The modulation of ureteral smooth muscle contractile responses by α1- and α2-adrenoceptor activation.

PURPOSE: This study was performed to investigate the influence of α-adrenoceptor subtypes upon ureteral smooth muscle contractile responses. METHODS: Rat ureters were challenged in vitro with noradrenaline (NA), the α1-adrenoceptor agonist phenylephrine (PE), and the α2-adrenoceptor agonist clonidine (CLON). The influences of the agonists on the magnitude and frequency of acetylcholine (ACh)-stimulated phasic contractile responses were recorded. RESULTS: The magnitude of the phasic contractile responses effected by ACh was not significantly influenced by the adrenoceptor agonists, but the frequency of the response was significantly enhanced by all three agonists (p < 0.05). Idazoxan and prazosin abolished the rise in frequency effected by CLON and PE, respectively, whereas both antagonists in combination were required to abolish the increase in frequency effected by NA. CONCLUSIONS: It has been demonstrated that α1- and α2-adrenoceptors modulate the contractile function of rat ureteral smooth muscle by increasing the frequency, but not the magnitude, of phasic contractile responses. The enhancement of contractile function by NA is mediated by mechanisms dependent upon both α1- and α2-adrenoceptors.

Influence of arterial diameter on vasomotor responses in the porcine coronary vasculature.

OBJECTIVE: The aim was to determine whether regional differences in arterial responses to vasoconstrictor and vasorelaxant agonists exist within the minipig coronary vasculature. METHODS: Hearts were obtained from miniature pigs (20-40 kg) immediately after death. First and third order arterial branches of the left anterior descending artery were dissected from within the subepicardium and mounted as ring preparations in a small vessel myograph for measurement of isometric tension under standardised conditions. Contractile responses to acetylcholine, noradrenaline, and U46619, and the relaxation responses to noradrenaline, bradykinin, and substance P were measured. Arterial tone was increased with KCl or acetylcholine prior to addition of vasodilator agonists. RESULTS: First order branches were more sensitive to the constrictor influence of acetylcholine than third order branches [pD2 values 6.42(SEM 0.07), n = 13, and 6.26(0.07), n = 13, for first and third order respectively, p < 0.05]. U46619 did not induce contractile responses in arteries less than 210 microns in diameter. Noradrenaline only induced small contractile responses in the presence of propranolol following removal of the endothelium. In arteries preconstricted with 40 mM KCl, noradrenaline induced relaxation which was inhibited by propranolol and was uninfluenced by arterial calibre. In the presence of propranolol, noradrenaline-mediated relaxations of acetylcholine-preconstricted arteries were endothelium dependent and alpha 2 adrenoceptor mediated, and greater in first order than in third order branches [58(5)%, n = 9, and 26(8)%, n = 9, for first and third order branches respectively, p < 0.05]. Relaxations mediated by bradykinin and substance P were not influenced significantly by arterial calibre but were greater in arteries preconstricted with acetylcholine than with KCl. CONCLUSIONS: In isolated minipig coronary arteries the vasoconstrictor responses to acetylcholine and U46619, and the endothelium dependent, noradrenaline mediated relaxations, differ according to the branching order studied. These data provide further evidence for a regional heterogeneity of vascular responses in the porcine coronary vasculature.

Increased wall-lumen ratio of mesenteric vessels from the spontaneously hypertensive rat is not associated with increased contractility under isobaric conditions.

We investigated the morphological (wall-lumen ratio) and contractile characteristics of distal mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls at a distending pressure of 63% of the mean aortic pressure of each rat using a pressure arteriograph. The wall-lumen ratios obtained were compared with those obtained at a pressure of 100 mm Hg. Experiments were carried out at 5 and 20 weeks. Mean aortic pressure of SHR was significantly increased at 5 weeks compared with that of WKY and was further increased by 20 weeks. At 63% of mean aortic pressure, no difference in the wall-lumen ratio of the arteries was observed between strains at 5 weeks; at 20 weeks, the wall-lumen ratio of SHR arteries was significantly increased compared that in WKY arteries. The wall-lumen ratio of SHR vessels did not differ at 63% mean aortic pressure compared with 100 mm Hg at either 5 or 20 weeks, whereas this parameter was significantly reduced in WKY vessels at 100 mm Hg compared with 63% mean aortic pressure at 5 and 20 weeks. In the presence of spontaneous myogenic tone, there was a borderline reduction in the lumen diameter of SHR vessels compared with WKY vessels and with increasing norepinephrine concentrations at 5 weeks. At 20 weeks, lumen diameter between strains did not differ in the presence of myogenic tone nor with increasing norepinephrine concentrations. Similar results were obtained when vessels from both rat strains were pressurized to 80 mm Hg. Thus, the increased wall-lumen ratio in the distal mesenteric arteries from adult SHR compared with those from WKY is not associated with an increased contractility under isobaric conditions when studied at physiological distending pressure.

