from 5 near-term fetal lambs with PPHN following ligation of the ductus arteriosus 10 days prior to delivery and age matched controls. Vessels were submaximally preconstricted with norepinephrine (NE, 1μM) following pretreatment with indomethacin. Relaxations to increasing concentrations of SNP (1-1000 nM) were then compared in PA with and without pretreatment with dipyridamole (30 μM). Without DIP, there was decreased sensitivity to SNP in hypertensive vessels (EC50's: Control = 52 ± 11 nM; Hypertensive = 145 ± 64 nM, p<0.05 by ANOVA). DIP significantly enhanced relaxations to SNP in both groups (EC50's: Control = 1.1 ± 0.6 nM; Hypertensive = 28 ± 9 nM). A second series of experiments directly measured cGMP concentrations in PA by 125I RIA following stimulation with 1 μM SNP, 30 μM DIP, or both compounds and subsequent rapid freeze-clamping. Data are expressed as fmol cGMP/mg tissue weight, and compared by ANOVA: *p <0.05 vs. without SNP, †p<0.05 hypertensive vs. control. Table

Functional changes of forearm resistance vessels in essential hypertension

Functional changes of forearm resistance vessels in essential hypertension

Immunohistochemical localization of extracellular matrix proteins in cerebral vessels in chronic hypertension.

Vascular hypertrophy or vascular remodeling are both associated with an increase in the extracellular matrix of cerebral arteries and arterioles in chronic hypertension. Rats with chronic renal hypertension were studied to determine whether the extracellular matrix proteins--collagen IV, laminin, and fibronectin--are increased in the thick-walled cerebral vessels in brain and those associated with areas of blood-brain barrier (BBB) breakdown to protein. The latter was detected by extravasation of endogenous serum proteins in brain. Serum proteins and the extracellular matrix proteins--fibronectin, laminin, and collagen IV--were detected by immunohistochemistry. Hypertensive rats having blood pressures over 150 mm Hg showed mild to moderate degrees of mural thickening of pial and intracerebral arterioles. In addition, these vessels demonstrated increased immunoreactivity with collagen IV, fibronectin, and laminin antisera. This occurred concomitant with the development of hypertension and prior to the observation of BBB breakdown to protein. Four rats having mean maximum systolic blood pressures in excess of 220 mm Hg developed multifocal areas of increased vascular permeability to endogenous serum proteins in the boundary zones of the territories supplied by the major cerebral arteries. The arterioles in these areas showed a severe degree of vascular thickening, which was due to medial hyperplasia/hypertrophy and increased mural deposition of serum proteins and the extracellular matrix proteins--laminin, fibronectin, and collagen IV. This study demonstrates that extracellular matrix proteins play an important role in the vascular response to increased intraluminal pressure. However, since this change occurs in diseases in the absence of hypertension it should be regarded as a nonspecific response of cellular components of vessel walls to injury.

Sick Vessel Syndrome

This review describes vascular changes in atherosclerotic and hypertensive vessels as well as effects of treatment. Changes in vascular structure in both atherosclerosis and hypertension are characterized by thickening of the vessel wall and vascular "remodeling." Remodeling tends to preserve the size of the lumen in atherosclerotic vessels and results in a smaller lumen in hypertensive vessels. Changes in vascular function are characterized by preservation of smooth muscle relaxation, with the exception of activity of ATP-sensitive potassium channels, and dysfunction of endothelium. Regression of atherosclerosis, by treatment of hyperlipidemia, results in quite rapid removal of lipid from the vessel wall but with inconsistent improvement in maximal vasodilator capacity. In contrast, endothelial function improves during regression of atherosclerosis, and hyperresponsiveness to serotonin subsides rapidly. Effective treatment of hypertension produces regression of vascular hypertrophy, and some approaches (especially angiotensin-converting enzyme inhibitors) are effective in correcting vascular remodeling. Endothelium-dependent relaxation generally improves during antihypertensive treatment. Reduction in pulse pressure may be more important than reduction in mean arterial pressure in reversing the structural and functional abnormalities of hypertensive vessels.

The heart and vascular changes in hypertension.

To review present knowledge on the causes of cardiovascular changes in hypertension and on the effects of antihypertensive treatment. The clinical manifestations of hypertensive heart disease have changed considerably in recent decades, from predominantly cardiac failure to predominantly left ventricular hypertrophy, which is an independent risk factor for all cardiovascular events. This change parallels the recent development of ultrasonic devices which make it possible to investigate the vessels as well as the heart. These devices have shown that there are different types of cardiac remodeling, which are associated with different hemodynamic profiles. Recent studies have shown that antihypertensive treatment, both pharmacological and non-pharmacological, can significantly reduce left ventricular hypertrophy in hypertensive patients without jeopardizing the hemodynamic balance. However, hypertensive vessel disease has been less extensively investigated, with many studies concentrating on the carotid arteries. There appears to be a correlation between cardiac and carotid artery changes but so far there is no information on the effects of the antihypertensive treatment on the carotid alterations.

Intracellular signal transduction for vasoactive peptides in hypertension.

