Taben M. Hale

Recovery of Erectile Function after Brief Aggressive Antihypertensive Therapy

PURPOSE We have previously demonstrated that antihypertensive therapy could structurally modulate blood vessels in the penis, although the impact on erectile function was not established. Given the importance of inadequate penile arterial inflow as a cause of erectile dysfunction we determined in spontaneously hypertensive rats the impact of brief aggressive antihypertensive therapy on structurally based penile vascular resistance, erectile function and mean arterial pressure during and after treatment. MATERIALS AND METHODS Young (15-week-old) and aged (40-week-old) spontaneously hypertensive rats were treated for 2 weeks (enalapril 30 mg./kg. daily plus a low salt diet). Mean arterial pressure was continuously monitored via radio telemetry. Erectile responses were assessed by administering apomorphine (80 microg./kg. subcutaneously) before, during and after treatment. Structurally based vascular resistance was determined in the isolated, perfused penile vasculature 2 weeks after stopping treatment in aged spontaneously hypertensive rats. Certain responses were determined, including resistance at maximum dilatation (lumen size) and at maximum constriction (medial bulk), and EC50 of the alpha-adrenoceptor agonist methoxamine. RESULTS In the period after the cessation of drug treatment there was a persistent reduction in the level of arterial pressure (16%) and a doubling of erectile responses compared with pre- treatment. Cardiac and vascular structure regressed, as determined by the mean decrease plus or minus standard deviation in vascular resistance at maximum dilatation (21% +/- 4.5%) and mean reduction in left ventricle mass (10.4% +/- 3.7%). Furthermore, treatment induced a significant right shift in alpha1-adrenoceptor concentration response curve in treated versus control rats (mean EC50 1.09 +/- 0.111 versus 0.76 +/- 0.111). CONCLUSIONS The improvement in erectile function after brief aggressive treatment may be related to improvement in structurally based vascular resistance within the penis and the decrease in responsiveness of alpha1-adrenoceptor mediated erectolytic signaling. These findings are suggestive of a new therapeutic strategy for hypertension and erectile dysfunction.

ANTIHYPERTENSIVE DRUGS INDUCE STRUCTURAL REMODELING OF THE PENILE VASCULATURE

PURPOSE There is a strong association between hypertension and erectile dysfunction. Studies of the treatment of hypertension have shown that some pharmacological agents are capable of inducing regression of the vascular structure during treatment. We determined whether penile vascular structure is as susceptible as other vascular beds to regression during antihypertensive drug treatment. MATERIALS AND METHODS Adult spontaneously hypertensive rats were treated for 1 or 2 weeks with 30 mg./kg. enalapril daily, or for 2 weeks with 45 mg./kg. hydralazine daily. Structurally based vascular resistance was determined in isolated penile and skeletal muscle vascular beds perfused with Tyrode-dextran. A cumulative alpha1-adrenoceptor concentration constrictor response curve to 1 to 100 microg./ml. methoxamine was constructed and the maximum constrictor response (vasopressin, methoxamine and angiotensin II) indicating the tissue yield point (that is the average medial bulk of vascular smooth muscle) was determined. The hearts were excised and the ventricles were separated and weighed. RESULTS Enalapril treatment progressively regressed cardiac and vascular structure during the 1 and 2-week treatment periods with a mean tissue yield point plus or minus standard deviation of -5.91% +/- 5.1% (p <0.05) and -12.1% +/- 6.0% (p <0.05), and a mean left ventricle mass of -11.8% +/- 2.2% (p <0.05) and -13.6% +/- 3.2% (p <0.05), respectively. Hydralazine treatment for 2 weeks was less effective on vascular regression with a mean yield of -7.3% +/- 2.9% (p <0.05) and it did not alter left ventricle hypertrophy compared with controls (3.7% +/- 5.0%). CONCLUSIONS The data suggest that renin-angiotensin system inhibition may at least partially normalize penile vascular structure. The impact of these changes on erectile function must be determined.