Arterial neuroeffector responses in early and mature spontaneously hypertensive rats.

Intramural sympathetic neuroeffector responses and presynaptic regulation of neurotransmission by amine uptake and alpha 2-adrenergic receptors were examined in young (5-week-old) and mature (12-week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar-Kyoto (WKY) control rats. Electrical field stimulation (20 V, 0.2-msec pulse width, 3-second pulse train each minute, 5-100 Hz) elicited contractile responses from isolated mesenteric arteries mounted in a myograph. There was a significant difference between the sensitivity of arteries to electrical field stimulation in the two age groups, with arteries from 12-week-old rats being more sensitive than arteries from 5-week-old animals. Also, there was a significant age-strain interaction: the sensitivity of arteries from SHR to electrical field stimulation increased dramatically with age compared with that of WKY rat arteries. Cocaine significantly increased the sensitivity to electrical field stimulation after inhibition of presynaptic alpha 2-adrenergic receptors, and had a significantly greater effect in arteries from 5-week-old SHR compared with WKY controls. This would reflect an overactive neuronal amine uptake mechanism in young SHR. At 12 weeks there was no significant interstrain difference in the effect of cocaine. Yohimbine increased the sensitivity to electrical field stimulation both before and after inhibition of neuronal amine uptake, but there was no difference in its effect with age or strain. Therefore, although sensitivity to sympathetic nerve stimulation varies with age in the SHR, there is no evidence that this can be ascribed to alpha 2-adrenergic receptor function.

In vitro perfusion studies of resistance artery function in genetic hypertension.

To examine the function of resistance-sized arteries in hypertension under in vitro conditions that approximate in vivo conditions as much as possible, we mounted segments of second-order mesenteric resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats aged 12 to 13 weeks in a perfusion myograph and exposed them to conditions of constant flow and pressure. The endothelial integrity was validated both functionally and histologically. Vascular sensitivity to norepinephrine was examined when the hormone was applied either intraluminally or extraluminally and before and after removal of the endothelium. Both endothelium-dependent and -independent dilatation was assessed by the intraluminal application of acetylcholine and sodium nitroprusside, respectively. Sodium nitroprusside was applied to arteries after endothelium removal. Arterial responses were measured by changes in intraluminal diameter recorded with a video camera and imaging system. Vessels from SHR demonstrated depressed endothelium-dependent relaxation but similar endothelium-independent relaxation and greater sensitivity to norepinephrine with both intraluminal and extraluminal application. Removal of the endothelium abolished the differences in sensitivity to norepinephrine between the two strains. The results demonstrate that resistance arteries from SHR when examined under in vitro perfusion display enhanced sensitivity to norepinephrine due to depressed endothelium-dependent dilatation, and the data suggest that functional modifications in the endothelium may play an important role in hypertensive vascular disease.

Contractility of resistance arteries of spontaneously hypertensive rats related to their media: lumen ratio.