Increased peripheral resistance is the hallmark of hypertension. It may result in part from exaggerated vascular reactivity of resistance arteries. Some changes in density of surface receptors for different vasoconstrictors and vasorelaxants have been described that could play a role in physiological findings in hypertension. Smooth muscle cells of resistance arteries have increased cytosolic free calcium concentration in some models of experimental hypertension, which may contribute to enhance vascular responses. Exaggerated response of the inositol phosphate-calcium pathway has been demonstrated after stimulation with some vasoconstrictor agents such as norepinephrine, angiotension II, and vasopressin. In contrast, responses to the potent vasoconstrictor peptide endothelin-1 are either normal (in spontaneously hypertensive rats) or blunted (in deoxycorticosterone-salt hypertension). In the latter case, endothelin receptor density, inositol phosphate and diacylglycerol generation, and cytosolic calcium responses agree with blunted response of blood vessels. Increased basal cytosolic calcium and exaggerated sensitivity of myosin light chain to calcium may be mechanisms underlying increases in sensitivity of signal transduction in smooth muscle in some models of hypertension. However, in general, signal transduction of receptors for vasoconstrictors appears to be blunted rather than exaggerated, except for responses to angiotensin II. Altered structure of resistance arteries (remodeling) may be a mechanism that, even in presence of blunted intracellular signal transduction, may result in enhanced pressor responsiveness of blood vessels in hypertension.

In vitro perfusion studies of human resistance artery function in essential hypertension.

To simulate in vivo conditions as closely as possible to in vitro conditions, we examined the morphological and functional characteristics of isolated human subcutaneous small arteries from 17 essential hypertensive patients and 14 normotensive control subjects using a perfusion myograph. Vessel segments were cannulated and exposed to conditions of constant flow and pressure. The ratio of media thickness to lumen diameter in arteries from hypertensive patients increased significantly. With the endothelium intact, sensitivity to extraluminally applied norepinephrine was not different, and this was not affected by inhibition of neuronal amine uptake with cocaine. After removal of the endothelium, sensitivity to norepinephrine was augmented in normotensive vessels to a greater extent than in hypertensive vessels. Endothelium-dependent relaxation to acetylcholine was significantly reduced in arteries from hypertensive patients, but endothelium-independent relaxation to sodium nitroprusside was not different from that observed in vessels from normotensive control subjects. These data demonstrate that sensitivity to exogenous norepinephrine is not different in essential hypertension but that there is defective endothelium-dependent dilatation, suggesting a contributory role for endothelium dysfunction in human essential hypertension.

Differentiation and growth of vascular smooth muscle cells in experimental hypertension.

In this review we have analyzed the present knowledge about the differentiation and growth processes in vascular smooth muscle cells (SMC) in hypertension. The study of smooth muscle (SM) and nonmuscle (NM) myosin isoform expression has permitted us to identify a three-stage specific maturational pathway, namely, fetal, postnatal, and adult. In the renovascular (rabbit) and genetic (rat) models of hypertension, adaptive changes occurring in hypertensive vessels make SMC resemble those found in the early stages of development (smooth muscle plasticity). In fact, based on SM- and NM-myosin isoform distribution, postnatal-type SMC predominate in the arterial media during the early remodeling of the arterial wall that occurs in hypertension, whereas postnatal- and fetal-type SMC predominate in the intimal thickening. Locally produced or activated autocrine/paracrine factors, such as growth factors or cytokines, along with circulating hormones, seem to be involved in the growth response or changes in the differentiation pattern of SMC. Thus, these factors not only play a specific role in the regulation of blood pressure, but also are likely to be responsible for the remodeling of the arterial wall in hypertension.

Long-term administration of L-arginine improves nitric oxide release from kidney in deoxycorticosterone acetate-salt hypertensive rats.

To examine the effects of L-arginine (L-Arg) on endothelial function, we administered 0.5 g/L L-Arg in drinking water to deoxycorticosterone acetate (DOCA)-salt rats for 8 weeks and then measured nitric oxide (NO) release from isolated kidneys using a newly developed real-time chemiluminescence method. Renal pathology was also analyzed. Acetylcholine caused much smaller declines in renal perfusion pressure (10(-7) mol/L acetylcholine: -24 +/- 2% [SEM] versus -50 +/- 2%, P < .001) and NO release in DOCA-salt rats (+3 +/- 1 versus +33 +/- 3 fmol/min per gram kidney weight, P < .001) compared with control rats. L-Arg did not influence the time course of systolic blood pressure elevation in DOCA-salt rats (211 +/- 5 versus 208 +/- 6 mmHg, DOCA versus L-Arg/DOCA, P = NS). However, oral administration of L-Arg improved acetylcholine-induced declines in renal perfusion pressure (10(-7) mol/L acetylcholine: L-Arg/DOCA, -39 +/- 3%, P < .01 versus DOCA). This change was associated with an increase in NO release by acetylcholine (10(-7) mol/L acetylcholine: L-Arg/DOCA, +10 +/- 1 fmol/min per gram kidney weight, P < .05 versus DOCA). However, morphological changes in renal vessels and glomeruli were similar between DOCA and L-Arg/DOCA rats. These results suggest that L-Arg administration partially reverses renal endothelial function with respect to vasorelaxation and NO release independent of blood pressure changes, indicating that hypertensive vessels seem to be depleted of L-Arg and/or have defects in the availability of L-Arg for NO synthesis.

