Hypertension is a major public health concern globally and a risk factor for cardiovascular diseases (CVD). 1 The number of hypertensive adults increased from 594 million in 1975 to 1.13 billion in 2015, mainly in low-income and middle-income countries. 2 Moreover, in Brazil, approximately one quarter of the adult population are reported to have hypertension. 3 Globally, CVD was responsible for approximately 17.5 million deaths in 2012. If current trends continue, the annual number of deaths will increase to 22.2 million by 2030. 4 Frequently, hypertension is associated with metabolic disorders, functional or structural alterations of target organs, which are aggravated by behavioural risk factors, such as smoking, obesity, excessive salt intake and aging. The most common form of hypertension is "essential hypertension"; however, the causes remain unknown. 5,6 The treatment of hypertension includes some classes of drugs, including: beta-blockers, diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel
Erectile dysfunction (ED) is one of the most common and underestimated complications of diabetes. Previous studies have shown that TRPM8 activation triggers relaxation of internal pudendal arteries (IPA) with increased sensitivity in hypertensive rats. Despite the correlation between ED and diabetes, research on the role of TRPM8 channels in the IPA and corpus cavernosum (CC) in diabetes still needs to be elucidated. We hypothesized that preserved TRPM8 channel function in diabetic mice could be a therapeutic target for the treatment of ED. Male lean and db/db mice were euthanized, and the IPA were mounted on DMT wire myographs and CC were mounted on AVS organ bath for the measurement of isometric force. Concentration-response curves to icilin or menthol (TRPM8 agonists) were obtained. The CC TRPM8 channels expression was evaluated by western blot. Second harmonic generation was used to evaluate collagen deposition in IPA. Data are expressed as mean ± S.E.M of 3-5 mice. Non-linear regression curve was performed, and the maximum response (Emax) was analyzed using Student’s t test (p<0.05). Similar TRPM8 channel expression was observed in the CC from lean and db/db mice. Menthol-induced relaxation of the CC was reduced in diabetic mice (Emax: 105.00 ± 5.00%) compared to lean mice (Emax: 139.44 ± 15.91%) . Relaxant effect induced by icilin and menthol was similar between IPA from db/db (Emax icilin: 95.56 ± 0.86% and Emax menthol: 93.88 ± 2.33%) and lean (Emax icilin: 97.05 ± 0.87% and Emax menthol: 101.10 ± 1.75%) mice. Interestingly, pre-incubation with icilin (10-4M) for 30 minutes decreased the potency of phenylephrine-induced contraction compared to untreated IPA rings in both db/db and lean mice. In the IPA, diabetes decreased the sensitivity to acetylcholine compared to lean. However, the relaxation induced by acetylcholine was not changed by pre-incubation with icilin. Diabetic mice (db/db) IPA tended to have a decrease in arterial collagen content compared to lean mice. Although menthol-induced relaxation of the CC was reduced in diabetic mice, icilin and menthol were able to promote similar relaxation in IPA from diabetic and lean mice. In this way, TRPM8 function was preserved in IPA from diabetic mice. Icilin reduced sensitivity to phenylephrine in IPA from both mice. These data suggest that activation of TRPM8 could be a therapeutic target for the treatment of ED. SMSNA, NIH (RO1DK132948) and FAPESB This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Introduction: Decreased bioavailability of nitric oxide (NO) plays a mechanistic role in hypertension and myocardial infarction. NO donors are potent vasodilators, but often exhibit toxicity or vascular tolerance. The aim of this study was to investigate the vascular activity possible tachyphylaxis of NONO2P, a novel NO donor. Methods: Male Wistar rats were euthanized, and the superior mesenteric artery was isolated for recordings of isometric force, and in vivo experiments were performed to evaluate blood pressure in non-anesthetized normotensive rats. Results: Cumulative administration of the NONO2P (10 -13 to 3x10 -6 M) induced endothelium-independent relaxation (Emax:111.51 ± 2.31%; pD2: 8.51 ± 0.08, n=9) in arterial rings pre-contracted with phenylephrine (Phe,1μM). However, the relaxation was reduced in pre-contracted rings with Phe exposed to Tyrode's solution containing 20 mM of K + (E max : 102.83 ± 2.10%; pD2: 7.73 ± 0.04, n=6), suggesting the participation of K + channels in the relaxation. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor, ODQ (10μM), abolished the vasorelaxant effect (E max : 15.38 ± 11.85%, n=7). Pre-incubation with cyclopiazonic acid (CPA) (10μM), inhibitor of sarcoendoplasmic reticulum calcium ATPase (SERCA), shifted the relaxation concentration-response to the right (E max : 106.17 ± 3.06%; pD2: 7.69 ± 0.04, n=6). Interestingly, repeated NONO2P administration did not induce tachyphylaxis, and NONO2P presented similar maximum efficacy to sodium nitroprusside (SNP) (E max : 114.24 ± 3.47%; pD2: 9.40 ± 0.04, n=6). Moreover, NONO2P lowered blood pressure in normotensive rats. Conclusion: The endothelium-independent vasorelaxant effect induced by NONO2P involves both sGC, SERCA and K + channel activation, and NONO2P does not appear to cause tachyphylaxis. NONO2P is able to promote vasorelaxation with the same magnitude as SNP. Finally, NONO2P reduces blood pressure, becoming a promising molecule as a novel therapeutic alternative for the treatment of cardiovascular diseases.
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