OBJECTIVE: The purpose of the study was to test the hypothesis that the increased media thickness: lumen diameter (M:L) ratio of spontaneously hypertensive rat (SHR) resistance arteries effects enhanced arterial contractile responses compared with those of Wistar-Kyoto (WKY) rat normotensive controls under pressurized conditions in vitro. DESIGN: Contractile responses to the vasoconstrictor agonists noradrenaline and the thromboxane A2 analogue U46619 were assessed in femoral and mesenteric resistance arteries (internal diameters approximately 150 microm) after the development of spontaneous myogenic tone at 100 mmHg and at estimated in vivo pressures. METHODS: Arterial contractile responses and structure were assessed in an arteriograph. Relaxed arterial structure was determined by light microscopy. Mean arterial pressure was determined subsequent to femoral artery cannulation. RESULTS: Under relaxed conditions M:L ratios were significantly greater in SHR arteries at 100 mmHg (P < 0.01) and at in vivo pressures (P<0.01). Myogenic responses were not significantly different between SHR and WKY. Under both pressure conditions the contractile responses of SHR femoral arteries were not significantly different to those of WKY in response to either agonist SHR mesenteric arteries achieved smaller diameters in response to noradrenaline (P<0.05) and U46619 (P<0.05) at 100 mmHg. At in vivo pressures, concentration-response relationships of SHR mesenteric arteries for both agonists were not significantly different compared with those of WKY; however, the maximum percentage reduction of lumen diameter in SHR mesenteric arteries in the presence of noradrenaline was greater than in WKY (P<0.05). CONCLUSION: The increased M:L ratio of SHR femoral resistance arteries does not impart an exaggerated contractile function in myogenically active resistance arteries in vitro. For mesenteric arteries the relationship is less clear because increased M:L ratio is associated with increased contractile responses under some, but not all, circumstances.

Effect of one-kidney, one clip hypertension on the structure and function of porcine intramyocardial small arteries.

OBJECTIVE: To determine the influence of experimental hypertension on the structure and function of porcine coronary small arteries. METHODS: Miniature pigs underwent partial left renal artery constriction and contralateral nephrectomy. Blood pressures were recorded, using indwelling carotid artery catheters. After 4 weeks the pigs were killed, the heart was removed and subepicardial third-order branches of the left anterior descending artery were dissected and mounted in a myograph for morphological and functional assessment. RESULTS: Final mean +/- SEM systolic and diastolic blood pressures were, respectively, 197 +/- 9 and 142 +/- 7 mmHg (n = 21) for the hypertensive pigs and 125 +/- 4 and 80 +/- 4 mmHg (n = 11) for the sham-operated control pigs. Hypertension was associated with significant left ventricular hypertrophy. The media thickness: lumen diameter ratio was increased significantly in hypertensive intramyocardial small arteries, caused mainly by remodelling (remodelling index 92%) rather than by medial growth. Maximal contractile responses to potassium and acetycholine were significantly depressed in the arteries from hypertensive pigs, whereas endothelium-dependent relaxation responses to bradykinin, substance P and serotonin were not significantly influenced by hypertension. CONCLUSIONS: These results demonstrate that even short-term hypertension induces both structural and functional changes in left ventricular intramyocardial small arteries.

The contractile effects of porcine tetradecapeptide renin substrate in human resistance vessels: evidence of activation by vascular wall renin and serine proteases.

In order to test the hypothesis that the contraction induced in human resistance arterioles by porcine tetradecapeptide renin substrate (TDP) is mediated by enzymes specific to the renin-angiotensin cascade, human resistance vessels from skin and subcutaneous fat were mounted in a myograph and exposed to TDP in the presence and absence of the human renin inhibitor H261, the serine protease inhibitor aprotinin, a polyclonal anti-human renin antibody and captopril. TDP induced a dose-dependent contraction that could be abolished by saralasin. The sensitivity to TDP was significantly attenuated by H261, aprotinin and combinations of captopril with aprotinin and captopril plus aprotinin and H261, as indicated by a significant reduction in pD2 (-log10ED50 [mmol/l]) for TDP. However, captopril alone was ineffective. It was concluded that at physiological pH, porcine TDP induces contraction in human resistance vessels by the action of enzymes not specific to the renin-angiotensin cascade. Whilst a clear inhibitory effect of H261 was demonstrated, a significant comparable inhibition by captopril and a polyclonal renin antibody was not observed. This may reflect the difficulty with which these inhibitors gain access to their intracellularly located substrates.

Motility of the ureter of the spontaneously hypertensive rat.