Effects of Antihypertensive Treatment on Vascular Remodeling in Essential Hypertensive Patients

Resistance arteries may play a critical role in hypertension, and correcting their structural abnormalities may improve the clinical outcome of hypertensive patients. There have been several studies of the effects of antihypertensive treatment on the structure of resistance vessels in hypertension. These studies have yielded inconclusive results regarding the ability of individual drugs to induce regression of the changes occurring in blood vessels in hypertension, both in experimental models and in humans. This article reviews the results of studies of antihypertensive treatment on resistance vessel structure and function, and in particular those of a recent study in which the effects of treatment with the angiotensin-converting enzyme inhibitor cilazapril and the beta-blocker atenolol on the structure and function of subcutaneous resistance arteries were evaluated in a double-blind randomized trial in patients with mild essential hypertension. In this study, patients were randomly assigned to receive either cilazapril or atenolol, and blood pressure was effectively controlled for 1 year. Treatment for 1 year with cilazapril resulted in a significant reduction in the media-to-lumen ratio of resistance arteries dissected from subcutaneous gluteal fat biopsy samples, although the ratio was still slightly but significantly larger than that of resistance arteries of normotensive controls. In arteries from patients treated with atenolol there was no significant change in media-to-lumen ratio with treatment. Contractile responses to several vasoconstrictors, particularly endothelin-1, which were blunted in hypertensive patients, were normalized in the cilazapril-treated patients, but were unchanged in those taking atenolol. These results suggest that in humans it is possible to correct in part the vascular remodeling present in hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension as a Risk Factor for Stroke Subtypes

Hypertension is one of the most important risk factors for stroke. However, it is less clear what stroke subtypes have particulary high relative risks associated with treated hypertension. On theoretical grounds, lacunar infarction syndromes and primary intracerebral haemorrhage are more likely to fall into this category since their pathogenesis is thought to relate to underlying hypertensive small vessel changes (lipohyalinosis). For lacunar infarction syndromes there is considerable debate as to whether hypertension is actually a more potent risk factor than for all other formms of cerebral infarction combined. In the case of cerebral haemorrhage, there have been very few studies performed in the post-CT scan era and hence the true relative risk is very poorly quantitated. More epidemiological studies are required to clearly identify stroke subgroups in which hypertension has had the most impact. (Hypertens Res 1994; 17 Suppl. I: S51-S54)

Early Structural Changes in Hypertension

The structural upward resetting of heart, vessels, and barostat functions represents what may be the most important long-term cardiovascular alteration in hypertension; the altered geometric design of the systemic precapillary resistance vessels is of profound hemodynamic relevance. This is especially true in primary (essential) hypertension, for which three major etiological elements can be distinguished: polygenetic predisposition, environmental factors, and the structural factor. The physical and biological principles behind the early "structural upward resetting" of heart and vessels in hypertension are outlined and experimentally illustrated. Further, the long-term hemodynamic effects of this per se "normal" structural adaptation are discussed, particularly concerning systemic precapillary resistance, but also concerning the heart, barostat mechanisms of reflex and renal nature, and the venous capacitance vessels. With this background in mind, the primary long-term goal of therapy must be to reverse these structural changes toward normal cardiovascular design and dimensions, whereas in the future preventive measures may be actualized. Thus, treatment should serve not only to reduce the increased load on heart and vessels but also, wherever possible, to reduce the influence of trophic, growth-promoting factors of local and remote nature, as exemplified by model studies in rats.

Biology of Blood Vessels in Hypertension

Increased peripheral vascular resistance is the hemodynamic characteristic of essential hypertension and is associated with structural and functional changes in resistance vessels. The major structural alterations constitute reduced vessel lumen diameter with thickening of the vascular wall. Only a 10% narrowing of the vessel lumen and a slight thickening of the vessel wall, which includes the medial and intimal layers, are sufficient to significantly increase peripheral resistance. At the cellular level, there is a significant increase in cell mass and collagen and elastin deposition with vascular smooth muscle hypertrophy and hyperplasia. Direct hemodynamic forces, as well as circulating and local growth regulators, stimulate cell growth in hypertensive vessels. Functional alterations that increase peripheral resistance include enhanced vascular reactivity to vasoconstrictor agents or impaired relaxation and reflect changes in excitation-contraction coupling and/or electrical properties of cells. Excess systemic or local production of vasoconstrictors or growth factors, abnormal agonist-receptor interactions, increased cell membrane permeability, defective transmembrane ion transport, intracellular calcium overload, exaggerated responses of the phosphoinositide signaling system, and altered endothelial function result in increased vascular smooth muscle growth and contractility. Whether these changes are a primary cause or secondary consequence of hypertension remains unclear but is a major focus of investigation. (Cardiol Rev 1993;1:2, 87-96)