The penis is not protected — in hypertension there are vascular changes in the penis which are similar to those in other vascular beds

In hypertension, small arteries in a variety of vascular beds undergo structural changes that increase resistance. To assess whether there are differential structural changes in the penis that accompany hypertension, we began with determining structurally-based vascular resistance properties in penile and hindlimb vascular beds of adult spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats.In anesthetized SHR, the penile and hindlimb vasculature were isolated and perfused, maximum dilation was induced, and a flow-pressure assessment and α1-adrenoceptor agonist concentration-response curves were generated.Both the baseline and maximum constrictor responses were similar in the two beds of each strain, and overall the maximum structurally-based vascular resistance in SHR was higher than in SD rats.Our data suggests that the penile vasculature is not protected from the structural changes that take place in the other vascular beds in hypertension. There does not appear to be an underlying functional control mechanism that protects the penile vasculature from structural changes that may have a negative impact on penile blood flow.

Persistent Lowering of Pressure by Transplanting Kidneys From Adult Spontaneously Hypertensive Rats Treated With Brief Antihypertensive Therapy

Kidney function is critical in determining the level of arterial pressure and in the pathogenesis of hypertension. Important evidence comes from studies in which the level of blood pressure is dictated by the donor when kidneys are transplanted between genetically hypertensive and normotensive rats. We have hypothesized that pharmacotherapy modifies specific properties of the kidney, particularly the vasculature, such that after kidney transplantation, there are persistent changes in the level of arterial pressure. Consistent with previous studies, a 2-week aggressive treatment of adult (15 weeks) spontaneously hypertensive rats with an angiotensin-converting enzyme inhibitor (enalapril) combined with a low-salt diet induced a persistent change in the kidney and a decrease in arterial pressure (18%). These persistent changes in arterial pressure could be completely transferred to untreated adult spontaneously hypertensive rats by kidney transplantation (ie, pressure in untreated rats was decreased after transplantation of a kidney donated from a previously treated rat). Further, the importance of kidney-specific changes was demonstrated by finding that the treatment-induced lowering of arterial pressure was completely reversed by transferring an untreated kidney into a previously treated rat. The specific treatment-induced changes to the kidney included a decrease in structurally based renal vascular resistance that was similar to the persistent lowering of arterial pressure. These data provide evidence for a link between the treatment-induced changes in kidney vascular structure and the persistent lowering of arterial pressure. The findings also suggest that a key pharmacotherapeutic target in hypertension should be kidney-specific changes, such as renal vascular structure.

Time Course of Vascular Structural Changes During and After Short-Term Antihypertensive Treatment

Abstract—The present study characterized the persistent changes (ie, off-treatment) resulting from short-term antihypertensive treatments on mean arterial pressure (MAP) and structurally based vascular resistance. Rats were treated for 14 days with enalapril (30 mg · kg−1 · d−1) with regular (ENAL, 0.4%) or low salt (ELS, 0.04%) diets, or a triple therapy (Triple: hydralazine 45 mg · kg−1 · d−1, hydrochlorothiazide 100 mg/L, and nifedipine 200 mg/d). MAP was continuously recorded via radiotelemetry. Structurally based hindlimb vascular resistance properties (resistance at maximum dilation [Max Dil]; resistance at maximum constriction [Max Con]) were assessed after 14-day enalapril treatment and 2 to 3 weeks after all drugs were withdrawn. Aortic urokinase plasminogen activator (uPA) activity was measured by zymography after 14 days of ELS. All treatments induced a significant, persistent decrease in the off-treatment MAP (ENAL ↓12±4.6%, ELS ↓16±2.6%, Triple ↓5±4.17%). During treatment (14 days) the enalapril group had significant changes in the index of medial bulk (Max Con ↓15±2.6%), but only minimal changes in lumen properties (Max Dil ↓3±6.5%, NS). After stopping therapy, vascular properties at Max Dil were significantly decreased only in the 2 enalapril groups (ENAL ↓15±7.9%, P <0.05; ELS ↓9±6.0%, P <0.05; Triple ↓2±9.8%, NS), whereas Max Con was significantly decreased in all groups (ENAL ↓12±8.0%, ELS ↓16±6.1%, Triple ↓7±5.4%). At 14 days of ELS treatment, there was increased aortic uPA activity (1.6-fold). The findings reveal that various short-term antihypertensive treatments can produce persistent long-term changes in MAP and vascular structure. Further, the magnitude of the depressor response may be as important in inducing persistent changes as is the removal of angiotensin II.