BACKGROUND: The spontaneously hypertensive rat (SHR) is a commonly used animal model of hypertension and transplantation studies provide evidence for a renal element to the aetiology of the hypertensive process. AIMS: This study was designed to test the hypothesis that the contractile function of the ureter of the SHR differs to that of the normotensive control Wistar-Kyoto (WKY) rat. METHODS: Ureter segments from SHR (n = 16) and WKY (n = 16) were cannulated and pressurised in vitro. Acetylcholine (ACh) was used to stimulate phasic contractile pressure responses. RESULTS: SHR ureter contractile frequencies were significantly greater than those of WKY (6.6 ± 0.8 vs. 3.8 ± 0.2 min(-1) in 10(-5) M ACh; p < 0.01). Magnitudes of contractile responses were not significantly different (SHR 14.3 ± 1.5 mmHg, WKY 15.2 ± 2.1 mmHg). CONCLUSIONS: SHR ureteral contractile function differs significantly to that of normotensive WKY. Ureteral dysfunction may be a contributory causative factor in the aetiology of the hypertensive disease process.

The assessment of rat ureteral pressure generation in vitro: regional heterogeneity and influence of distending pressure.

Contraction of ureteral smooth muscle drives the urine bolus to the urinary bladder for storage prior to micturition. This study describes a novel approach to the measurement of ureteral pressure generation in vitro and the influence of distending pressure on acetylcholine-stimulated ureteral lumenal pressure generation. Isolated segments of ureters obtained from Wistar rats were pressurised in a blind-ended sac arrangement and contractile responses were recorded as phasic oscillations in ureteral luminal pressure. Distal segments generated greater luminal pressures than proximal segments (p<0.001) in response to acetylcholine. Increasing baseline distending pressures in the range 2-10 mmHg in proximal segments was associated with greater frequency of contraction (p<0.001) and decreased magnitude of contraction (p<0.001) when expressed as % maximum response. Nifedipine (10(-5) M) or removal of extracellular Ca(2+) abolished the contractions. Isometric contractile responses of ureteral ring preparations were not significantly influenced by pretensions equivalent to distending pressures in the range 2-10 mmHg. This is the first study to fully establish the influence of baseline ureteral distending pressure upon ureteral luminal pressure generation in vitro and demonstrates regional heterogeneity of ureteral contractile responses. It is suggested that this experimental approach may be a useful methodology for the investigation of ureteral function during urinary outflow obstruction.

Characteristics of the myogenic behaviour of arteries of the common European frog (Rana temporaria).

Mammalian small arteries exhibit pressure-dependent myogenic behaviour characterised by an active constriction in response to an increased transmural pressure or an active dilatation in response to a decreased transmural pressure. This study aimed to determine whether pressure-dependent myogenic responses are a functional feature of amphibian arteries. Mesenteric and skeletal muscle arteries from the common European frog (Rana temporaria) were cannulated at either end with two fine glass micropipettes in the chamber of an arteriograph. Arterial pressure-diameter relationships (5-40 mmHg) were determined in the presence and absence of Ca2+. All arteries dilated passively with increasing pressure in the absence of Ca2+. In the presence of Ca2+ proximal mesenteric branches and tibial artery branches dilated with increasing transmural pressure but tone (p < 0.05) was evident in both arteries. A clear myogenic response to a step increase or decrease in pressure was observed in small distal arteries (6 of 13 mesenteric and 7 of 10 sciatic branches) resulting in significantly (p < 0.05) narrower diameters in Ca2+ in the range 10-40 mmHg in mesenteric and 20-40 mmHg in sciatic arteries, respectively. The results demonstrate that arteries of an amphibian can generate spontaneous pressure-dependent tone. This is the first study to demonstrate myogenic contractile behaviour in arteries of nonmammalian origin.

Mechanical properties of small femoral arteries in spontaneously hypertensive rats.

The purpose of the study was to compare the mechanical properties of small femoral arteries from spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto rats (WKY) to determine whether these could contribute to the narrowed lumens and thicker medial layers observed during the development of hypertension. Rats were used at either 5, 12, or 24 weeks of age. Third order branches of the right femoral artery were mounted in a myograph for morphological measurement and determination of wall mechanical properties. At 5 weeks SHR and WKY arteries were structurally similar but progressive medial thickening and hypertrophy in conjunction with lumenal narrowing was observed in SHR compared with those from WKY in the older rats. However, stress-strain and incremental elastic modulus-stress relationships were similar between strains at all three ages. These data indicate that modifications of arterial wall mechanical properties do not contribute to these progressive arterial structural modifications.

Influence of mode of contraction on the mechanism of acetylcholine-mediated relaxation of coronary arteries from normotensive and spontaneously hypertensive rats.

1. Endothelium-dependent acetylcholine-mediated relaxations of small coronary arteries (approximately 200 microns internal diameter) from 20 weeks old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls were compared under pressurized no-flow conditions after the development of myogenic tone or constriction with the thromboxane A2 mimetic U46619. 2. Relaxations of WKY and SHR arteries following development of myogenic tone did not differ and were not significantly influenced by indomethacin alone (10 mumol/l) or in combination with N omega-nitro-L-arginine (L-NNA, 0.1 mmol/l). Maximum relaxations were significantly attenuated by 30 mmol/l K+ in the SHR, from 85 +/- 7% (n = 11) to 20 +/- 8% (n = 8), P < 0.001, and in the WKY from 86 +/- 5% (n = 9) to 39 +/- 14% (n = 8), P < 0.01. 3. Relaxations following constriction with U46619 were also similar in both rat strains. Maximum relaxations were 50 +/- 11% (n = 8) in SHR and 60 +/- 7% (n = 6) in WKY. Indomethacin did not influence these relaxations. The combination of indomethacin and L-NNA attenuated relaxations in WKY (P < 0.01), but in the SHR the attenuation did not achieve statistical significance (P = 0.07) compared with controls; the maximum responses were reduced to 25 +/- 7% (n = 8) and 14 +/- 11% (n = 6) in the SHR and WKY respectively, but only in the WKY was this reduction significant (P < 0.05). 4. These data demonstrate that, under control conditions, SHR and WKY coronary arteries relax equally effectively, regardless of mode of contraction, and also that the mechanism of acetylcholine-mediated relaxation differs according to the mode of contraction. Acetylcholine relaxes myogenic tone by a K(+)-sensitive mechanism in both WKY and SHR, consistent with a role for endothelium-derived hyperpolarizing factor; NO contributes substantially to the relaxation of U46619-induced tone by acetylcholine in the WKY, but to a diminished extent in the SHR. 5. These data indicate that the choice of vasoconstrictor agent is of critical concern when assessing mechanisms of endothelium-dependent relaxation and abnormalities thereof in hypertension.

Spontaneously hypertensive rat resistance artery structure related to myogenic and mechanical properties.

This investigation related arterial structure to myogenic (pressure-dependent) contractile responses in resistance arteries from spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) normotensive control rats under pressurized conditions in vitro. Femoral and mesenteric resistance arteries from either strain were cannulated and pressurized in an arteriograph for the determination of pressure-diameter relationships under passive and active conditions in the range 5-200 mmHg transmural pressure. Arterial geometrical measurements were made under relaxed conditions at 100 mmHg. Media thickness/lumen diameter (M/L) ratios were significantly increased in SHR femoral (5.00+/-0.44% compared with 3.63+/-0.34%; P<0.05) and mesenteric (4.40+/-0.29% compared with 2.62+/-0.23%; P<0.001) arteries compared with those from WKY rats. Maximum myogenic contractions, assessed as minimum normalized diameters, were not significantly different in SHR and WKY rat femoral (0.41+/-0.03 and 0.40+/-0.02 respectively) or mesenteric (0.56+/-0.02 and 0.63+/-0.03 respectively) arteries. Arterial mechanical analyses demonstrated that incremental elastic modulus is reduced in SHR mesenteric arteries, but is not significantly different in SHR femoral arteries, compared with those from WKY rats. Additionally, wall stress at estimated in vivo pressures under passive and active conditions are similar in SHR and WKY rat arteries. These data demonstrate that increased M/L ratios in resistance arteries from SHRs are not associated with increased maximum pressure-dependent contractile responses. Increased M/L ratios in resistance arteries from SHRs are not accounted for by increased vessel wall stiffness, but the hypertension-associated arterial geometrical abnormalities act to normalize wall stress in the face of increased arterial pressure.

Nitric oxide modulation of coronary artery myogenic tone in spontaneously hypertensive and Wistar-Kyoto rats.