Impact of antihypertensive treatments on erectile responses in aging spontaneously hypertensive rats

Objective We previously demonstrated that brief, aggressive antihypertensive therapy recovered erectile function in 40-week-old spontaneously hypertensive rats (SHR). The present study examined the impact of antihypertensive and testosterone treatments on erectile function in aging SHR. Design and methods Centrally initiated erections were determined in response to apomorphine throughout. At 30 and 49 weeks, SHR were treated for 2 weeks with enalapril or hydralazine. A third more aggressive treatment (68 weeks) involved enalapril or losartan plus a low salt diet or a triple therapy (hydralazine, nifedipine, hydrochlorothiazide). In a separate study, cross-over kidney transplantations were performed between untreated and losartan-treated SHR. Arterial pressure was assessed post-transplantation using radio-telemetric transducers. Results There was an age-related decrease in erections between 30 and 68 weeks (3.1 ± 0.79 versus 0.2 ± 0.38) that was not improved by testosterone administration. Early treatment with enalapril or hydralazine did not prevent this decline, although the second treatment resulted in significant improvements (enalapril, 0.8 ± 0.70; hydralazine, 0.8 ± 0.41 versus control, 0.3 ± 0.60). A 2-week aggressive antihypertensive treatment at 68 weeks increased erections approximately two-fold, with the previously treated rats receiving triple therapy having markedly improved erectile responses (0.2 ± 0.53 versus 1.1 ± 1.67). In the transplantation study, previously losartan-treated SHR given an untreated kidney had higher arterial pressure but twice the number of erections in comparison with the SHR with lower arterial pressure resulting from transplanting a treated kidney. Conclusions Aggressive antihypertensive treatments may be more beneficial in improving erectile function in aged SHR, via an effect that appears to be tissue specific, and not based on changes in blood pressure.

Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response

Purpose: In spite of rapidly growing interest, few research tools have been developed to study female sexual dysfunction. Using the D1/D2 agonist, apomorphine (APO), our objective was to develop a new model of the sexual arousal response in female rats based on one previously established for the male condition. Methods: APO (80 μg/kg, s.c.) was given during proestrus (P), estrus (E), metestrus (M), early diestrus (DI) and late diestrus (DII), and in ovariectomized (OVX) female Wistar rats. APO-induced behavioral and genital responses were characterized (30 min) using video monitoring. Results: APO-induced reproducible, periodic morphological changes in the external genitalia. The onset, timing and duration of these female APO responses were consistent with genital vasocongestive arousal (GVA) responses in males (ie erections). APO-induced GVAs occurred throughout the estrous cycle, peaking in E (1.4±1.21 overall; 0.9±0.64 in DII; 1.8±1.66 in E) and were markedly diminished by ovariectomy (OVX, 0.4±0.51). Conclusion: APO induced a reproducible sexual arousal response in female rats involving obvious genital vasocongestive engorgement. Further, the findings demonstrate that the APO-induced genital arousal responses are hormonally regulated.

Changes critical to persistent lowering of arterial pressure in spontaneously hypertensive rat occur early in antihypertensive treatment

Objectives Angiotensin-converting enzyme inhibition (ACEI) in adult spontaneously hypertensive rats (SHRs) produces reductions in mean arterial pressure (MAP) and vascular structure that persist after treatment cessation. This study used an intermittent treatment strategy to determine the time course of changes in MAP, vascular resistance properties, and the tissue levels of endothelin. Methods Adult SHRs were treated with enalapril and low sodium diet for three 2-week treatment cycles, each separated by 2-week washout periods. MAP was measured via radiotelemetry. Hindlimb structurally based vascular resistance properties were assessed after two treatment cycles. Endothelin was measured in mesenteric vessels, renal cortex and medulla in untreated SHR (Con), and at day 10 of the first and third treatment cycles. Results Treatment produced a persistent reduction in MAP; however, the magnitude of change in the ‘off-treatment’ level decreased following successive treatments (cycle 1: −15 ± 1.7%, cycle 2: −8 ± 1.9%, and cycle 3: −1 ± 1.7%). Reduction in hindlimb vascular structure after two cycles of treatment was not different from that previously observed after one cycle. Endothelin levels were significantly elevated during the third cycle in renal medulla (Con: 797 ± 102 pg/g tissue, cycle 1: 767 ± 81 pg/g tissue, cycle 3: 1097 ± 205 pg/g tissue) and mesenteric vessels (Con: 711 ± 226 pg/g tissue, cycle 1: 696 ± 231 pg/g tissue, cycle 3: 1063 ± 741 pg/g tissue). Concomitant treatment with an endothelin antagonist did not impact arterial pressure. Conclusion These findings demonstrate that during ACEI treatment, most of the changes that confer persistent changes in MAP and vascular structure occur within the first 2 weeks. Elevation in endothelin levels is likely unrelated to arterial pressure.

A framework for the present and future development of experimental models of female sexual dysfunction

Female sexual dysfunction (FSD) is currently categorized according to disorders of (i) desire, (ii) arousal, (iii) orgasm and (iv) sexual pain. The advancement of research defining the physiological, pathophysiological and psychological mechanisms of these disorders, and to develop treatments for FSD, has been hampered by the paucity of experimental paradigms and animal models. It may be that animal models of FSD are best suited to address arousal disorders that include persistent or routine inability to attain or maintain genital lubrication or engorgement. Although still limited in scope, experimental models of FSD have involved a range of in vitro to in vivo methodologies. Specifically, the in vitro and in situ models include vaginal or clitoral smooth muscle preparations, histological evaluation and vaginal blood flow assessments. Previously, in vivo studies of sexual responses focussed on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method. Recently, a new model of female sexual arousal was developed using pharmacological CNS stimulation; responses that were found to be sensitive to cardiovascular status, aging and hormonal conditions. It is important that a wide variety of animal models continue to be developed to reflect the multifactorial basis of the condition.

NQO1 activation: a novel antihypertensive treatment strategy?

D espite numerous antihypertensive drug treatment options that are currently on the market, a recent analysis of the National Health and Nutrition Examination Survey revealed that of the participants currently undergoing antihypertensive treatment, only 53% had achieved blood pressures less than 140/90 mmHg [1]. Although there may be many reasons for poor control rates, there remains an opportunity, and perhaps a necessity for identifying novel strategies for the treatment of hypertension. Endothelial dysfunction is a common comorbidity of hypertension and it has been shown to significantly increase the risk of future cardiovascular events, including coronary artery disease [2]. As such, improving endothelial function has been proposed as an important goal of antihypertensive therapy. Whether improving endothelial function alone is sufficient to lower blood pressure long-term remains to be determined, but there is certainly evidence to support the benefits to reducing the risk of target organ damage [2]. Endothelial dysfunction can be characterized by impaired production of nitric oxide, a potent vasodilator that functions in healthy blood vessels to directly relax vascular smooth muscle cells and to oppose the actions of endothelial-derived contracting factors. However, under pathophysiological conditions, decreased nitric oxide bioavailability may result from a number of factors, including reductions in endothelial nitric oxide synthase (eNOS) levels or activity, as well as reductions in eNOS substrate (L-arginine) or cofactor (tetrahydrobiopterin: BH4) [3]. Under conditions in which a suitable substrate is present, but there is low BH4 availability, eNOS can become ‘uncoupled’, whereby superoxide is produced rather than