1. The endothelium contributes substantially to the modulation of myogenic tone in coronary arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). This study has addressed the contributions of endothelium-derived nitric oxide and cyclo-oxygenase products to this modulation in small coronary arteries (approximately 200 microns internal diameter) from 20-week-old SHR and WKY under pressurized, no-flow conditions in an arteriograph. 2. Active pressure-diameter relationships were uninfluenced by the cyclo-oxygenase inhibitor indomethacin (10 mumol/l) in either rat strain. In the presence of indomethacin and the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA, 0.1 mmol/l), coronary arteries from SHR and WKY generated significantly greater myogenic tone. This increase in tone was similar in both strains. 3. In endothelium-denuded arteries, indomethacin and L-NNA did not influence tone. 4. Therefore, these results demonstrate that endothelium-derived nitric oxide is basally released to attenuate SHR and WKY coronary artery myogenic tone, whereas endothelium-derived cyclo-oxygenase products have no net vasoactive influence. Additionally, these data suggest that basal nitric oxide-mediated relaxation is normal in SHR coronary arteries and is therefore unlikely to be a pathogenic mechanism in this animal model of hypertension.

Long-term structural changes in human hypertensive vessels.

Indirect assessments of the haemodynamics of the circulation in human essential hypertension demonstrate that when the disease is established there is an increase in peripheral vascular resistance and a normal cardiac output. The resistance to blood flow is maintained by an adaptive alteration in the geometry of precapillary vessels which is brought about as a result of the pressure excess; the change is manifested as an increased wall-to-lumen ratio. How this is achieved is the subject of intense research at this time, but in addition, there is some controversy as to the exact nature of the cellular alterations to the vascular architecture at the level of the resistance artery. The purpose of this work is to address problems that have arisen in trying to solve this question, and to identify therapeutic implications for future management of hypertension, and for reducing the number of cardiac events.

Effects of protection from pressure on resistance artery morphology and reactivity in spontaneously hypertensive and Wistar-Kyoto rats.

The effects of regional hypotension on femoral resistance artery reactivity and morphology were investigated in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats. A partially constricting ligature (0.4 mm i.d.) was placed around the left external iliac artery at 5 weeks, which resulted in significantly reduced femoral mean arterial pressures distal to the ligature at 12 and 24 weeks. The femoral mean arterial pressure distal to the ligature in SHR was similar to that in WKY unprotected hind limbs. Resistance arteries (approximately 200 microns i.d.) were taken from unligatured and protected hind limbs and mounted in a myograph for reactivity and morphological measurements. Each experiment therefore utilized one artery distal to a ligature and one from the control hind limb. Histological examination revealed that nuclear density differed neither between strains nor between arteries from protected and unprotected femoral beds. Media thickness, media cross-sectional area, and media/lumen ratios were reduced in arteries from the hypotensive hind limb in SHR and WKY rats at 12 and 24 weeks. Arteries from the protected hind limbs of SHR were structurally indistinguishable from those from the normally perfused WKY vasculature. It is concluded that the medial content and maximal contractile responses of femoral resistance arteries from SHR and WKY rats are mainly determined by the local perfusion pressure and that normalization of perfusion pressure in SHR normalizes resistance artery structure.

Effects of drug treatment on human resistance arteriole morphology in essential hypertension: direct evidence for structural remodelling of resistance vessels.

To examine whether effective drug treatment would reverse the morphological changes in resistance arterioles which characterise untreated essential hypertension, the vessels' media thickness and contractility were measured before and after long-term treatment. Nine patients underwent skin biopsy before and after a mean 13 months of antihypertensive treatment (range 4-24 months). Subcutaneous resistance arterioles were dissected and mounted in a myograph. Treatment did not affect the shift in sensitivity to noradrenaline in the presence of cocaine, sensitivity to exogenously administered calcium, and the rate of relaxation after withdrawal of vasoconstrictor stimuli. The media/lumen ratio fell significantly (p = 0.011) owing to a significant regression in media thickness (p = 0.0195), but this was not complete. Thus, effective antihypertensive treatment can reverse some of the structural change observed in the untreated state, although it apparently does not affect calcium sensitivity or relaxation rate; these features are thought to be consequences of the disease after it has become established.